Compound and use thereof in synthesis of brivaracetam intermediate and crude drug

Abstract

The present application provides a compound in formula III, and further provides a use of the compound in the synthesis of a Brivaracetam intermediate and a crude drug, and a synthesis method. A raw material involved in the method of the present application is low in costs and easily available; (R)-4-propyl-dihydrofuran-2-ketone having high optical purity can be prepared; complicated separation and purification steps are avoided; costs are reduced, and the method is more applicable to industrial production. ##STR00001##

Claims

1. A compound having the structure of formula III: ##STR00057## wherein, R represents C.sub.1-C.sub.5 alkyl, C.sub.6-C.sub.12 aryl, or 5-12 membered heteroaryl, wherein R is optionally substituted by one or more groups selected from halogen, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, methoxy, nitro or cyano.

2. The compound of claim 1, wherein the compound is selected from: ##STR00058## wherein, R is ##STR00059##

3. A method for the preparation of the compounds of claim 2, comprising the step of: ##STR00060##

4. The method according to claim 3, when the method comprises preparation of the compound of formula II from the compound of formula I, the method comprises the following steps: reacting the compound of the formula I with R-epichlorohydrin in a solvent under the action of a base (a), followed by treatment with an acid or a base (b) to prepare the compound of the formula II.

5. The method according to claim 4, wherein the base (a) is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the acid is selected from one or more of acetic acid, propionic acid, citric acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; the base (b) is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate.

6. The method according to claim 4, wherein the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.

7. The method according to claim 3, wherein when the method comprises preparation of the compound of formula II from the compound of formula I, the method comprises the following steps: reacting the compound of the formula I with R-epichlorohydrin in a solvent under the action of a base (a), followed by treatment with an acid or a base (b) to prepare the compound of the formula II, wherein the base (a) is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the equivalent of alkali (a) is between 1 and 10; the equivalent of R-epichlorohydrin is between 0.1 and 5; the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N,N-dimethylformamide; the acid is selected from one or more of acetic acid, propionic acid, hydrochloric acid or sulfuric acid; and the base (b) is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate.

8. The method according to claim 3, when the method comprises preparation of the compound of formula III from the compound of formula II, the method comprises the following steps: preparing the compound of formula III by reacting a compound of formula II with an ethyl metal reagent in an aprotic organic solvent.

9. The method according to claim 8, wherein the ethyl metal reagent includes ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium or diethyl lead.

10. The method according to claim 9, wherein the ethyl metal reagent is used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride.

11. The method according to claim 10, wherein the aprotic organic solvent is selected from tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether or methyl tert-butyl ether.

12. The method according to claim 3, when the method comprises preparation of the compound of formula III from the compound of formula II, the method comprises the following steps: in an aprotic organic solvent, reacting the compound of formula II with ethyl metal reagents which is used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride to prepare the compound of III; wherein the aprotic organic solvent is selected from tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether or methyl tert-butyl ether; the ethyl metal reagent include ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium or diethyl lead, which is used in molar equivalents between 1-5; and the molar equivalent of cuprous iodide, cuprous cyanide or anhydrous zinc chloride is between 0.01 and 2.

13. A method for preparing a compound of formula IV of Brivaracetam intermediate using the compound according to claim 1, comprising the step of ##STR00061## preparing the compound of formula IV by removing a sulfonyl group on the compound of formula III by a reducing agent in an organic solvent; wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, or a mixed solvent with water; the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethylchlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methyl magnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.

Description

DEFINITIONS

(1) Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below. Variables defined in this section, such as A, R, X, Z and the like, are for reference within this section only, and are not meant to have the save meaning as may be used outside of this definitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this definitions section of typical substituents is exemplary and is not intended to limit the substituents defined elsewhere within this specification and claims.

(2) “” represents the position of the substituent.

(3) “C.sub.m-C.sub.n” refers to the carbon atoms contained in m-n.

(4) “Alkyl” refers to a saturated aliphatic hydrocarbon radical or linker including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. “Lower alkyl” refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include —(CH.sub.2).sub.3—, methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and —NR.sup.xR.sup.y, where R.sup.x and R.sup.y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring.

(5) “Aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and —NR.sup.xR.sup.y, with R.sup.x and R.sup.y as defined above.

(6) “Heteroaryl” refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated π-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and —NR.sup.xR.sup.y with R.sup.x and R.sup.y as defined above.

(7) “Cyano” refers to a —C≡N group.

(8) “Nitro” refers to a —NO.sub.2 group.

(9) “Ester” refers to a —C(O)OR″ group with R″ as defined herein except that R″ cannot be hydrogen.

(10) The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.

(11) The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

(12) “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocycle group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.

(13) As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

(14) Compounds of Formula III include, but are not limited to optical isomers of compounds of Formula I, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds of Formula III include Z- and E-forms (or cis- and trans-forms) of compounds with double bonds. Where compounds of Formula I exist in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.

EXAMPLES

(15) The invention includes, but is not limited to, the following examples to further illustrate the preparation of the compounds described herein.

(16) The following embodiments are only used to illustrate the specific embodiments of the invention, which can enable the professional and technical personnel to understand the invention more comprehensively, but can not limit the invention in any way. In the specific embodiments of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the technical field, etc.

(17) The chemical reagents used in the following examples are all commercially available chemical reagents.

(18) In an exemplary embodiment of the present invention, the synthesis of formula III and the route for preparing the key intermediate (R)-4-propyl-dihydrofuran-2-one of Brivaracetam are as follows:

(19) ##STR00016##

(20) In the above synthetic routes, those skilled in the field may also make changes to the above synthetic routes, such as changing specific reaction conditions as required or adjusting the synthetic routes of one or more steps, which are not separated from the essential contents of the present invention and are within the scope of protection of the present application.

Example 1 Preparation of Compound II

(21) To a 100 mL three-necked flask with mechanical stirring was added compound I (5.1 mmol) and 30 mL of methanol at room temperature. Sodium methoxide (1.10 g, 20.4 mmol) was added portionwise. The resulting mixture was heated to 35-40° C. and stirred for 10 minutes. Then the temperature was cooled to 20-25° C., and R-epichlorohydrin (0.71 g, 0.97 mmol) was added and the addition was completed in about 10 minutes. The internal temperature rose to 50-55° C. and stirred for 4 h. A mixture of 5 mL of water and 5 mL of acetic acid was added to the reaction mixture and stirred for another 15 h. The reaction mixture was diluted with 20 mL of water, and extracted with dichloromethane (30 mL*2). The combined organic phases was washed with a saturated NaHCO.sub.3 solution (15 mL*2), and dried over anhydrous sodium sulfate. Most of the solvent was removed under reduced pressure, and the residue was purified by recrystallization with ethanol or by column chromatography to give compound II as shown in Table 1.

(22) TABLE-US-00001 TABLE 1 Comp. MS No. Structure Name [M + 1] II-1 (1R,5S)-1-(methylsulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 177 II-2 (1R,5S)-1-(phenylsulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 239 II-3 (1R,5S)-1-tosyl-3-oxa- bicyclo[3.1.0]hexan-2-one 253 II-4 0 (1R,5S)-1-((4-chloro- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 273 II-5 (1R,5S)-1-((4-(trifluoro- methyl)phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 307 II-6 (1R,5S)-1-((3-chloro- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 273 II-7 (1R,5S)-1-((3-methoxy- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 269 II-8 (1R,5S)-1-((4-methoxy- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 269 II-9 (1R,5S)-1-((2,4-dimethyl- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 267 II-10 (1R,5S)-1-((4-(tert- butyl)phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 295 II-11 (1R,5S)-1-((4-nitro- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 284 II-12 (1R,5S)-1-(pyridin-3-ylsulfonyl)- 3-oxabicyclo[3.1.0]hexan-2- one 240 II-13 (1R,5S)-1-(naphthalen-1- ylsulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 289 II-14 0 (1R,5S)-1-(naphthalen-2- ylsulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 289 II-15 (1R,5S)-1-(quinolin-8- ylsulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 290 II-16 (1R,5S)-1-((4- ethylphenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 267 II-17 (1R,5S)-1-((4- propylphenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 281 II-18 (1R,5S)-1-((4-isopropyl- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 281 II-19 (1R,5S)-1-((4-fluoro- phenyl)sulfonyl)-3- oxabicyclo[3.1.0]hexan-2-one 257 II-20 4-(((1R,5S)-2-oxo-3- oxabicyclo[3.1.0]hexan- 1-yl)sulfonyl)benzonitrile 264

Example 2 Preparation of Compound III

(23) To a 100 mL three-necked flask with mechanical stirring was added THF (10 mL) and CuI (224 mg, 1.18 mmol). Cooled to −45° C.-50° C., and Ethyl magnesium chloride solution (2.1 mL, 4.2 mmol) was added dropwise over 1 h. The resulting mixture was warmed to −5° C. and continued to stirred for 1 h. Then a solution of compound II (1.49 mmol) in THF (5 mL) was added dropwise over 45 min and the temperature was retained at −5˜-10° C. during the addition. The reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and MTBE (5 mL) after reacting for 15 min. The resulting mixture was stirred for another 2.5 h. The organic phase was collected and the aqueous phase was extracted with 10 mL MTBE again. The combined organic phases was washed with water (10 mL*2) and brine (10 mL), then dried with anhydrous Na.sub.2SO.sub.4. The solid was filtered off by suction, and the filtrate was concentrated. The residue was added an appropriate amount of ethanol, mixed and concentrated again. The crude was purified by stirring in ethanol or by column chromatography. Dried under vacuum to constant weight gives compound III as shown in Table 2.

(24) TABLE-US-00002 TABLE 2 Comp. MS No. Structure Name [M + 1] III-1 (4S)-3-(methyl- sulfonyl)-4- propyldihydro- furan-2(3H)- one 207 III-2 (4S)-3-(phenyl- sulfonyl)-4- propyldihydro- furan-2(3H)- one 269 III-3 (4S)-4-propyl- 3-tosyldihydro- furan-2(3H)- one 283 III-4 0 (4S)-3-((4-chloro- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 303 III-5 (4S)-4-propyl- 3-((4-(trifluoro- methyl)phe- nyl)sulfonyl)di- hydrofuran- 2(3H)-one 337 III-6 (4S)-3-((3- chloro- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 303 III-7 (4S)-3-((3- methoxy- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 299 III-8 (4S)-3-((4- methoxy- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 299 III-9 (4S)-3-((2,4- dimethyl- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 297 III-10 (4S)-3-((4-(tert- butyl)phenyl)sul- fonyl)-4- propyldihydro- furan-2(3H)- one 325 III-11 (4S)-3-((4-nitro- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 314 III-12 (4S)-4-propyl- 3-(pyridin-3- ylsulfonyl)di- hydrofuran- 2(3H)-one 270 III-13 (4S)-3-(naph- thalen-1-yl- sulfonyl)-4- propyldihydro- furan-2(3H)- one 319 III-14 0 (4S)-3-(naph- thalen-2-yl- sulfonyl)-4- propyldihydro- furan-2(3H)- one 319 III-15 (4S)-4-propyl- 3-(quinolin-8- ylsulfonyl)di- hydrofuran- 2(3H)-one 320 III-16 (4S)-3-((4-ethyl- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 297 III-17 (4S)-4-propyl- 3-((4-propyl- phenyl)sul- fonyl)dihydro- furan-2(3H)-one 311 III-18 (4S)-3-((4-iso- propylphenyl)sul- fonyl)-4- propyldihydro- furan-2(3H)- one 311 III-19 (4S)-3-((4-fluoro- phenyl)sulfonyl)- 4-propyldihydro- furan-2(3H)- one 287 III-20 4-(((4S)-2-oxo- 4-propyltetra- hydrofuran-3- yl)sul- fonyl)benzo- nitrile 294

Example 3 Preparation of Compound II-2

(25) To the mixture of toluene/water (v/v, 5/5 mL) in the reaction flask was added (Phenylsulfonyl)acetonitrile (500 mg, 2.8 mmol), NaOH (276 mg, 6.9 mmol) and Tetrabutylammonium hydrogen sulfate (50 mg). After stirring for 15 min, R-epichlorohydrin (381 mg, 4.1 mmol) was added into the mixture. The resulting mixture was stirred at 100° C. for 1 h, then was added 1 mL of conc. HCl (aq.) and continued to stir for 3 h. The reaction mixture was diluted with DCM (10 mL), and the organic phase was collected, dried and concentrated. The residue was purified by column chromatography to give white solid, Yield: 25.7%.

Example 4 Preparation of Compound II-2

(26) To a 5.0 L three-necked flask with mechanical stirring function was added (Phenylsulfonyl)acetonitrile (92.4 g, 0.51 mol) and sodium ethoxide (436.0 g, 20% ethanol solution), and the mixture was stirred at 15 to 20° C. for 30 minutes. R-epichlorohydrin (70.7 g, 0.97 mol) was added dropwise, and the addition was completed in about 10 minutes. The internal temperature was raised to 50-55° C., and the mixture was reacted for about 1 h, then concentrated. To the residue was added MTBE (1.0 L), water (0.5 L), and NaOH (51 g), and the mixture was stirred for 1 h. The aqueous phase was collected, and acidified to pH˜1 with conc. HCl (aq.), then stirred at 50° C. for 15 h. The aqueous phase was extracted with MTBE (300 mL*3). The combined organic phases were washed once with saturated sodium bicarbonate (0.5 L) and water (0.5 L) respectively and concentrated. The residue was crystallized with 400 mL of ethanol, filtered to give compound II-2 as a solid (56.7 g, yield: 46.7%).

Example 5 Preparation of Compound II-3

(27) To a 2.0 L three-necked flask with mechanical stirring function was added 4-(Methylphenyl)sulfonylacetonitrile (100 g, 0.51 mol) and sodium ethoxide (436.0 g, 20% ethanol solution), and the mixture was stirred at 20° C. for 30 minutes. R-epichlorohydrin (70.7 g, 0.97 mol) was added dropwise, and the addition was completed in about 10 minutes. The internal temperature was raised to 50-55° C., and the mixture was reacted for about 1 h, then concentrated. To the residue was added MTBE (1.0 L), water (0.5 L), and NaOH (51 g), and the mixture was stirred for 1 h. The aqueous phase was collected, and acidified to pH˜1 with conc. HCl (aq.), then stirred at 50° C. for 6 h. The aqueous phase was extracted with MTBE (300 mL*3). The combined organic phases were washed once with saturated sodium bicarbonate (0.5 L) and water (0.5 L) respectively and concentrated. The residue was crystallized with 400 mL of MeOH, filtered to give compound II-3 as a solid, yield: 50.2%.

Example 6 Preparation of Compound III-2

(28) To a 2.0 L three-necked flask with mechanical stirring function was added THF (100 mL) and CuI (22.4 g, 117.8 mmol). Cooled to −45° C.-50° C., and ethylmagnesium bromide (185 mL, 370.0 mmol) was added dropwise. The addition was completed in about 1 hour. The mixture was continued to stir for 1 h, then warmed to −15° C. To the mixture was added dropwise a solution of the compound II-2 (39.9 g) in THF (240 mL), and the addition was completed in about 1 h. The mixture was continued to stir at −15° C. for 2 h, then saturated NH.sub.4Cl solution (400 mL) was added, followed by ethyl acetate (400 mL), and stirred for another 2 h. The mixture was allowed to stand, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (200 mL*2), brine (200 mL) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was crystallized from isopropanol to give a white solid (27.4 g, Yield: 61.0%).

Example 7 Preparation of Compound III-3

(29) To a 2.0 L three-necked flask with mechanical stirring function was added THF (100 mL) and CuCN (10.6 g, 117.8 mmol). Cooled to −45° C.-50° C., and ethylmagnesium bromide (185 mL, 370.0 mmol) was added dropwise in about 1 hour. After stirring for 1 h, a solution of the compound II-3 (42.2 g) in THF (240 mL) was added dropwise in about 1 h, and kept the temperature at −45° C.-50° C. during the addition. The mixture was warmed to −15° C. and stirred for 2 h. Then saturated NH.sub.4Cl solution (400 mL) was added, followed by ethyl acetate (400 mL), and stirred for another 2 h. The mixture was allowed to stand, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed with water (200 mL*2), brine (200 mL) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was crystallized from isopropanol to give a white solid (23.8 g, Yield: 50.4%).

Example 8 Preparation of Compound III-3

(30) To a 20.0 L reactor with mechanical stirring function was added THF (2.8 L) and CuI (152.4 g, 0.8 mol), and cooled to −45° C.-50° C., then ethylmagnesium bromide (2.0 L, 4.0 mol) was added dropwise in about 1 hour. After stirring for 1 h, a solution of the compound II-3 (400.0 g) in THF (3.2 L) was added dropwise in about 1 h, and kept the temperature at −45° C.-50° C. during the addition. The mixture was warmed to −5° C. and stirred for 2 h. Then saturated NH.sub.4Cl solution (4.0 L) was added, followed by MTBE (4.0 L), and stirred for another 2 h. The mixture was allowed to stand, the organic phase was separated, and the aqueous phase was extracted with MTBE (4.0 L). The combined organic phase was washed with water (2.0 L*2), brine (4.0 L) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was crystallized from EtOH (1.5 L) to give a white solid (293.1 g, Yield: 65.5%).

Example 9 Preparation of Compound IV

(31) To a 100 mL three-necked flask with mechanical stirring was added compound III-2 (2.68 g, 10.0 mmol), magnesium turnings (4.8 g, 200.0 mmol) and methanol (100 mL) under nitrogen atmosphere. The resulting mixture was warmed to 50° C. and stirred for 48 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (100 mL*2). The collected phases were washed with water (100 mL*2) and saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (1.21 g), which was distilled under reduced pressure to give a colorless oil (865 mg, 67.5%).

Example 10 Preparation of Compound IV

(32) To a 100 mL three-necked flask with mechanical stirring was added compound III-3 (2.82 g, 10.0 mmol), magnesium turnings (2.4 g, 100.0 mmol) and methanol (100 mL) under nitrogen atmosphere. The resulting mixture was warmed to 50° C. and stirred for 48 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (100 mL*2). The collected phases were washed with water (100 mL*2) and saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (1.21 g), which was distilled under reduced pressure to give a colorless oil (720 mg, 56.6%).

Example 11 Preparation of Compound IV

(33) To a 100 mL three-necked flask with mechanical stirring was added compound III-3 (2.82 g, 10.0 mmol), magnesium turnings (2.4 g, 100.0 mmol) and DMF (100 mL) under nitrogen atmosphere. The resulting mixture was warmed to 50° C. and stirred for 48 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (100 mL*2). The collected phases were washed with water (100 mL*2) and saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (1.18 g), which was distilled under reduced pressure to give a colorless oil (602 mg, 47.2%).

Example 12 Preparation of Compound IV

(34) To a 100 mL three-necked flask with mechanical stirring was added compound III-3 (2.82 g, 10.0 mmol), magnesium turnings (2.4 g, 100.0 mmol) and DMF (100 mL) under nitrogen atmosphere, then TMSCl (0.2 mL) was added at room temperature. The resulting mixture was warmed to 50° C. and stirred for 24 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (100 mL*2). The collected phases were washed with water (100 mL*2) and saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (1.35 g), which was distilled under reduced pressure to give a colorless oil (845 mg, 66.0%).

Example 13 Preparation of Compound IV

(35) To a 100 mL three-necked flask with mechanical stirring was added compound III-3 (2.82 g, 10.0 mmol), magnesium turnings (2.4 g, 100.0 mmol) and DMF (100 mL) under nitrogen atmosphere, then HCl (6N aq., 0.5 mL) was added at room temperature. The resulting mixture was warmed to 50° C. and stirred for 48 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (100 mL*2). The collected phases were washed with water (100 mL*2) and saturated brine (100 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (1.28 g), which was distilled under reduced pressure to give a colorless oil (751 mg, 58.7%).

Example 14 Preparation of Compound IV

(36) To a 2 L three-necked flask with mechanical stirring was added compound III-3 (56.4 g, 0.2 mol), activated magnesium turnings (48 g, 2.0 mol) and DMF (1.0 L) under nitrogen atmosphere, then HCl (6N aq., 0.5 mL) was added at room temperature. The resulting mixture was warmed to 50° C. and stirred for 48 h, then poured into an aqueous hydrochloric acid solution, and extracted twice with DCM (500 mL*2). The collected phases were washed with water (500 mL*2) and saturated brine (500 mL), dried with anhydrous Na.sub.2SO.sub.4, and filtered. The filtrate was evaporated to dryness in vacuum to give a crude (22.0 g), which was distilled under reduced pressure to give a colorless oil (15.5 g, 60.5%).

(37) Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the present invention should not be limited to the description of the preferred versions described herein. All features disclosed in the specification, including the abstract and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in the specification, including abstract and drawings, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is herein incorporated by reference in its entirety.