CN101066967B - Synthesis process of dibenzo dioxy octanone compound - Google Patents

Abstract

The present invention belongs to the field of medicine synthesis technology, and is especially dibenzo dioxy octanone compound in the structure as shown and its new synthesis process. The compound is cholesterol transferase inhibitor, and may be used in increasing high density lipoprotein cholesterol selectively to treat coronary heart disease and other cardiovascular system diseases. Compared with available technology, the present invention has the advantages of lowered cost, saving in resource, and greatly raised target product yield.

Description

A kind of synthetic method of active dibenzodioxoctanone compound

technical field

The invention belongs to the field of pharmaceutical synthesis, and relates to a dibenzodioxoctanone compound of formula (I) and a new synthesis preparation method.

Background technique

Dibenzodioxoctanones were first isolated from natural products by Sassa T. and named Penicillide (11-hydroxyl-3-[(1S)-1-hydroxyl-3-methylbutyl]-4 -Methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxoctan-5-one (Tetrahedron Letter 1974, 15, 45, 3941-3942).

Through high-throughput activity screening, it was found that dibenzodioxoctanone compounds are a new cholesterol transferase inhibitor (CETP), which can selectively increase high-density lipoprotein cholesterol, and can treat cardiovascular systems such as coronary heart disease disease. Bayer Corporation used Penicillide as a lead substance and cholesterol transferase as a pharmacological model to conduct a systematic study on the structure-activity relationship, and found that compound I has an IC ₅₀ (μM)=0.2, t _1/2 (rat plasma)(h)= 4.2 Excellent efficacy (Bayer patent WO2004039453, Bioorganic & Medicinal Chemistry Letter, 15(2005), 3611-3614).

Contents of the invention

The object of the present invention is to provide a new method for synthesizing the compound of formula (I).

The total yield of Compound I prepared by the method of the present invention is 1.68%, and the total yield of Compound I prepared by the prior art (patent WO2004039453) is 0.12%, and the total yield of the product of the present invention is higher than that of the latter nearly fourteen times.

Compared with the synthetic method about compound I adopted in the prior art (patent WO2004039453), the present invention has the following characteristics: first, the present invention, from the perspective of chemical economy, first carries out the chlorination reaction before the docking of the two fragments , the intermediate compound XII is prepared, compared with the method adopted in the patent WO2004039453, the cost is reduced; second, the present invention uses the method of hydrogenation debenzylation in the process of preparing compound V (VI → V), which improves the Its yield (being 95%) is obviously better than the method (yield is 63%) of ferric chloride debenzylation adopted in the patent WO2004039453; the third, the present invention is in the preparation of intermediate compound III (racemate ) process, the Negeish coupling reaction was used to introduce an ethyl group at the 10-position of its structure, and the reagent used was diethylzinc (1-3 equivalents); the solvent was nitrogen, nitrogen-dimethylformamide ( DMF); Catalyst is tri-o-cresyl phosphine and palladium acetate; Its yield is 40%, is better than the Still coupling reaction (yield is 22%) adopted in the patent WO2004039453; The 4th, the present invention adopts chemical resolution The method prepares the isomer compounds IIIS and IIIR of the absolute configuration of the intermediate compound III, wherein, the S-isomer IIIS is further esterified with the intermediate raw material XVI to obtain the target compound I, and the R-isomer IIIR is further obtained by Oxidation, and then use the method of asymmetric reduction (Corey reduction method) to convert and generate the required S-isomer IIIS, thereby saving resources and improving the yield of the target product.

The inventive method adopts following synthetic route:

Among them, the synthesis method of starting material XV adopts the method adopted in patent WO2004039453, the synthesis method of intermediate raw material XI adopts the method adopted in patent US5198463, and the synthesis method of compound XVI adopts Journal of Organic Chemistry, Vol.44, No. .19, 1979, 2206-2210 the method used.

Description of drawings

Fig. 1 is the sp diagram of target compound (I) single molecule.

Figure 2 is an sp diagram of the hydrogen bond relationship of the target compound (I).

Fig. 3 is the unit cell sp diagram of target compound (I) packing.

Fig. 4 is the chiral separation diagram of compound dl-III.

Figure 5 is a chiral separation diagram of compound III-S.

Figure 6 is a chiral separation diagram of compound III-R.

FIG. 7 is a HPLC purity analysis chart of compound I.

Detailed ways

Example 1

(1) Synthesis of 2-hydroxy-3-benzyloxy-5-methyl-6-chlorobenzoic acid

396 grams (1.52mole) of 2-hydroxy-3-benzyloxy-5-methylbenzoic acid was dissolved in the mixed solution of 2500ml ethanol and 1200ml water, added 301.5 grams (2.27mole) of chlorosuccinimide and 340 grams (2.1 mole) ferric chloride, stirred at room temperature for 3 hours. Then ethanol was removed, dichloromethane was added, the pH of the aqueous phase was adjusted to 1, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the organic phase was recovered to obtain 334 g (75%) of compound XIV as pale yellow needle crystals.

¹ H-NMR (CD ₃ OD): δ: 2.30 (s, 3H); 5.08 (s, 2H); 6.79 (s, 1H); 7.37-7.46 (m, 5H) ppm.

(2) Synthesis of 2-benzyloxy-4-methyl-5-chloro-6-hydroxymethylphenol

280 g (0.96 mole) of compound XIV was dissolved in 1500 ml of dry tetrahydrofuran, cooled to 0°C while stirring, 90 g (2.3 mole) lithium aluminum tetrahydrogen was added in batches, and further refluxed for 1 hour. Slowly add ethyl acetate and water to the reaction solution, adjust the pH to 6 with saturated ammonium chloride, extract twice with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous magnesium sulfate, filter, and recover the organic phase , recrystallized (petroleum ether/ethyl acetate) to obtain 240 g (90%) of compound XIII as white crystals.

¹ H-NMR (CD ₃ Cl): δ: 2.30 (s, 3H); 4.92 (s, 2H); 5.08 (s, 2H); 6.79 (s, 1H); 7.37-7.46 (m, 5H) ppm.

(3) Synthesis of 2-benzyloxy-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl]phenol

175 grams (0.63 mole) of compound XIII and 2 grams of p-toluenesulfonic acid were dissolved in 600 ml of dry dichloromethane, and at 0°C, 45 ml (0.66 mole) of 3,4-dihydropyran was slowly added dropwise to the reaction solution, the reaction was further stirred for 5 hours. 2ml of triethylamine was added to the reaction solution, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, the organic phase was recovered, and recrystallized (petroleum ether/acetone) to obtain 196 g (86%) of compound XII as white crystals. ¹ H-NMR (CD ₃ Cl): δ: 1.70-1.90 (m, 6H); 2.30 (s, 3H); 3.60 (m, 1H); 3.95 (m, 1H); 4.92 (d, 2H); (d, 1H); 5.12 (s, 2H); 6.79 (s, 1H); 7.37-7.46 (m, 5H) ppm.

(4) 6-{2-Benzyloxy-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl]phenoxy}-3-formyl- Methyl 2-methoxybenzoate

Under argon protection, 30.5 grams (112 mmole) of compound XI, 48 grams (133 mmole) of compound XII and 41.6 grams of 4-N, N-lutidine were dissolved in 800 ml of dry acetonitrile, and 18 grams of active Copper powder and 23 grams of copper oxide were reacted for 12 hours under stirring at 80 degrees. The reaction solution was diluted with dichloromethane, filtered, and the organic phase was concentrated in vacuo. The residue was separated and purified by silica gel chromatography, eluent (petroleum ether/ethyl acetate=6:1), to obtain 42 g (68%) of compound X as a pale yellow oil.

¹ H-NMR (CD ₃ Cl): δ: 1.20-1.60 (m, 6H); 2.30 (s, 3H); 3.45 (m, 1H); 3.95 (s, 3H); 3.98 (s, 3H); 4.50 (d, 1H); 4.60(m, 1H); 4.93(d, 1H); 5.02(s, 2H); 6.47(d, 1H); 6.92(s, 1H); 7.37-7.46(m, 5H); 7.73 (d, 1H); 10.22 (s, 1H) ppm.

(5) 6-{2-Benzyloxy-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl]phenoxy}-3-(1- Hydroxy-3,3'-dimethylbutyl)-2-methoxybenzoic acid methyl ester

Suspend 3.46 grams of magnesium powder in 10 ml of dry ether, dissolve 16.7 ml of 1-bromo-2,2-dimethylpropane in 32 ml of dry ether, add dropwise to the above solution under stirring at room temperature, and further react 12 hours; the above-prepared Grignard reagent was slowly added dropwise to a solution of 28 g (51 mmole) of compound X dissolved in 207 ml of dry tetrahydrofuran at -78°C, and the mixture was further stirred for 2 hours. Then slowly add saturated ammonium chloride solution to the reaction solution, extract 3 times with ethyl acetate, combine the organic phases, wash the organic phase with water and brine, dry over anhydrous magnesium sulfate, filter, recover the organic phase, and chromatograph the residue on silica gel Separation and purification, eluent (chloroform/ethyl acetate=50:1), yielded 21 g (65%) of compound IX as a pale yellow oil.

¹ H-NMR (CD ₃ Cl): δ: 1.01 (s, 9H); 1.20-1.70 (m, 8H); 2.02 (s, 1H); 2.37 (s, 3H); 3.45 (m, 1H); 3.86 (s, 3H); 3.92(s, 3H); 4.50(dd, 1H); 4.65(m, 1H); 4.93(dd, 1H); 5.02(s, 2H); 5.08(m, 1H); 6.38( d, 1H); 6.90 (s, 1H); 7.18-7.35 (m, 6H) ppm.

(6) 6-[2-Benzyloxy-4-methyl-5-chloro-6-(hydroxymethyl)phenoxy]-3-(1-hydroxy-3,3'-dimethylbutyl )-Methyl 2-methoxybenzoate

25 g (40 mmole) of compound IX and 44 mg of p-toluenesulfonic acid were dissolved in 170 ml of isopropanol and 44 ml of water, and the reaction solution was refluxed for 5 hours. After finishing the reaction, add water and ethyl acetate, wash the organic phase with brine, dry over anhydrous magnesium sulfate, filter, recover the organic phase, separate and purify the residue by silica gel chromatography, eluent (petroleum ether/ethyl acetate=12:1- 6:1), to obtain 16.3 g (75%) of compound VIII as a colorless oil.

¹ H-NMR (CD ₃ Cl): δ: 1.01(s, 9H); 1.50-1.78(m, 2H); 2.05(s, 1H); 2.38(s, 3H); 3.88(s, 3H); 3.93 (s, 3H); 4.79 (d, 2H); 5.00 (s, 2H); 5.10 (m, 1H); 6.38 (d, 1H); 6.87 (s, 1H); .

(7) 6-[2-Benzyloxy-4-methyl-5-chloro-6-(hydroxymethyl)phenoxy]-3-(1-hydroxy-3,3'-dimethylbutyl )-2-methoxybenzoic acid

38.2 grams (70 mmole) of compound VIII and 83.7 grams of potassium hydroxide were dissolved in 900 ml of methanol, the reaction solution was heated to reflux for 9 hours, cooled to room temperature, added dichloromethane and water, separated the organic phase, the organic phase was washed with brine, without Dry over magnesium sulfate, filter, recover the organic phase, and the residue can be directly used in the next reaction without further purification to obtain 35.3 g (95%) of compound VII as a colorless crystalline powder.

¹ H-NMR (d-DMSO): δ: 0.92 (s, 9H); 1.10-1.50 (m, 2H); 2.31 (s, 3H); 3.81 (s, 3H); 4.39 (s, 2H); 4.90 (m, 1H); 5.09(s, 2H); 6.10(d, 1H); 7.05(d, 1H); 7.20-7.26(m, 6H)ppm.

(8) 11-benzyloxy-3-(1-hydroxy-3,3'-dimethylbutyl)-4-methoxy-8-chloro-9-methyl-5 hydrogen, 7 hydrogen-di Benzo[b,g],[1,5]dioxoctan-5-one

34.3 grams (65 mmole) of compound VII and 48.8 ml of dry triethylamine were dissolved in 600 ml of dry acetonitrile, and the solution prepared above was slowly added dropwise to 49 grams of 2-chloro-iodide at 70 degrees. 1-picoline was dissolved in a solution made of 1600ml of dry acetonitrile, and it took 9 hours under stirring. After the dropwise addition was completed, it was further reacted at this temperature for 8 hours. Then concentrate in vacuo, add dichloromethane, wash the organic phase with water and brine, dry over anhydrous magnesium sulfate, filter, recover the organic phase, separate and purify the residue by silica gel chromatography, eluent (petroleum ether/ethyl acetate=10:1 -3:1), yielding 26.5 g (80%) of compound VI as a colorless oil.

¹ H-NMR (CD ₃ Cl): δ: 1.03 (s, 9H); 1.50-1.78 (m, 2H); 2.30 (s, 3H); 3.99 (s, 3H); 5.18 (m, 1H); 5.20 (s, 2H); 5.45 (d, 2H); 6.90 (d, 1H); 6.93 (s, 1H); 7.32-7.45 (m, 5H); 7.53 (d, 1H) ppm.

(9) 11-hydroxy-3-(1-hydroxy-3,3'-dimethylbutyl)-4-methoxy-8-chloro-9-methyl-5 hydrogen, 7 hydrogen-dibenzo [b,g], [1,5]dioxoctan-5-one

39 g (76 mmole) of compound VI and 13.26 mg of 10% palladium carbon were dissolved in 720 ml of ethyl acetate and 240 ml of ethanol, hydrogen was passed at normal pressure, the spot plate was traced to no raw material, filtered, the filtrate was concentrated in vacuo, and the resulting residue The product was directly used in the next reaction without further purification to obtain 30.3 g (95%) of compound V as a colorless crystalline powder. ¹ H-NMR (CD ₃ Cl): δ: 1.02(s, 9H); 1.54(m, 1H); 1.59(m, 1H); 2.28(s, 3H); 3.96(s, 3H); , 1H); 5.33 (dd, 1H); 5.49 (dd, 1H); 6.78 (d, 1H); 6.93 (s, 1H); 7.55 (d, 1H) ppm. ¹³ C-NMR (CD ₃ Cl): δ: 20.5; 30.1(3C); 30.8; 52.4; 62.3; 65.8; 66.5; 116.9; 118.3; 118.5; 123.3; 124.2; : m/z=419.0(MH) ⁺

(10) 11-hydroxy-3-(1-hydroxy-3,3'-dimethylbutyl)-4-methoxy-8-chloro-9-methyl-10-bromo-5 hydrogen, 7 hydrogen -Dibenzo[b,g],[1,5]dioxoctan-5-one

32 grams (76 mmole) of compound V and 14.98 grams (84 mmole) of bromosuccinimide were dissolved in 1000 ml of ethanol, the reaction solution was stirred at room temperature for 2 hours, the reaction was terminated, ethyl acetate and water were added, and the organic phase was separated , the organic phase was washed with saturated sodium sulfite solution brine, dried over anhydrous magnesium sulfate, filtered, the organic phase was reclaimed, and the residue could be directly used in the next step without purification to obtain 33.3 grams (88%) of compound IV as light yellow-green crystalline powder. ¹ H-NMR (CD ₃ Cl): δ: 1.03 (s, 9H); 1.57-1.61 (m, 2H); 2.51 (s, 3H); 3.98 (s, 3H); 5.18 (dd, 1H); 5.41 (dd, 2H); 6.84(s, 1H); 6.85(d, 1H); 6.95(s, 1H); 7.60(d, 1H)ppm.

(11) 11-hydroxy-3-(1-hydroxy-3,3'-dimethylbutyl)-4-methoxy-8-chloro-9-methyl-10-ethyl-5 hydrogen, 7 Hydrogen-dibenzo[b,g],[1,5]dioxoctan-5-one

Under argon protection, 18 grams (36 mmole) of compound IV, 532 mg of tri-o-cresyl phosphine and 172 mg of palladium acetate were dissolved in dry tetrahydrofuran, and 112 ml of 1M diethylzinc The toluene solution was added to the reaction solution, and the reaction was further performed at this temperature for 3 hours. Quench the reaction with saturated ammonium chloride solution, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phase with brine, dry over anhydrous magnesium sulfate, filter, recover the organic phase, and separate and purify the residue by silica gel chromatography , eluent (petroleum ether/ethyl acetate=8:1-1:1), to obtain 6.4 g (39.7%) of compound dl-III as a colorless crystalline powder.

¹ H-NMR (CD ₃ Cl): δ: 1.03(s, 9H); 1.15(t, 3H); 1.57(m, 1H); 1.61(m, 1H); 1.93(d, 1H); , 3H); 2.77(q, 2H); 3.99(s, 3H); 5.16(m, 1H); 5.37(dd, 1H); 5.48(dd, 1H); 6.26(s, 1H); 1H); 6.95(s, 1H); 7.59(d, 1H) ppm.

¹³ C-NMR (CD ₃ Cl): δ: 13.3; 16.2; 20.7, 30.1 (3C); 30.8; 52.4; 62.3; 65.9; 66.6; 116.9; ; 144.1; 151.1; 154.2; 167.4ppm. HRMS (MALDI/DHB): 471.1550 (M+Na) ⁺ ; C ₂₄ H ₂₉ O ₆ ClNa ⁺¹

(12) 11-Hydroxy-3-[(1s)-Hydroxy-3,3'-dimethylbutyl]-4-methoxy-8-chloro-9-methyl-10-ethyl-5 hydrogen , 7H-dibenzo[b,g], [1,5]dioxoctan-5-one

Compound dl-III was subjected to chiral resolution, and the separation and purification conditions were as follows: chiral column: Chiralpak AD-H; mobile phase: n-hexane/ethanol = 80:20.

Under this separation condition, the fraction collected at 5.13-5.90 minutes is IIIR, and the fraction collected at 7.81-8.84 minutes is IIIS. Please refer to attached drawings 4, 5, and 6 for specific analysis spectra.

(13) 11-{7'-methylbicyclo[2.2.1]heptane-7-formyloxy}-3-[(1s)-hydroxy-3,3'-dimethylbutyl-4 -Methoxy-8-chloro-9-methyl-10-ethyl-5hydro,7hydro-dibenzo[b,g],[1,5]dioxoctan-5-one

Under the protection of argon, 5.2 g (11.6 mmole) of compound IIIS was dissolved in dry tetrahydrofuran, and 351 mg (14.6 mmole) of sodium hydrogen was added at 0°C, and the reaction solution was stirred at room temperature for 1 hour. The prepared compound XVI was dissolved in dry tetrahydrofuran to prepare a solution and added to the above reaction solution at room temperature, and further stirred for 5 hours. After finishing the reaction, add brine and ethyl acetate, wash the organic phase with brine, dry over anhydrous magnesium sulfate, filter, recover the organic phase, separate and purify the residue by silica gel chromatography, eluent (petroleum ether/ethyl acetate=10:1 -6:1), 6.7 g (99.6%) of compound I were obtained as colorless crystals (petroleum ether/ethyl acetate).

¹ H-NMR (CD ₃ Cl): δ: 1.03 (s, 9H); 1.12 (t, 3H); 1.23-2.08 (m, 14H); 2.32 (s, 5H); 2.63 (br., s, 2H) ); 3.98(s, 3H); 5.13-5.19(m, 1H); 5.21-5.60(br., s, 2H); 6.98(d, 1H); 7.59(d, 1H)ppm.

¹³ C-NMR (CD ₃ Cl): δ: 13.5; 16.3; 17.3; 21.6; 27.9 (2C); 29.4; 29.7; 30.1 (3C); 30.8; 42.2 (2C); ;117.8;119.2;123.0;130.9;131.1;131.3;138.2;138.3;139.4;147.7;151.4;154.2;167.2;175.2ppm.

MS-ESI: 607.2 (M ⁺ +Na), 567.3 (M ⁺ -OH).

MP: 177-179°C.

[α] _D ²⁰ =+2.626° (c=1.0, CHCl ₃ )

See accompanying drawing 7 for HPLC purity analysis.

X-ray diffraction determination of compound I

，b＝7.3221(9)

，c＝15.0743(18)

，V＝1601.5(3)

³，Z＝2，D_calc＝1.213mg/cm³，λ＝0.71073

，μ＝0.164mm^-1，F(000)＝624，T＝293(2)K.收集衍射点数为8856，独立衍射点数5761，优化方法基于F²，全矩阵最小二乘法，衍射区为-30≤h≤30，-30≤k≤30，-12≤k≤12，最后修正值R(4σ_F)为0.0672，R(al1)为0.1022 GOF(all)为0.915。在一个晶包有二个分子，具有相同的构型，彼此间以不同的氢键相连。Cultivated in petroleum ether/ethyl acetate mixed solvent for 2 weeks, the crystal system is monoclinic, the crystal size is 0.497mm×0.436mm×0.158mm, the space group is P2(1), and the crystal packet parameter is a=14.7275( 18)

, b=7.3221(9)

, c=15.0743(18)

, V=1601.5(3)

³ , Z=2, D _calc =1.213 mg/cm ³ , λ=0.71073

, μ=0.164mm ^-1 , F(000)=624, T=293(2)K. The number of collected diffraction points is 8856, and the number of independent diffraction points is 5761. The optimization method is based on F ² , full matrix least square method, and the diffraction area is - 30≤h≤30, -30≤k≤30, -12≤k≤12, the final correction value R(4σ _F ) is 0.0672, R(al1) is 0.1022 and GOF(all) is 0.915. In a crystal packet there are two molecules, with the same configuration, connected to each other by different hydrogen bonds.

Example 2

(1) 11-Hydroxy-3-(3,3'-dimethylbutyryl)-4-methoxy-8-chloro-9-methyl-10-ethyl-5hydrogen, 7hydrogen-diphenyl And[b,g],[1,5]dioxoctan-5-one

The compound IIIR of 3.68 grams (8.2mmole), the pyridinium chromate hydrochloride of 3.05 grams (17mmole) and the aluminum oxide of 1.74 grams (17mmole) are dissolved in the dichloromethane of 15ml, and the reaction solution is further stirred at room temperature for 5 hours . Filtration, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, the organic phase was recovered, the residue was separated and purified by silica gel chromatography, eluent (petroleum ether/ethyl acetate=12:1), and 3.1 g (85% ) Compound II is a colorless crystalline powder.

¹ H-NMR (CD ₃ Cl): δ: 1.03(s, 9H); 1.15(t, 3H); 2.32(s, 3H); 2.80(q, 2H); 2.90(s, 2H); 3.97(s , 3H); 5.44(s, 2H); 6.26(m, 1H); 6.86(d, 1H); 7.60(d, 1H)ppm.

(2) 11-Hydroxy-3-[(1s)-Hydroxy-3,3'-dimethylbutyl]-4-methoxy-8-chloro-9-methyl-10-ethyl-5 hydrogen , 7H-dibenzo[b,g], [1,5]dioxoctan-5-one

207 mg of diphenyl ((R)-pyrroline-2-yl) methanol and 8 ml of 1M borane tetrahydrofuran solution were dissolved in 30 ml of dry tetrahydrofuran, the reaction solution was heated to reflux for 0.5 hour, cooled to room temperature, and 2.3 g (5 mmole) of compound II was added to the reaction solution, further stirred for 4 hours, quenched with water, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, the organic phase was recovered, and the residue was separated and purified by silica gel chromatography , eluent (petroleum ether/ethyl acetate=8:1-3:1), to obtain 2.18 g (95%) of a mixture of compounds IIIR and IIIS as a colorless crystalline powder. The content of compound IIIS is 75.537%, and the content of compound IIIR is 24.463%; ee: 50.4%.

Claims (3)

1. the synthetic method that has the dibenzo dioxy octanone compound of active structures formula (I),

It is characterized in that synthetic route is as follows:

In the described synthetic route, the chlorinating agent that preparation compound X IV adopts is a chlorosuccinimide, and consumption is the 1-3 equivalent, and solvent is an ethanol/water, and ratio is 0-100%, and the reaction times is 1-5 hour, and temperature of reaction is the 0-80 degree;

The reaction solvent that preparation compound VIII adopts is a Virahol;

In the preparation compound V process, the method that reaction adopts hydrogenation to take off benzyl, solvent adopts ethanol/ethyl acetate, and ratio is 30-90%, and the catalysis of palladium carbon is catalyzer;

In the preparation compound d l-III process, adopt the Negishi reaction, reaction reagent is a zinc ethyl, and 1-3 equivalent, solvent are tetrahydrofuran (THF) or nitrogen, nitrogen-dimethyl formamide; Catalyzer is the tri-o-tolyl phosphine, palladium; Temperature of reaction is the 20-120 degree; Reaction times is 1-10 hour.

2. by the described synthetic method of claim 1, it is characterized in that the compound d l-III chiral separation that relates to, the chiral separation condition is a column type: Chiralpak AD-H, mobile phase: normal hexane/ethanol=80: 20; Under this separation condition, the composition that compound d l-III was collected at 5.13-5.90 minute is III R, and the composition of collecting at 7.81-8.84 minute is III S.

3. by the described synthetic method of claim 1, it is characterized in that the compound ii that relates to adopts the method for asymmetric reduction, the chiral environment that utilization phenylbenzene ((R)-pyrroline-2-yl) methyl alcohol and borine tetrahydrofuran solution form is carried out asymmetric reduction to compound ii, obtain compound III S, yield is 95%, ee:50.4%.

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