NEBIVOLOL SYNTHESIS METHOD AND INTERMEDIATE COMPOUND THEREOF

Abstract

The present invention relates to a nebivolol synthesis method and intermediate compound thereof. Specifically, the present invention relates to a method for synthesizing nebivolol, intermediate compound thereof, and a method for preparing the intermediate compound.

Claims

1. A process for preparation of (A) the compound of formula VII (S*/R*), ##STR00139## wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S), ##STR00140## the process comprising the following steps: 1) epoxidation of the compound of formula IV1 in trans-configuration in the presence of epoxidating reagent to give epoxide intermediate V, ##STR00141## wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but R shown in the follow formulae is represented by benzyl (Bn) as an example, ##STR00142## wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*) ##STR00143## and 2) deprotecting the compound of formula V (2R*,3R*), followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*), wherein R is defined as above, but R shown in the follow formulae is represented by benzyl (Bn) as an example, ##STR00144## wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S) ##STR00145## or (B) the compound of formula VIII (R*/R*), ##STR00146## wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S), ##STR00147## the process comprising the following steps: 1) epoxidation of the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediate VI, ##STR00148## wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but R shown in the follow formulae is represented by benzyl (Bn) as an example, ##STR00149## wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*) ##STR00150## and 2) deprotecting the compound of formula VI (2R*,3S*), followed by cyclization reaction, to give the intermediate compounds of formula VIII (R*/R*), wherein R is defined as above, but R shown in the follow formulae is represented by benzyl (Bn) as an example, ##STR00151## wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S), ##STR00152##

2. The process according to claim 1 for preparation of the compound of formula VIII (R*/R*).

3. (canceled)

4. (canceled)

5. (canceled)

6. A process for preparation of formula III; ##STR00153## wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, allyl, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, the process comprising the following steps: ##STR00154## step a): reacting the compound of formula XIV, wherein R is hydroxy-protecting group as described above and X is halogen, with 3-(tri-substituted silyl)-prop-2-yne-1-lithium to give the compound of formula XV, wherein each of R.sub.1, R.sub.2 and R.sub.3 is independently selected from alkyl or aryl, such as methyl, tert-butyl or phenyl; step b): removing the silyl protective group at the terminal of alkynyl in the compound of formula XV to give the compound of formula XVI, wherein R is defined as above; step c): reacting the compound of formula XVI with paraformaldehyde in the presence of base or organometallic reagent to give the compound of formula III, wherein R is defined as above; and optionally step d): to the compound of formula III obtained by step c), adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula III as solid.

7-14. (canceled)

15. A process for preparation of (A) racemic Nebivolol of formula I, ##STR00155## wherein I (S*R*R*R*) represents racemate, which is a racemic mixture consisting of equimolar amounts of D-Nebivolol Ia (SRRR) and the enantiomer thereof L-Nebivolol Ib (RSSS) having the following configurations; ##STR00156## the process comprising the following steps: 1) reducing the compound of formula III with metal composite hydride to give the compound of formula IV1 in trans-configuration, and optionally the following step: to the resulting compound of formula IV1, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV1 as solid, ##STR00157## wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, 2) reducing the compound of formula III via selective catalytic hydrogenation to give the compound of formula IV2 in cis-configuration, and optionally the following step: to the resulting compound of formula IV2, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV2 as solid, ##STR00158## wherein R is defined as above 1), 3) epoxidation of the compound of formula IV1 in trans-configuration and the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediates V and VI, respectively, wherein R is defined as above, ##STR00159## wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*) ##STR00160## wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*) ##STR00161## 4) deprotecting the compound of formula V and the compound of formula VI, followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*) and formula VIII (R*/R*), respectively, wherein R is defined as above, ##STR00162## wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S), ##STR00163## wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S), ##STR00164## 5) sulfonylating the compounds of formula VII and formula VIII with sulfonyl halide of formula M-SO.sub.2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the compounds IX (S*/R*) and X (R*/R*), respectively, ##STR00165## wherein IX (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula IXa (S/R) and the enantiomer IXb (R/S), ##STR00166## ##STR00167## wherein X (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Xa (R/R) and the enantiomer Xb (S/S), ##STR00168## 6) reacting the compound of formula IX or X with benzyl amine to perform alkylation of amine, to give the corresponding compound XI or XII; ##STR00169## wherein XI (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIa (S/R) and the enantiomer XIb (R/S), ##STR00170## wherein XII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIa (R/R) and the enantiomer XIIb (S/S) ##STR00171## 7) cross-coupling reaction of the intermediate compounds IX (S*/R*) and XII (R*/R*) or the intermediate compounds X (R*/R*) and XI (S*/R*) under basic condition, to give the compounds XIII (S*R*R*R*) and XIII′ (S*R*S*S*), wherein the definition of R″ is the same as the above definition of M, ##STR00172## wherein XIII (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS), ##STR00173## XIII′ (S*R*S*S*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIII′a (SRSS) and the enantiomer XIII′b (RSRR), ##STR00174## 8) Forming salt of a mixture of the compounds of formula XIII and formula XIII′, and purifying by recrystallization to remove the isomer XIII′ (S*R*S*S*), to give the intermediate compound XIII (S*R*R*R*), and 9) deprotecting the intermediate compound XIII (S*R*R*R*) to yield racemic Nebivolol of formula I ##STR00175## wherein I (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS); or (B) D-Nebivolol (formula Ia), ##STR00176## the process comprising the following steps: 3′) asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to give intermediate compounds Va and VIa, respectively, wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl; ##STR00177## 4′) deprotecting the intermediate compounds Va and VIa, followed by cyclization, to give the intermediate compounds VIIa and VIIIa, respectively, wherein R is defined as above, ##STR00178## 5′) sulfonating the intermediate compounds VIIa and VIIIa with sulfonyl halide of formula M-SO.sub.2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the intermediate compounds IXa and Xa, respectively, ##STR00179## 6′) reacting the intermediate compound IXa or the intermediate compound Xa with benzyl amine to perform alkylation of amine, to give the corresponding compound XIa or XIIa: ##STR00180## 7′) cross-coupling reaction of the intermediate compounds IXa and XIIa or the intermediate compounds Xa and XIa under basic condition, to give the intermediate compound XIIIa, wherein the definition of Ar′ is the same as the above definition of M, ##STR00181## and optionally converting the intermediate compound XIIIa to the hydrochloride thereof, and 8′ deprotecting the intermediate compound XIIIa to give D-Nebivolol (formula Ia) ##STR00182## or converting the hydrochloride of the intermediate compound XIIIa to the intermediate compound XIIIa in free form by neutralization with base, followed by deprotection to give D-Nebivolol (formula Ia); or (C) L-Nebivolol (formula Ib), ##STR00183## the process comprising the following steps: 3″) asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to give intermediate compounds Vb and VIb, respectively, wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, ##STR00184## 4″) deprotecting the intermediate compounds Vb and VIb, followed by cyclization, to give the intermediate compounds VIIb and VIIIb, respectively, wherein R is defined as above, ##STR00185## 5″) sulfonating the intermediate compounds VIIb and VIIIb with sulfonyl halide of formula M-SO.sub.2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the intermediate compounds IXb and Xb, respectively, ##STR00186## 6″) reacting the intermediate compound IXb or the intermediate compound Xb with benzyl amine to perform alkylation of amine, to give the intermediate compound XIb or XIIb ##STR00187## 7″) cross-coupling reaction of the intermediate compounds IXb and XIIb or the intermediate compounds Xb and XIb under basic condition, to give the intermediate compound XIIIb, wherein the definition of Ar′ is the same as the above definition of M, ##STR00188## and optionally converting the intermediate compound XIIIb to the hydrochloride thereof, and 8″) deprotecting the intermediate compound XIIIb to give L-Nebivolol (formula Ib) ##STR00189## or converting the hydrochloride of the intermediate compound XIIIb to the intermediate compound XIIIb in free form by neutralization with base, followed by deprotection to give L-Nebivolol (formula Ib).

16-41. (canceled)

42. A compound of formula III ##STR00190## wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, allyl, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl; or a compound of formula IV1′ ##STR00191## wherein R.sup.a is hydrogen or R.sup.a is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl; or compound of formula IV2′ ##STR00192## wherein R.sup.b is hydrogen or R.sup.b is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl; or a compound of formula V′ (2R*,3R*) ##STR00193## wherein R.sup.c is hydrogen or R.sup.c is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, wherein the compound V′ is racemate, the relative configuration of which is represented by V′ (2R*,3R*), which is a racemic mixture consisting of equimolar amounts of Va′(2R,3R) and the enantiomer Vb′(2S,3S), such as the compounds having the following formulae wherein R.sup.c is benzyl; ##STR00194## or a compound of formula VI′ (2R*,3S*) ##STR00195## wherein R.sup.d is hydrogen or R.sup.d is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, wherein the compound VI′ is racemate, the relative configuration of which is represented by VI′ (2R*,3S*), which is a racemic mixture consisting of equimolar amounts of VIa′(2R,3S) and the enantiomer VIb′ (2S,3R), such as the compounds having the following formulae wherein R.sup.d is benzyl; ##STR00196## or a compound of formula XI′ ##STR00197## wherein R′ is substituted or unsubstituted aralkyl, C.sub.1-6 alkoxycarbonyl or C.sub.5-10 aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl; or a compound of formula XII′ ##STR00198## wherein R′ is substituted or unsubstituted aralkyl, C.sub.1-6 alkoxycarbonyl or C.sub.5-10 aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl; or a compound of formula XVI′ ##STR00199## wherein R.sup.e is hydrogen or R.sup.e is hydroxy-protecting group, said hydroxy-protecting group being selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl in which the phenyl ring has substituent(s), or silyl protective group, such as t-BuMe.sub.2Si, t-BuPh.sub.2Si, (i-Pr).sub.3Si, Et.sub.3Si, methoxymethyl, benzyl or —CH.sub.2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.

43. A The compound of formula IV1′ according to claim 42.

44. The compound of formula IV2′ according to claim 42.

45. The compound of formula V′ (2R*,3R*) according to claim 42.

46. The compound of formula VI′ (2R*,3S*) according to claim 42.

47. The compound of formula XI′ according to claim 42.

48. The compound of formula XII′ according to claim 42.

49. The compound of formula XVI′ according to claim 42.

50. A compound according to claim 42, wherein the compound is selected from the group consisting of: 1-benzyloxy-2-bromomethyl-4-fluorobenzene, 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane, 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene, 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yne-1-ol, trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol, (2R*,3R*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol, cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol, (2R*,3S*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2R*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol, (S*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S*,R*)-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (R*,R*)-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,R)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,S)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, and (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol.

51. The compound of formula III according to claim 42.

52. The process according to claim 1 for preparation of the compound of formula VII (S*/R*).

Description

EXAMPLES

[0262] The processes of the present invention will be further illustrated by the following examples. It should be understood that the following examples are provided to help further understand the present invention, not intended to limit the scope of the present invention in any manner.

[0263] The abbreviations used in the present application have the following meanings.

ABBREVIATIONS

[0264] Boc tert-butyloxycarbonyl

[0265] DEAD diethyl azodicarboxylate

[0266] DIPEA diisopropylethylamine

[0267] DMF dimethylformamide

[0268] DMA dimethylacetamide

[0269] EtOAc ethyl acetate

[0270] TBAF tetrabutylammonium fluoride

[0271] THE tetrahydrofuran

[0272] TLC thin layer chromatography

[0273] t-Bu(Me).sub.2Si tert-butyldimethylsilyl

[0274] TBS tert-butyldimethylsilyl

[0275] TBSCl tert-butyldimethylchlorosilane

Example 1: Preparation of 1-benzyloxy-2-bromomethyl-4-fluorobenzene (compound XIV, wherein R is benzyl)

[0276] ##STR00104##

[0277] The starting material 2-benzyloxy-5-fluorobenzene-methanol used in this Example can be prepared from the known compound 2-hydroxy-5-fluorobenzenemethanol (Medicinal Chemistry Letters, 2010, vol. 1, #7, p. 321-325, References, Bioorganic & Medicinal Chemistry, 2006, vol. 14, #6, p. 2022-2031).

[0278] 5.14 g (22 mmol) 2-benzyloxy-5-fluorobenzene-methanol was dissolved in 180 mL anhydrous diethyl ether, to which a solution of PBr.sub.3 (2.3 mL, 24.4 mmol) in 20 mL anhydrous diethyl ether was added dropwise at 0° C. The temperature was warmed to room temperature and the reaction was carried out for 2 hours. TLC indicated the reaction was completed.

[0279] Work-up: 50 mL water was added. After different layers appear, organic layer was removed. Water layer was extracted with DCM (50 mL×3). Organic phases were combined, and washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The resulting organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated, to give 6 g crude product. The crude product obtained was recrystallized from PE/Et.sub.2O, to obtain 5.9 g of desired product as crystal. Total yield is 91.2%.

[0280] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.33˜7.47 (m, 5H), 7.06˜7.09 (dd, J=7.6, 2.8 Hz, 1H), 6.91˜6.96 (m, 1H), 6.82˜6.86 (dd, J=8.8, 4.4 Hz, 1H), 5.11 (s, 2H), 4.53 (s, 2H)

Example 2: Preparation of 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane (compound XV, wherein R is benzyl)

[0281] ##STR00105##

[0282] 2.4 mL (16.1 mmol) trimethylsilylpropyne was added to 40 mL anhydrous THF. The mixture was cooled to −23° C., to which 2.5 M n-BuLi 7.7 mL (19.3 mmol) was added dropwise. After the addition, the solution was stirred at this temperature for 2 hours, until the reaction solution became orange red. Then the temperature was decreased to below −100° C. A solution of 3.5 g (11.9 mmol) compound XIV (wherein R is benzyl) in 5 mL anhydrous THF was added. After that, the reaction was carried out for 1 hour. TLC indicated the reaction was completed.

[0283] Work-up: The reaction was terminated with 10% saturated ammonium chloride solution. After different layers appear, water layer was extracted with diethyl ether (100 mL×2). Organic phases were combined, washed with saturated ammonium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated. After column chromatography (PE/Et.sub.2O=100:1), 3.79 g pure product was obtained. The yield is 97.6%.

[0284] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.38˜7.42 (m, 5H), 6.93˜6.96 (dd, J=8.8, 2.4 Hz, 1H), 6.78˜6.85 (m, 2H), 5.05 (s, 2H), 2.86˜2.90 (t, J=7.2 Hz, 2H), 2.50˜2.53 (t, J=7.2 Hz, 2H), 1.96 (s, 1H), 0.15 (s, 9H)

Example 3: Preparation of 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene (compound XVI, wherein R is benzyl)

[0285] ##STR00106##

[0286] 1.15 g (3.52 mmol) compound XV (wherein R is benzyl) was dissolved in 20 ml MeOH, to which 0.5 g (3.6 mmol) K.sub.2CO.sub.3 was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was extracted with EtOAc, washed with water and saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4, and filtered. After the filtrate was evaporated to dryness, 0.87 g colorless oil was obtained. After filtration with short silica gel column and elution with PL/EtOAc (100/2), 0.85 g colorless oil was obtained.

[0287] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.33˜7.42 (m, 5H), 6.93˜6.96 (dd, J=9.6, 2.8 Hz, 1H), 6.81˜6.86 (m, 2H), 5.05 (s, 2H), 2.86˜2.90 (t, J=7.2 Hz, 2H), 2.47˜2.51 (t, J=7.2 Hz, 2H), 1.96 (s, 1H)

Example 4: Preparation of 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yne-1-ol (compound III, wherein R is benzyl)

[0288] ##STR00107##

[0289] 1.49 g (5.6 mmol) compound XVI (wherein R is benzyl) was dissolved in 20 ml THF, cooled to −100° C., to which 2.9 ml 2.4 M BuLi (6.9 mmol) was added dropwise. After the addition was completed, the mixture was stirred at −100° C. for 30 min, and warmed to 0° C., to which 0.6 g (20 mmol) (CH.sub.2O).sub.n was added. After the addition was completed, the reaction mixture was stirred at 0° C. to room temperature for 2.5 hours. Saturated NH.sub.4Cl solution was added to terminate the reaction. Organic phase was separated, and water layer was extracted with Et.sub.2O twice. The extract solutions were combined, washed with water, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered and the resulting filtrate was evaporated to dryness. After purification on short silica gel column by eluting with petroleum ether/EtOAc (4/1), 1.51 g colorless oil was obtained.

[0290] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.33˜7.42 (m, 5H), 6.93˜6.96 (dd, J=9.6, 2.8 Hz, 1H), 6.81˜6.86 (m, 2H), 5.05 (s, 2H), 2.86˜2.90 (t, J=7.2 Hz, 2H), 2.47˜2.51 (t, J=7.2 Hz, 2H), 1.96 (s, 1H)

[0291] HR-MS (ESI) calculated C18H18O2F (M+H)+: 285.1285, found 285.1290.

Example 4′: Preparation of 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yne-1-ol (compound III, wherein R is benzyl)

[0292] ##STR00108##

[0293] 1.49 g (5.6 mmol) compound XVI (wherein R is benzyl) was dissolved in 20 ml THF, cooled to −100° C., to which 2.9 ml 2.4M BuLi (6.9 mmol) was added. After the addition was completed, the solution was stirred at −100° C. for 30 min, and then warmed to 0° C., to which 0.6 g (20 mmol) (CH.sub.2O).sub.n was added. After the addition was completed, the reaction mixture was stirred at 0° C. to room temperature for 2.5 h. Saturated NH.sub.4Cl solution was added to terminate the reaction. Organic phase was separated, and water layer was extracted with Et.sub.2O twice. The extract solutions were combined, washed with water, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered, the resulting filtrate was evaporated to dryness and oil was obtained. 10 ml n-hexane was added to the oil. The resulting mixture was stirred, cooled to −20° C. Crystal precipitated. After filtration, 1.2 g white solid with purity of 98% was obtained.

[0294] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.33˜7.42 (m, 5H), 6.93˜6.96 (dd, J=9.6, 2.8 Hz, 1H), 6.81˜6.86 (m, 2H), 5.05 (s, 2H), 2.86˜2.90 (t, J=7.2 Hz, 2H), 2.47˜2.51 (t, J=7.2 Hz, 2H), 1.96 (s, 1H)

[0295] HR-MS (ESI) calculated C18H18O2F (M+H).sup.+: 285.1285, found 285.1290.

Example 5: Preparation of trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol (compound IV-1, wherein R is benzyl)

[0296] ##STR00109##

[0297] 1.05 g (3.6 mmol) compound III (wherein R is benzyl) was dissolved in 25 ml THF, cooled in the ice bath, to which 2.1 ml 3.4 M (7.1 mmol) Red-Al was added. After the addition was completed, The reaction mixture was stirred at room temperature overnight (TLC indicated Rf value of the product is the same as the starting material under the condition of PL/EtOA=4/1). In the next day, saturated potassium sodium tartrate solution (about 20 ml) was added dropwise carefully to terminate the reaction. Organic phase was separated, and water layer was extracted with 20 ml×2 EtOAc. The extract solutions were combined, washed with 1N HCl, washed with water, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered and the resulting filtrate was evaporated to dryness, yielding 1.0 g of product (light yellow oil).

[0298] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.32˜7.42 (m, 5H), 6.85˜6.87 (d, J=8.4 Hz, 1H), 6.81˜6.83 (m, 2H), 5.61˜5.74 (m, 2H), 5.04 (s, 2H), 4.05˜4.07 (d, J=5.6 Hz, 2H), 2.71˜2.75 (t, J=7.6 Hz, 2H), 2.33˜2.38 (q, 2H), 1.39 (s, 2H).

[0299] HR-MS (ESI) calculated C18H20O2F (M+H).sup.+: 287.1448, found 287.1441.

Example 5′: Preparation of trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol (compound IV-1, wherein R is benzyl)

[0300] ##STR00110##

[0301] 1.05 g (3.6 mmol) compound III (wherein R is benzyl) was dissolved in 25 ml THF, cooled in the ice bath, to which 2.1 ml 3.4 M (7.1 mmol) Red-Al was added. After the addition was completed, the reaction mixture was stirred at room temperature overnight (TLC indicated Rf value of the product is the same as the starting material under the condition of PL/EtOA=4/1). In the next day, saturated potassium sodium tartrate solution (about 20 ml) was added dropwise carefully to terminate the reaction. Organic phase was separated, and water layer was extracted with 20 ml×2 EtOAc. The extract solutions were combined, washed with 1N HCl, washed with water, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered and the resulting filtrate was evaporated to dryness, yielding oil. To the oil, 8 ml n-hexane was added. The resulting mixture was stirred, cooled to −20° C. Crystal precipitated. After filtration, 0.7 g off-white solid with purity of 99% was obtained, melting point: 18-20° C.

[0302] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.32˜7.42 (m, 5H), 6.85˜6.87 (d, J=8.4 Hz, 1H), 6.81˜6.83 (m, 2H), 5.61˜5.74 (m, 2H), 5.04 (s, 2H), 4.05˜4.07 (d, J=5.6 Hz, 2H), 2.71˜2.75 (t, J=7.6 Hz, 2H), 2.33˜ 2.38 (q, 2H), 1.39 (s, 2H).

[0303] HR-MS (ESI) calculated C18H20O2F (M+H).sup.+: 287.1448, found 287.1441.

Example 6: Preparation of (2R*,3R*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound V, wherein R is benzyl)

[0304] ##STR00111##

[0305] 1.06 g (4 mmol) compound IV-1 (wherein R is benzyl) was dissolved in 20 ml DMC, and 1.01 g 75% MCPBA (4.4 mmol) was added with stirring. After the addition was completed, the reaction mixture was stirred at room temperature for 4 h. The reaction solution was diluted with DMC, sequentially washed with 5% NaOH twice, washed with water, dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated to dryness, yielding 1.08 g light yellow oil (90%).

[0306] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.32˜7.41 (m, 5H), 6.88˜6.90 (d, J=8.4 Hz, 1H), 6.83˜6.85 (m, 2H), 5.04 (s, 2H), 3.80˜3.83 (d, J=12.5 Hz, 1H), 3.51˜3.57 (m, 1H), 2.97˜2.99 (t, J=5.6 Hz, 1H), 2.75˜2.85 (m, 3H), 1.84˜1.91 (m, 2H).

Example 7: Preparation of 1-[6-fluoro-(2S*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol (compound VII)

[0307] Method One:

##STR00112##

[0308] 1.08 g compound V (wherein R is benzyl) was dissolved in 20 ml EtOAc, to which 0.2 g 10% Pd/C was added. The reaction mixture was subjected to hydrogenation under ordinary pressure at room temperature overnight. After filtration, the filtrate was evaporated to dryness, yielding 0.85 g oil. The oil was dissolved in 20 ml DMC, cooled in ice bath, to which 10 ml 10% NaOH—NaCl solution was added. The resulting solution was stirred in ice bath for 30 min. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. Organic phase was separated, and water layer was extracted with 10 ml DMC. The extract solutions were combined, washed with water, dried with anhydrous Na.sub.2SO.sub.4. After purification on short silica gel column by eluting with PL/EtOAc (1/1), 0.71 g white solid was obtained (95%).

[0309] Method Two:

##STR00113##

[0310] To 1.5 g compound V (wherein R is benzyl), 25 ml anhydrous ethanol, 200 mg 10% Pd/C and 100 mg anhydrous Na.sub.2CO.sub.3 were added. The reaction mixture was subjected to hydrogenation under ordinary pressure until no hydrogen was absorbed (about 1.5 hours), and then was stirred with heating at 60° C. for 2.5 hours. The mixture was filtered and the resulting filtrate was evaporated to dryness, yielding 0.95 g white solid.

[0311] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 6.70˜6.80 (m, 3H), 3.99˜4.02 (dd, J=10.4, 3.6 Hz, 1H), 3.82˜3.89 (m, 3H), 2.75˜2.85 (m, 2H), 2.11˜2.16 (m, 1H), 1.82˜1.90 (m, 1H)

[0312] HR-MS (EI) calculated C.sub.11H.sub.13O.sub.3F (M).sup.+: calculated 212.0849, found 212.0851.

Example 8: Preparation of cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol (compound IV-2, wherein R is benzyl)

[0313] ##STR00114##

[0314] A 250 ml round bottom flask was charged with Ni(OAc).sub.2.4H.sub.2O (42.0 mg, 1.7 mmol), evacuated to vacuum, and argon was introduced. 20 ml 95% ethanol which had been degassed was added. Sodium borohydride (100 mg, 2.6 mmol) was added to the reaction mixture with stirring under argon. The reaction mixture was stirred for 15 min, and the reaction mixture became black. Then ethylenediamine (0.5 ml, 7.5 mmol) was added. The reaction mixture was stirred for 5 min and NaOH solution (2 M, 6.0 μL, 0.1 mmol) which had been degassed was added. The compound III (wherein R is benzyl) (3.2 g, 11.3 mmol) was dissolved in 10 ml 95% ethanol, and the resulting solution was added dropwise to the reaction mixture. After that, argon used in the reaction was replaced with hydrogen and the reaction was carried out at room temperature for 18 h. TLC indicated the reaction was completed.

[0315] Work-up: hydrogen used in the reaction was replaced with argon. After removing hydrogen, the reaction mixture was filtered with Celite. The filter cake was washed with 100 ml ethyl acetate and water (3×20 ml). Organic phase was dried with anhydrous sodium sulfate. The mixture was filtered and the resulting filtrate was evaporated to dryness, yielding 3.15 g product. The yield is 97%.

[0316] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.34˜7.43 (m, 5H), 6.80˜6.86 (m, 3H), 5.53˜5.62 (m, 2H), 5.04 (s, 2H), 3.97˜4.00 (d, J=12 Hz, 2H), 2.63˜2.68 (t, J=8 Hz, 2H), 2.35˜2.40 (q, 2H), 1.27 (bs, 1H).

[0317] HR-MS (ESI) calculated C18H20O2F (M+H)+: 287.1448, found 287.1441.

Example 8′: Preparation of cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol (compound IV-2, wherein R is benzyl)

[0318] ##STR00115##

[0319] A 250 ml round bottom flask was charged with Ni(OAc).sub.2.4H.sub.2O (42.0 mg, 1.7 mmol), evacuated to vacuum, and argon was introduced. 20 ml 95% ethanol which had been degassed was added. Sodium borohydride (100 mg, 2.6 mmol) was added to the reaction mixture with stirring under argon. The reaction mixture was stirred for 15 min, and the reaction mixture became black. Then ethylenediamine (0.5 ml, 7.5 mmol) was added. The reaction mixture was stirred for 5 min and NaOH solution (2 M, 6.0 μL, 0.1 mmol) which had been degassed was added. The compound III (wherein R is benzyl) (3.2 g, 11.3 mmol) was dissolved in 10 ml 95% ethanol, and the resulting solution was added dropwise to the reaction mixture. After that, argon used in the reaction was replaced with hydrogen and the reaction was carried out at room temperature for 18 h. TLC indicated the reaction was completed.

[0320] Work-up: hydrogen used in the reaction was replaced with argon. After removing hydrogen, the reaction mixture was filtered with Celite. The filter cake was washed with 100 ml ethyl acetate and water (3×20 ml). Organic phase was dried with anhydrous sodium sulfate. The mixture was filtered and the resulting filtrate was evaporated to dryness, yielding oil. To the oil, 30 ml n-hexane was added. The resulting mixture was stirred, cooled to −20° C. Crystal precipitated. After filtration, 2.7 g off-white solid with purity of 99% was obtained, melting point: 32-34° C.

[0321] .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.34˜7.43 (m, 5H), 6.80˜6.86 (m, 3H), 5.53˜5.62 (m, 2H), 5.04 (s, 2H), 3.97˜4.00 (d, J=12 Hz, 2H), 2.63˜2.68 (t, J=8 Hz, 2H), 2.35˜2.40 (q, 2H), 1.27 (bs, 1H).

[0322] HR-MS (ESI) calculated C18H20O2F (M+H)+: 287.1448, found 287.1441.

Example 9: Preparation of (2R*,3S*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound VI, wherein R is benzyl)

[0323] ##STR00116##

[0324] According to the method similar to Example 6, compound IV-2 (wherein R is benzyl) was used as starting material to obtain compound VI.

[0325] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.34˜7.41 (m, 5H), 6.88˜6.90 (d, J=8.4 Hz, 1H), 6.84˜6.86 (m, 2H), 5.03 (s, 2H), 3.48˜3.56 (m, 2H), 3.03˜3.09 (m, 2H), 2.71˜2.87 (m, 2H), 1.89˜1.96 (m, 1H), 1.75˜1.83 (m, 1H).

Example 10: Preparation of 1-[6-fluoro-(2R*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol (compound VIII)

[0326] ##STR00117##

[0327] According to the methods which are the same as the two methods of Example 7, compound VI (wherein R is benzyl) was used as starting material to obtain compound VIII.

[0328] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 6.73˜ 6.81 (m, 3H), 4.04˜4.07 (m, 1H), 3.81˜ 3.85 (m, 2H), 3.76˜3.76 (m, 1H) 2.84˜2.86 (m, 1H), 2.74˜2.79 (m, 1H), 1.78˜2.02 (m, 2H), 2.04 (bs, 2H)

[0329] HR-MS (EI) calculated C.sub.11H.sub.13O.sub.3F (M).sup.+: calculated 212.0849, found 212.0844.

Example 11: Preparation of (S*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound IX)

[0330] ##STR00118##

[0331] 4.24 g (20 mmol) compound VII was suspended in 100 ml toluene, to which 0.5 g (2 mmol) dibutyltin oxide (Bu.sub.2SnO) was added. The mixture was stirred at room temperature for 1 h, and then diisopropylethylamine (3.95 ml, 24 mmol) and 3.99 g (21 mmol) p-methylphenylsulfonyl chloride (TsCl) were added to the mixture. The reaction mixture was stirred at room temperature overnight. In the next day, the reaction mixture was washed with 2N HCl, washed with water, dried with anhydrous Na.sub.2SO.sub.4. After purification on short silica gel column by eluting with PL/EtOAc (3/1), 6.89 g white solid was obtained (94%).

[0332] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.80˜7.82 (d, J=7.6 Hz, 2H), 7.34˜7.35 (d, J=7.6 Hz, 2H), 6.7 (s, 2H), 6.58˜6.61 (m, 1H), 4.36˜4.39 (d, J=10.4 Hz, 1H), 4.21˜4.23 (m, 1H), 3.91 (s, 2H), 2.75˜2.8 (m, 2H), 2.45 (s, 3H), 2.16˜2.19 (m, 1H), 1.75˜1.79 (m, 1H)

[0333] HR-MS (ESI) calculated C.sub.18H.sub.19O.sub.5FNaS(M+Na).sup.+: calculated 389.0829, found 389.0822.

Example 12: Preparation of (R*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound X)

[0334] ##STR00119##

[0335] 4.24 g (20 mmol) compound VIII was suspended in 100 ml toluene, to which 0.5 g (2 mmol) dibutyltin oxide (Bu.sub.2SnO) was added. The mixture was stirred at room temperature for 1 h, and then diisopropylethylamine (3.95 ml, 24 mmol) and 3.99 g (21 mmol) p-methylphenylsulfonyl chloride (TsCl) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 2 N HCl, washed with water, dried with anhydrous Na.sub.2SO.sub.4. After purification on short silica gel column by eluting with PL/EtOAc (3/1), 7.07 g product was obtained as colorless syrup (98%).

[0336] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.80˜7.82 (d, J=8.0 Hz, 2H), 7.33˜7.35 (d, J=8.0 Hz, 2H), 6.73˜6.79 (m, 2H), 6.64˜6.67 (m, 1H), 4.21˜4.22 (d, J=5.6 Hz, 2H), 4.0˜4.02 (m, 1H), 3.91˜3.95 (m, 1H), 2.72˜2.87 (m, 2H), 2.44 (s, 3H), 1.93˜1.95 (m, 2H)

[0337] HR-MS (ESI) calculated C.sub.18H.sub.19O.sub.5FNaS(M+Na).sup.+: calculated 389.0829, found 389.0823.

Example 13: Preparation of (S*,R*)-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (compound XI)

[0338] ##STR00120##

[0339] 1.83 g (5 mmol) compound IX was dissolved in 20 ml THF, to which 2.72 ml benzyl amine was added. The reaction mixture was heated under reflux for 16 hours (TLC indicated the spot of starting material disappeared), and evaporated under reduced pressure to dryness. 10% Na.sub.2CO.sub.3 was added to the residue, and the resulting solution was extracted with EtOAc for three times. The extract solutions were combined, washed with 10% Na.sub.2CO.sub.3, washed with water, washed with saturated NaCl solution, and dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated under reduced pressure to remove EtOAc. 20 ml cyclohexane was added to the residue and white crystal precipitated. After filtration, 1.25 g white solid was obtained.

[0340] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.28˜7.36 (m, 5H), 6.6˜6.8 (m, 3H), 3.85˜3.89 (m, 3H), 3.74˜3.81 (m, 1H), 2.98˜3.02 (dd, J=4.12 Hz, 1H), 2.73˜2.86 (m, 3H), 2.12˜2.15 (m, 1H), 1.76˜1.86 (m, 1H)

[0341] HR-MS (ESI) calculated C.sub.18H.sub.21O.sub.2FN (M+H).sup.+: calculated 302.1550, found 302.1546.

Example 14: Preparation of (R*,R*-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol compound XII)

[0342] ##STR00121##

[0343] 1.95 g (5.3 mmol) compound X was dissolved in 20 ml THF, to which 2.72 ml benzyl amine was added. The reaction mixture was heated under reflux for 16 hours (TLC indicated the spot of starting material disappeared), and evaporated under reduced pressure to dryness. 10% Na.sub.2CO.sub.3 was added to the residue, and the resulting solution was extracted with EtOAc for three times. The extract solutions were combined, washed with 10% Na.sub.2CO.sub.3, washed with water, washed with saturated NaCl solution, and dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated under reduced pressure to remove EtOAc. 20 ml cyclohexane was added to the residue and 0.91 g white crystal precipitated.

[0344] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.28˜7.38 (m, 5H), 6.7˜6.8 (m, 3H), 3.86˜3.95 (m, 4H), 2.91˜2.92 (d, J=5.6 Hz, 2H), 2.75˜2.84 (m, 2H), 1.91˜1.94 (m, 2H)

Example 15: Preparation of N-benzyl-(+/−)-Nebivolol (compound XIII)

[0345] ##STR00122##

[0346] 1.19 g (3.2 mmol) compound IX and 0.94 g (3.12 mmol) compound XII was dissolved in 15 ml EtOH, to which 0.5 g solid anhydrous sodium carbonate was added. The reaction mixture was heated under reflux with stirring for 16 hours, and evaporated under reduced pressure to dryness. 50 ml water was added to the residue and the resulting solution was extracted with EtOAc twice. The extract solutions were combined, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated under reduced pressure to dryness, to give 1.59 g product as syrup. 25 ml isopropanol was added to the product and heated to dissolve it. 0.5 g oxalic acid (FW=126) was added. The resulting solution was heated with stirring for 20 min, cooled, placed at room temperature for 5 hours, filtered, dried by oven, to give 1.59 g white solid. The resulting product was recrystallized from ethanol twice to yield 0.69 g compound XIII as oxalate. The resulting product was suspended in 20 ml methylene dichloride, to which 10 ml 10% sodium carbonate was added. The mixture was stirred at room temperature for 25 minutes, organic phase was separated, washed with water, and dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated under reduced pressure to dryness, to yield 0.58 g free base (compound XIII).

[0347] .sup.1HNMR (500 MHz, CDCl.sub.3) δ 7.27˜7.34 (m, 5H), 6.67˜6.78 (m, 6H), 3.94˜3.97 (d, J=15 Hz, 1H), 3.82˜3.86 (m, 4H), 3.69˜3.71 (d, J=15 Hz, 1H), 2.98˜3.01 (m, 1H), 2.90˜2.92 (m, 1H), 2.68˜2.83 (m, 7H), 2.11˜2.14 (m, 1H), 1.78˜1.86 (m, 3H)

[0348] HR-MS (ESI) calculated C.sub.29H.sub.31O.sub.4F.sub.2N (M+H).sup.+: calculated 496.2293, found 496.2287.

Example 16: Preparation of (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound Va, wherein R is benzyl)

[0349] ##STR00123##

[0350] 2 g powdered 4 A molecular sieve in 25 ml anhydrous methylene dichloride was cooled to −25° C., to which 1.85 g D-(−)-DIPT (7.9 mmol) and 2.06 g (7.2 mmol) Ti(OPr-i).sub.4 were added sequentially. After the addition was completed, the mixture was stirred at −25° C. for 20 min, to which 6.7 ml 3.2 N TBHP (19.8 mmol) (a solution in toluene) was then added dropwise. After the addition was completed, the mixture was stirred at −25° C. for 20 min, to which a solution of 1.89 g (6.6 mmol) compound IV1 (wherein R is benzyl) in 20 ml methylene dichloride was then added dropwise (within about 15 min). After the addition was completed, the reaction mixture was stirred at −25 to −22° C. for 6 h (until the spot of starting material disappeared).

[0351] Work-up: the reaction mixture was poured into a fresh solution of FeSO.sub.4/tartaric acid/H.sub.2O (2.5 g FeSO.sub.4+1.0 g tartaric acid+20 ml H.sub.2O). The resulting mixture was stirred at room temperature for 1 h, and filtered with Celite. Organic layer was separated from the filtrate, and water layer was extracted with methylene dichloride twice. The extract solutions were combined, washed with water, dried with anhydrous Na.sub.2SO.sub.4, and evaporated under reduced pressure to dryness, yielding 4.0 g oil.

[0352] The oil was dissolved in 40 ml DCM, to which 20 ml of the solution of 30% NaOH in saturated NaCl solution was added dropwise with cooling in ice bath. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Organic layer was separated, and water layer was extracted with DCM twice. The extract solutions were combined, washed with water, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered and the resulting filtrate was evaporated to dryness. The residue was loaded on silica gel column and eluted with PL/EtOAc (3/1), to obtain 1.54 g colorless oil.

[0353] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.32˜7.41 (m, 5H), 6.88˜6.90 (d, J=8.4 Hz, 1H), 6.83˜6.85 (m, 2H), 5.04 (s, 2H), 3.80˜3.83 (d, J=12.5 Hz, 1H), 3.51˜3.57 (m, 1H), 2.97˜2.99 (t, J=5.6 Hz, 1H), 2.75˜2.85 (m, 3H), 1.84˜1.91 (m, 2H).

[0354] HR-MS (ESI) calculated C.sub.18H.sub.19O.sub.3FNa (M+Na).sup.+: 325.1210, found 325.1201.

[0355] [α].sub.D.sup.20; +22.9 (CHCl.sub.3, C 1.0)

Example 17: Preparation of (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound Vb, wherein R is benzyl)

[0356] ##STR00124##

[0357] According to the method similar to Example 16, compound IV1 was used as starting material and L-(+)-diisopropyl tartrate was used as chiral inducer, to obtain compound Vb.

[0358] [α].sub.D.sup.20; −23.1 (CHCl.sub.3, C 1.0)

Example 18: Preparation of (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound VIa, wherein R is benzyl)

[0359] ##STR00125##

[0360] 2 g powdered 4 A molecular sieve in 25 ml anhydrous methylene dichloride was cooled to −25° C., to which 1.85 g D-(−)-DIPT (7.9 mmol) and 2.06 g (7.2 mmol) Ti(OPr-i).sub.4 were added sequentially. After the addition was completed, the mixture was stirred at −25° C. for 20 min, to which 6.7 ml 3.2 N TBHP (19.8 mmol) (a solution in toluene) was then added dropwise. After the addition was completed, the mixture was stirred at −25° C. for 20 min, to which a solution of 1.92 g (6.7 mmol) compound IV2 (wherein R is benzyl) in 20 ml methylene dichloride was then added dropwise (within about 15 min). After the addition was completed, the reaction mixture was stirred at −25 to −22° C. for 6 h. The reaction mixture was poured into a fresh solution of FeSO.sub.4/tartaric acid/H.sub.2O (2.5 g FeSO.sub.4+1.0 g tartaric acid+20 ml H.sub.2O). The resulting mixture was stirred at room temperature for 1 h, and filtered with Celite. Organic layer was separated from the filtrate, and water layer was extracted with methylene dichloride twice. The extract solutions were combined, washed with water, dried with anhydrous Na.sub.2SO.sub.4, and evaporated under reduced pressure to dryness, yielding oil.

[0361] The oil was dissolved in 40 ml Et.sub.2O, to which 20 ml of the solution of 30% NaOH in saturated NaCl solution was added dropwise with cooling in ice bath. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Organic layer was separated, and water layer was extracted with DCM twice. The extract solutions were combined, washed with water, dried with anhydrous Na.sub.2SO.sub.4. The mixture was filtered and the resulting filtrate was evaporated to dryness. The residue was loaded on silica gel column and eluted with PL/EtOAc (3/1), to obtain 1.63 g colorless oil.

[0362] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.34˜7.41 (m, 5H), 6.88˜6.90 (d, J=8.4 Hz, 1H), 6.84˜6.86 (m, 2H), 5.03 (s, 2H), 3.48˜3.56 (m, 2H), 3.03˜3.09 (m, 2H), 2.71˜2.87 (m, 2H), 1.89˜1.96 (m, 1H), 1.75˜1.83 (m, 1H).

[0363] [α].sub.D.sup.20; −1.5 (CHCl.sub.3, c 1.0)

Example 19: Preparation of (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound VIb, wherein R is benzyl)

[0364] ##STR00126##

[0365] According to the method similar to Example 16, compound IV2 (wherein R is benzyl) was used as starting material and L-(+)-diisopropyl tartrate was used as chiral inducer, to obtain compound VIb.

[0366] [α].sub.D.sup.20; +1.6 (CHCl.sub.3, c 2.0)

Example 20: Preparation of 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol (compound VIIa)

[0367] ##STR00127##

[0368] 1.09 g compound Va (wherein R is benzyl) was dissolved in 25 ml EtOH, to which 0.25 g 10% Pd—C and 0.075 g anhydrous sodium carbonate was added, and hydrogenation was carried out under ordinary pressure (about 1 h). The hydrogenation was stopped. The reaction mixture was stirred at 60° C. in oil bath for 2 h, and filtered to remove Pd/C. The residue was washed with EtOH. The filtrate was evaporated to dryness, yielding 0.75 g white solid.

[0369] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 6.70˜6.80 (m, 3H), 3.99˜4.02 (dd, J=10.4, 3.6 Hz, 1H), 3.82˜3.89 (m, 3H), 2.75˜2.85 (m, 2H), 2.11˜2.16 (m, 1H), 1.82˜1.90 (m, 1H)

[0370] [α].sub.D.sup.20; +89.6 (CH.sub.3OH, c 1.0)

Example 21: Preparation of 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol (compound VIIb)

[0371] ##STR00128##

[0372] According to the method similar to Example 20, compound Vb (wherein R is benzyl) was used as starting material to obtain compound VIIb.

[0373] [α].sub.D.sup.20; −87.9 (CH.sub.3OH, c 1.0)

Example 22: Preparation of 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol (compound VIIIa)

[0374] ##STR00129##

[0375] 1.3 g compound VIa (wherein R is benzyl) was dissolved in 25 ml EtOH, to which 0.2 g 10% Pd—C and 0.1 g anhydrous sodium carbonate was added. Hydrogenation was carried out under ordinary pressure until no hydrogen was absorbed. The hydrogenation was stopped. The reaction mixture was stirred at 60° C. in oil bath for 2 h, and filtered to remove Pd/C. The residue was washed with EtOH. The filtrate was evaporated to dryness, yielding 0.88 g white solid.

[0376] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 6.73˜6.81 (m, 3H), 4.04˜4.07 (m, 1H), 3.81˜3.85 (m, 2H), 3.76˜3.76 (m, 1H) 2.84˜2.86 (m, 1H), 2.74˜2.79 (m, 1H), 1.78˜2.02 (m, 2H), 2.04 (bs, 2H)

[0377] [α].sub.D.sup.20; −113.1 (CH.sub.3OH, c 1.0), [α].sub.D.sup.20; −112.0 (CH.sub.3Cl, c 0.1)

Example 23: Preparation of 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol (compound VIIIb)

[0378] ##STR00130##

[0379] According to the method similar to Example 22, compound VIb (wherein R is benzyl) was used as starting material to obtain compound VIIIb as white solid; [α].sub.D.sup.20; +95.6 (CH.sub.3Cl, c 0.045).

Example 24: Preparation of (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound IXa)

[0380] ##STR00131##

[0381] According to the method similar to Example 11, compound VIIa was used as starting material to obtain compound IXa.

[0382] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.80˜7.82 (d, J=7.6 Hz, 2H), 7.34˜7.35 (d, J=7.6 Hz, 2H), 6.7 (s, 2H), 6.58˜6.61 (m, 1H), 4.36˜4.39 (d, J=10.4 Hz, 1H), 4.21˜4.23 (m, 1H), 3.91 (s, 2H), 2.75˜2.8 (m, 2H), 2.45 (s, 3H), 2.16˜2.19 (m, 1H), 1.75˜1.79 (m, 1H)

[0383] [α].sub.D.sup.20; +82.1 (CHCl.sub.3, c 0.56)

Example 25: Preparation of (R,R)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound Xa)

[0384] ##STR00132##

[0385] According to the method similar to Example 11, compound VIIIa was used as starting material to obtain compound Xa.

[0386] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.80˜7.82 (d, J=8.0 Hz, 2H), 7.33˜7.35 (d, J=8.0 Hz, 2H), 6.73˜6.79 (m, 2H), 6.64˜6.67 (m, 1H), 4.21˜4.22 (d, J=5.6 Hz, 2H), 4.0˜4.02 (m, 1H), 3.91˜3.95 (m, 1H), 2.72˜2.87 (m, 2H), 2.44 (s, 3H), 1.93˜1.95 (m, 2H)

[0387] HR-MS (ESI) calculated C.sub.18H.sub.19O.sub.5FNaS(M+Na).sup.+: calculated 389.0829, found 389.0823.

[0388] [α].sub.D.sup.20; −48.4 (CH.sub.3Cl, c 0.68)

Example 26: Preparation of (R,S)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound IXb)

[0389] ##STR00133##

[0390] According to the method similar to Example 11, compound VIIb was used as starting material to obtain compound IXb.

[0391] [α].sub.D.sup.20; −80.3 (CHCl.sub.3, c 0.85)

Example 27: Preparation of (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (compound Xb)

[0392] ##STR00134##

[0393] According to the method similar to Example 11, compound VIIIb was used as starting material to obtain compound Xb.

[0394] [α].sub.D.sup.20; +50.3 (CH.sub.3Cl, c 0.50)

Example 28: Preparation of (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (compound XIa)

[0395] ##STR00135##

[0396] According to the method similar to Example 13, compound IXa was used as starting material to obtain compound XIa.

[0397] Compound XIa is a white solid, [α].sub.D.sup.20; +82.1 (CHCl.sub.3, c 0.56)

Example 29: Preparation of (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (compound XIb)

[0398] ##STR00136##

[0399] According to the method similar to Example 13, compound IXb was used as starting material to obtain compound XIb.

[0400] [α].sub.D.sup.20; −79.3 (CHCl.sub.3, c 0.45)

Example 30: Preparation of N-benzyl-D-Nebivolol (Compound XIIIa)

[0401] ##STR00137##

[0402] 287 mg (0.95 mmol) compound XIa and 350 mg (0.95 mmol) compound Xa was dissolved in 5 ml ethanol, to which 150 mg anhydrous Na.sub.2CO.sub.3 was added. The reaction mixture was heated under reflux with stirring for 16 h.

[0403] The reaction mixture was evaporated under reduced pressure to dryness. 10 ml water was added to the residue, and the resulting mixture was extracted with EtOAc twice. The extract solutions were combined, washed with saturated NaCl solution, dried with anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was evaporated under reduced pressure to dryness, and 453 mg product was obtained as syrup, which was then recrystallized from ethanol/water, yielding 373 mg white solid (79%).

Example 30′: Preparation of N-Benzyl-D-Nebivolol Hydrochloride (Compound XIIIa Hydrochloride)

[0404] 287 mg (0.95 mmol) compound XIa and 350 mg (0.95 mmol) compound Xa was dissolved in 5 ml ethanol, to which 150 mg anhydrous Na.sub.2CO.sub.3 was added. The reaction mixture was heated under reflux with stirring for 16 h.

[0405] The reaction mixture was evaporated under reduced pressure to dryness. 10 ml water was added to the residue, and the resulting mixture was extracted with EtOAc twice. The extract solutions were combined, to which 2 ml 1 N hydrochloric acid was added. The resulting mixture was stirred and crystal precipitated. After filtration, 390 mg white solid with purity of 99.5% was obtained.

Example 30″: Preparation of N-Benzyl-D-Nebivolol (Compound XIIIa)

[0406] 390 mg compound XIIIa hydrochloride was added to 10 ml methylene dichloride. The resulting mixture was stirred, and was neutralized by adding aqueous sodium bicarbonate solution. Different layers appeared. Organic layer was dried and concentrated to give 355 mg white solid with purity of 99.7%.

Example 31: Preparation of N-Benzyl-L-Nebivolol (Compound XIIIb)

[0407] ##STR00138##

[0408] According to the method similar to Example 30, compounds XIb and Xb were used as starting materials to obtain compound XIIIb.

Example 31′: Preparation of N-benzyl-L-Nebivolol hydrochloride (Compound XIIIb Hydrochloride)

[0409] According to the method similar to Example 30′, compounds XIb and Xb were used as starting materials to obtain compound XIIIb hydrochloride with purity of 99.6%.

Example 31″: Preparation of N-benzyl-L-Nebivolol (Compound XIIIb)

[0410] According to the method similar to Example 30″, compound XIIIb was obtained with purity of 99.8%.

Example 32: Preparation of DL-Nebivolol (Compound I) hydrochloride

[0411] 200 mg (0.4 mmol) compound I was dissolved in 5 ml ethanol, to which 50 mg 10% Pd—C was added. Hydrogenation was carried out under ordinary pressure at room temperature for 18 hours. After filtration, the residue was washed with ethanol. Hydrogen chloride gas was introduced into the filtrate. Then the solution was evaporated under reduced pressure to remove ethanol, and white solid was obtained, to which anhydrous diethyl ether was added. The resulting mixture was stirred and filtered, yielding 160 mg product (89%).

[0412] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 8.81 (bs, 2H), 6.90˜6.94 (m, 4H), 6.75˜6.76 (dd, 2H), 5.99 (bs, 1H), 5.80 (bs, 1H), 4.11 (m, 1H), 3.98˜4.02 (m, 2H), 3.89˜3.91 (m, 1H), 3.17˜3.22 (m, 2H), 3.05˜3.07 (m, 1H), 2.74˜2.82 (m, 4H), 2.10˜2.13 (m, 1H), 1.92˜1.94 (m, 1H), 1.75˜1.80 (m, 1H), 1.67˜1.71 (m, 1H)

[0413] HR-MS (FAB.sup.+) calculated C.sub.22H.sub.26F.sub.2NO.sub.4S (M+1−HCl).sup.+: calculated 406.1829, found 406.1825.

Example 32′: Preparation of DL-Nebivolol (Compound I) hydrochloride

[0414] 100 mg compound XIIIa′ and 100 mg compound XIIIb′ was added to 15 ml methylene dichloride. The resulting solution was neutralized by adding aqueous sodium bicarbonate solution. Different layers appeared. Organic layer was concentrated to dryness. 50 ml methanol and 50 mg 10% Pd—C were added to the residue. Hydrogenation was carried out under ordinary pressure at room temperature for 18 hours. After filtration, the residue was washed with methanol. 2 ml 1 N hydrochloric acid was added to the filtrate. Crystal precipitated. The mixture was filtered. The resulting solid was washed and dried to give 100 mg white solid with purity of 99.9%.

[0415] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 8.81 (bs, 2H), 6.90˜6.94 (m, 4H), 6.75˜6.76 (dd, 2H), 5.99 (bs, 1H), 5.80 (bs, 1H), 4.11 (m, 1H), 3.98˜4.02 (m, 2H), 3.89˜3.91 (m, 1H), 3.17˜3.22 (m, 2H), 3.05˜3.07 (m, 1H), 2.74˜2.82 (m, 4H), 2.10˜2.13 (m, 1H), 1.92˜1.94 (m, 1H), 1.75˜1.80 (m, 1H), 1.67˜1.71 (m, 1H)

[0416] HR-MS (FAB.sup.+) calculated C.sub.22H.sub.26F.sub.2NO.sub.4S(M+1−HCl).sup.+: calculated 406.1829, found 406.1825.

Example 32″: Preparation of DL-Nebivolol (Compound I) hydrochloride

[0417] 100 mg compound XIIIa obtained according to Example 30″ and 100 mg compound XIIIb obtained according to Example 31″ were added to 50 ml methanol, to which 50 mg 10% Pd—C was added. Hydrogenation was carried out under ordinary pressure at room temperature for 18 hours. After filtration, the residue was washed with methanol. 2 ml 1 N hydrochloric acid was added to the filtrate. Crystal precipitated. The mixture was filtered. The resulting solid was washed and dried to give 105 mg white solid with purity of 99.9%.

[0418] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 8.81 (bs, 2H), 6.90˜6.94 (m, 4H), 6.75˜6.76 (dd, 2H), 5.99 (bs, 1H), 5.80 (bs, 1H), 4.11 (m, 1H), 3.98˜4.02 (m, 2H), 3.89˜3.91 (m, 1H), 3.17˜3.22 (m, 2H), 3.05˜3.07 (m, 1H), 2.74˜2.82 (m, 4H), 2.10˜2.13 (m, 1H), 1.92˜1.94 (m, 1H), 1.75˜1.80 (m, 1H), 1.67˜1.71 (m, 1H)

[0419] HR-MS (FAB.sup.+) calculated C.sub.22H.sub.26F.sub.2NO.sub.4S (M+1−HCl).sup.+: calculated 406.1829, found 406.1825.

Example 33a: Preparation of D-Nebivolol (Compound Ia) hydrochloride

[0420] According to the method similar to Example 32, compound XIIIa was used as starting material to obtain compound Ia as hydrochloride. [α].sub.D.sup.20; +22.0 (CH.sub.3OH, C 0.5)

Example 33b: Preparation of L-Nebivolol (Compound Ib) hydrochloride

[0421] According to the method similar to Example 32, compound XIIIb was used as starting material to obtain compound Ib as hydrochloride. [α].sub.D.sup.20; −21.2 (CH.sub.3OH, C 0.4).

[0422] In view of the above, the novel processes provided by the present invention have high stereoselectivity, the preparation of the key intermediates can avoid separation with the column chromatography, and the reaction conditions are mild and do not require special reagents. Compared with the prior art, the processes for preparation of Nebivolol according to the present invention have greatly reduced cost and are very suitable for industrial production. Especially the purification by crystallization of intermediate compounds of formulae III, IV1 and IV2 greatly improves the quality of intermediate compounds and products, resulting in that the quality of products is controllable, the yield is improved and the production cost is remarkably reduced. Moreover, the compounds of formulae XIIIa and XIIIb are purified by formation of salt and crystallization, which greatly improves the product quality and enables the purity of the final product can be 99.9% or more.

[0423] While some embodiments and specific examples of the present invention are provided herein, it will be understood by those skilled in the art that these embodiments and examples are merely illustrative examples of the present invention and that other modifications and changes can be made without departing from the spirit of the present invention.