Preparation method of paroxetine intermediate

Abstract

The invention relates to a preparation method of a paroxetine main intermediate as shown in a formula I. The preparation method comprises the following steps: by taking p-fluoroacetophenone as a raw material, obtaining a 1-(4-fluorophenyl)-3-methylamino-1-acetone hydrochloride intermediate as shown in a formula II in one step; generating a 1-(4-fluorophenyl)-3-methylamino-1-propanol intermediate shown in a formula III from the intermediate shown in the formula II under the condition of a transition metal ruthenium-chiral ligand complex catalyst; reacting the intermediate shown in the formula III with malonic acid monoester at room temperature to obtain an amide intermediate shown in the formula IV; reacting the intermediate formula IV with various chlorophosphodiesters at room temperature to obtain an intermediate formula V; generating an intermediate VI from the intermediate V under an alkaline condition; and generating the paroxetine main intermediate shown in the formula I from the intermediate shown in the formula VI under the action of reducing agents such as lithium aluminum hydride. The process has the characteristics of relatively high yield, simple process, environmental friendliness and the like, and has a relatively good industrial application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for preparing the main intermediate of paroxetine (Formula VII), (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine (Formula I). ​​The process has the characteristics of high yield, simple process, environmental friendliness, etc., and has good industrial application prospects.

[0002] Background Art

[0003] Paroxetine, scientific name paroxetine, is a phenylpiperidine compound developed by GlaxoSmithKline and launched in 1991. It has a highly selective 5-HT reuptake blocking effect. Its antidepressant effect is similar to that of tricyclic antidepressants (TCAs), but its side effects are significantly smaller than those of tricyclic antidepressants (TCAs). It belongs to the third generation of antidepressants. Its main intermediate is (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The method used in the prior art to synthesize the above intermediate is mainly chemical splitting, which will waste precursor raw materials and lead to serious waste of energy and resources. Summary of the invention

[0004] The present invention overcomes the serious problems of energy consumption and resource waste caused by traditional chemical splitting. The present invention provides a method for preparing the main intermediate of paroxetine (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The present invention uses p-fluoroacetophenone as a raw material, and obtains 1-(4-fluorophenyl)-3-methylamino-1-acetone hydrochloride intermediate formula II in one step; intermediate formula II generates 1-(4-fluorophenyl)-3-methylamino-1-propanol intermediate formula III under transition metal ruthenium-chiral ligand complex catalyst conditions; intermediate formula III reacts to obtain amide intermediate formula IV; intermediate formula IV reacts with various chlorophosphate diesters at room temperature to obtain intermediate formula V; intermediate formula V generates intermediate formula VI under alkaline conditions; intermediate formula VI generates formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine under the action of a reducing agent such as lithium aluminum hydride. This process has the characteristics of high yield, simple process, and environmental friendliness. It has good prospects for industrial application and also has advantages in raw material utilization.

[0005]

[0006] Firstly, the present invention provides a method for obtaining 1-(4-fluorophenyl)-3-methylamino-1-propanone hydrochloride intermediate formula II in one step by using p-fluoroacetophenone as a raw material.

[0007]

[0008] Secondly, the present invention provides an intermediate of formula II for generating 1-(4-fluorophenyl)-3-methylamino-1-propanol intermediate of formula III under the conditions of transition metal ruthenium-chiral ligand complex catalyst.

[0009]

[0010] Furthermore, the present invention provides an intermediate of formula III which is subjected to different reactions to obtain an amide intermediate of formula IV;

[0011]

[0012] Then, the present invention provides the reaction of the intermediate IV with various chlorophosphate diesters at room temperature to obtain the intermediate V;

[0013]

[0014] Afterwards, the present invention provides the intermediate formula V to generate the intermediate formula VI under alkaline conditions;

[0015]

[0016] Finally, the present invention provides an intermediate of formula VI which is subjected to the action of a reducing agent such as lithium aluminum hydride to reduce the ester group and the amide to generate formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine.

[0017]

[0018] Among them, R 1 C 1 ~C 4 Alkyl, preferably methyl or ethyl; R 2 C 1 ~C 4 The alkyl group is preferably a methyl group or an ethyl group. DETAILED DESCRIPTION

[0019] The invention provides a method for preparing a main intermediate of paroxetine, (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, which is prepared according to the following synthetic route.

[0020]

[0021] The synthesis method of formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine comprises the following steps:

[0022] (1) In a specific embodiment, p-fluoroacetophenone is used as a raw material and an intermediate of formula II is obtained by a one-step Mannich reaction.

[0023]

[0024] The molar ratio of p-fluoroacetophenone, paraformaldehyde and methylamine hydrochloride is 1.0:(1.0-1.5):(1.0-2.0), and the acid can be selected from concentrated hydrochloric acid and p-toluenesulfonic acid.

[0025] (2) Under acidic conditions, the intermediate II is treated with a transition metal ruthenium-chiral ligand complex catalyst to generate a chiral amino alcohol intermediate III.

[0026]

[0027] The preferred chiral transition metal-chiral ligand catalyst has the general formula [M(L)(N * )]X, wherein M is Rh, Ru, Ir or Fe; L is 1,5-cyclooctadiene or 2,5-norbornadiene; N * is a chiral ligand compound, such as ScRp-DuanPhos, RcSp-DuanPhos, SSRR-TangPhos, RRSS-TangPhos, (S)-Segphos, (S,S)-Ts-DPEN, (S)-BINAP, (R)-BINAP, (S)-DM-Segphos, (R)-DM-Segphos, (S)-MeO-BIPHEP, (S,S)-Ts-DPEN, (S,S)-Me-Duphos, (S,S)-teth-TsDPEN; X is BF 4 , ClO 4 , SbF 6 , PF 6 , C.F. 3 SO 3 , RCOO or a mixture thereof;

[0028] In a preferred embodiment, M is Rh, Ru, Ir or Fe; L is 1,5-cyclooctadiene or 2,5-norbornadiene; N * (S)-Segphos, (S,S)-Ts-DPEN, (S)-BINAP, (S)-DM-Segphos, (S)-MeO-BIPHEP, (S,S)-Ts-DPEN, (S,S)-Me-Duphos, (S,S)-teth-TsDPEN;

[0029] In at least one specific embodiment of this step, the hydrogen pressure may be between 10 and 50 bar;

[0030] The reaction medium of the conversion is selected from one or more of dichloromethane, methanol, tetrahydrofuran, toluene, isopropanol and ethyl acetate; preferably methanol, isopropanol or tetrahydrofuran; further preferably methanol. The suitable reaction temperature for the intermediate II to generate the intermediate III is 10-100°C, preferably 20-80°C.

[0031] (3) The intermediate III is reacted to obtain the amide intermediate IV.

[0032] Method 1: The intermediate III reacts with malonic acid monoester under the action of a condensing agent to generate the intermediate IV;

[0033]

[0034] R 1 =Me,Et

[0035] Among them, the malonate monoester is preferably monomethyl malonate or monoethyl malonate, the molar ratio of the intermediate formula III, the malonate monoester, the condensing agent, and the base is 1.0:(1.0-2.0):(1.0-2.0):(1.0-2.0), the condensing agent can be selected from DCC, EDCI, HATU, preferably EDCI, the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine or pyridine, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether, and toluene.

[0036] Method 2: Intermediate III is reacted with malonate chloride under alkaline conditions at room temperature to generate intermediate IV;

[0037]

[0038] R 1 =Me,Et

[0039] Among them, the malonate chloride is preferably methyl malonate chloride or ethyl malonate chloride, the molar ratio of the intermediate formula III, malonate chloride, and base is 1.0:(1.0-2.0):(1.0-2.0), the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether, and toluene.

[0040] Method 3: Intermediate Formula III reacts with active ester to generate intermediate Formula IV;

[0041]

[0042] R 1 =Me,Et;R 3 =Et,i-Bu

[0043] Among them, the malonate monoester is preferably monomethyl malonate or monoethyl malonate, the molar ratio of the intermediate formula III, the malonate monoester, the acyl chloride and the base is 1.0:(1.0-1.5):(1.0-1.5):(1.0-2.0), the acyl chloride is preferably ethyl chloroformate or isobutyl chloroformate, the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine or N-methylmorpholine, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate and toluene.

[0044] (4) Under alkaline conditions, the intermediate IV reacts with chlorophosphate diester at room temperature to generate the intermediate V.

[0045]

[0046] R 1 =Me,Et;R 2 =Me,Et

[0047] The base can be selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), N-methylimidazole, 4-dimethylaminopyridine (DMAP), N-methylmorpholine, pyridine, etc., preferably N-methylimidazole, the chlorophosphate diester can be selected from dimethyl chlorophosphate and diethyl chlorophosphate, preferably diethyl chlorophosphate, the molar ratio of the intermediate formula IV, the chlorophosphate diester and the base is 1.0:(1.5-2.5):(1.0-2.0), and the solvent can be selected from dichloromethane, tetrahydrofuran, dichloroethane, acetonitrile, toluene, preferably dichloromethane.

[0048] (5) Under alkaline conditions, the intermediate V undergoes intramolecular cyclization to generate the intermediate VI.

[0049]

[0050] R 1 =Me,Et

[0051] The base can be selected from sodium hydride, potassium carbonate, potassium tert-butoxide, cesium carbonate, LDA, etc., preferably cesium carbonate, the molar ratio of the intermediate formula V to the base is 1.0: (1.0-2.0), the solvent can be selected from toluene, dioxane, acetone, acetonitrile, DMF, DMSO, preferably dioxane, and the reaction temperature is 30-100°C, preferably 40-60°C.

[0052] (6) In a specific embodiment, the intermediate of formula VI is reduced to the ester group and the amide under the action of a reducing agent such as lithium aluminum hydride to generate formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine.

[0053]

[0054] The molar ratio of the intermediate IV to the reducing agent is 1.0:(2.0-3.0), the reducing agent can be selected from lithium aluminum hydride, sodium borohydride, potassium borohydride, etc., and the reaction medium can be selected from tetrahydrofuran, toluene, methanol, tert-butanol, preferably tetrahydrofuran.

[0055] Example 1: Preparation of 1-(4-fluorophenyl)-3-methylamino-1-propanone hydrochloride intermediate Formula II

[0056]

[0057] Add 4.2g of paraformaldehyde, 8.16g of methylamine hydrochloride, 13.8g of p-fluoroacetophenone, 0.5mL of concentrated hydrochloric acid to a 100mL pressure tube equipped with a stirrer, add 50mL of ethanol, heat to 110°C, and react for 14h. After the reaction is completed, the reaction solution is cooled to room temperature. Add ethyl acetate and stir, the product precipitates, filter and wash with ethyl acetate to obtain 13.7g of white solid, with a yield of 63%.

[0058] 1 HNMR (400MHz, CDCl 3 ): δ9.58(s,2H),8.00-7.96(m,2H),7.12-7.08(m,2H),3.64(t,J=6.9Hz,2H),3.41-3.38(m,2H),2.76(t,J=5.5Hz,3H).

[0059] 13 CNMR (100MHz, CDCl 3 ):δ195.19,166.27(d,J C-F =256.2Hz),132.24(d,J C-F =2.7Hz),131.10(d,J C-F =9.5Hz),116.11(d,J C-F =22.0Hz),44.74,34.84,33.70.

[0060] MS (ESI) m / z calcd for C 10 H 13 FNO[M-Cl] + 182.1,Found:182.1.

[0061] Example 2: Preparation of Intermediate Formula III

[0062]

[0063] Add 218mg (1mmol) of intermediate II, 158mg formic acid, 101mg triethylamine, 10mL methanol and 1mol% RuCl[(s,s)-teth-TsDPEN] to the autoclave, hydrogenate the autoclave to 45bar, heat to 45℃, and react for 20h. After the reaction, remove the solvent under reduced pressure, add 2mL hydrochloric acid (concentration 1.0M), extract the reaction solution with 9mL dichloromethane three times (9mL×3), discard the organic phase, add saturated sodium bicarbonate solution to adjust the pH to 8-10, extract with 15mL dichloromethane three times (15mL×3), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain 174mg of white solid product. By comparing with the racemate, HPLC analysis was performed on chiral OD-H column and E1 column, ee=95%.

[0064] 1 HNMR (400MHz, CDCl 3 ): δ7.34-7.31(m,2H),7.03-6.98(m,2H),4.91(dd,J=3.1,8.8Hz,1H),2.92-2.81(m,2H),2.44(s,3H),1.86-1.67(m,2H).

[0065] 13 CNMR (100MHz, CDCl 3 ):δ161.99(d,J C-F =243.9Hz),141.07(d,J C-F =3.1Hz),127.30(d,J C-F =8.0Hz),115.08(d,J C-F =21.2Hz),75.32,50.66,37.06,36.18.

[0066] MS (ESI) m / z calcd for C 10 H 15 FNO[M+H] + 184.1,Found:184.1.

[0067] Example 3: Preparation of Intermediate Formula IV

[0068] Method 1: Preparation of intermediate formula IV

[0069]

[0070] In a 250mL two-necked flask equipped with a stirrer, add 4.58g of intermediate formula III, 7.19g of EDCI, 5.06g of HOBt, under argon protection, add 50mL of anhydrous dichloromethane, take 4.43g of monomethyl malonate and drop it into the reaction solution, take 5.05g of triethylamine and slowly drop it into the reaction system, and react overnight at room temperature. After the reaction is completed, add 50mL of saturated sodium bicarbonate solution, extract the reaction solution with 150mL of dichloromethane three times (150mL×3), wash it with 1.0M hydrochloric acid solution and saturated brine once each, dry it with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain a colorless liquid, which is directly used in the next step without further purification.

[0071] Method 2: Preparation of intermediate formula IV

[0072]

[0073] Add 4.58g of intermediate III to a 250mL two-necked flask equipped with a stirrer, add 50mL of anhydrous dichloromethane under argon protection, take 5.05g of triethylamine and drop it into the reaction solution, stir at 0℃, take another 5.12g of methyl malonate chloride and slowly drop it into the reaction system, stir at 0℃ for 1h, and slowly warm to room temperature overnight. After the reaction is completed, add 50mL of saturated sodium bicarbonate solution, extract the reaction solution with 150mL of dichloromethane three times (150mL×3), wash it with 1.0M hydrochloric acid solution and saturated brine once each, dry it with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain a colorless liquid, which is directly used in the next step without further purification.

[0074] Method 3: Preparation of intermediate formula IV

[0075]

[0076] Add 4.43g of monomethyl malonate and 5.05g of N-methylmorpholine to a 250mL two-necked flask equipped with a stirrer, and add 50mL of anhydrous dichloromethane under argon protection. Stir at 0°C, take 4.07g of ethyl chloroformate and slowly drop it into the reaction solution. Stir at 0°C for 30min and then warm to room temperature for reaction. After the reaction is completed, take 4.58g of intermediate formula III, add 25mL of anhydrous dichloromethane to dissolve, and slowly drop it into the reaction solution. React overnight at room temperature. After the reaction is completed, add 75mL of saturated sodium bicarbonate solution, extract the reaction solution with 150mL of dichloromethane three times (150mL×3), wash it with 1.0M hydrochloric acid solution and saturated brine once each, dry it with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a colorless liquid, which is directly used in the next step without further purification.

[0077] Example 4: Preparation of Intermediate Formula V

[0078]

[0079] The intermediate IV obtained in Example 3 was added to a 250 mL two-necked flask equipped with a stirrer, and 4.11 g of N-methylimidazole was added. Under argon protection, 50 mL of anhydrous dichloromethane was added, and 8.63 g of diethyl chlorophosphate was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, 75 mL of 1.0 M hydrochloric acid solution was added, and the reaction solution was extracted three times with 150 mL of dichloromethane (150 mL × 3), washed once with 1.0 M hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a colorless liquid, which was directly used in the next step without further purification.

[0080] 1 HNMR (400MHz, CDCl 3 ): δ7.35-7.29(m,2H),7.06-6.98(m,2H),5.27-5.21(m,1H),4.09-3.76(m,4H),3.69(s,3H) ,3.51-3.23(m,4H),2.95(s,3H),2.24-2.11(m,2H),1.25-1.16,(m,3H),1.13-1.08(m,3H).

[0081] 13 CNMR (100MHz, CDCl 3 ): δ168.07,165.93,162.73,135.55,128.21,115.66,77.86,63.93,52.52,45.96,41.03,35.17,34.97,16.03.

[0082] MS (ESI) m / z calcd for C 18 H 28 FWf 7 P[M+Na] + 442.1,Found:442.1.

[0083] Example 5: Preparation of Intermediate Formula VI

[0084]

[0085] The intermediate formula V obtained in Example 4 was added to a 250 mL two-necked flask equipped with a stirrer, 12 g of cesium carbonate was added, argon was protected, 100 mL of dioxane was added, and the temperature was raised to 50 ° C for overnight reaction. After the reaction was completed, it was cooled to room temperature, 100 mL of 1.0 M hydrochloric acid solution was added, and the reaction solution was extracted three times with 150 mL of dichloromethane (150 mL×3), washed once with 1.0 M hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a thick solid, which was pulped to obtain 3.5 g of a white solid, and the three-step yield was 53%.

[0086] 1 HNMR (400MHz, CDCl 3 ): δ7.16-7.12(m,2H),7.01-6.96(m,2H),3.58(s,3H),3.53-3.30(m,4H),2.98(s,3H),2.08-2.02(m,2H).

[0087] 13 CNMR (100MHz, CDCl 3 ): δ170.54,165.64,162.03(d,J C-F =245.6Hz),137.24(d,J C-F =3.1Hz),128.43(d,J C-F =8.0Hz),115.85(d,J C-F =21.4Hz),56.65,52.42,49.02,41.98,34.94,29.51.

[0088] MS (ESI) m / z calcd for C 14 H 17 FNO 3 [M+H] + 266.1,Found:266.1.

[0089] Example 6: Preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine

[0090]

[0091] Add 850 mg of lithium aluminum hydride to a 100 mL bottle equipped with a stirrer, protect with argon, add 10 mL of anhydrous tetrahydrofuran, stir at 0 ° C, take 2.65 g of intermediate formula VI, dissolve in 10 mL of anhydrous tetrahydrofuran, slowly drop into the reaction system, react at 0 ° C for 30 min, then slowly warm to room temperature, and react at room temperature for 3 h. After the reaction is completed, slowly drop ethyl acetate until the reaction solution no longer emits bubbles, add 10 mL of water, extract the reaction solution with 45 mL of ethyl acetate three times (45 mL × 3), wash once with saturated brine, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain a crude product, which is recrystallized from toluene / n-hexane to obtain 1.56 g of a white solid with a yield of 70%.

[0092] 1 HNMR (400MHz, CDCl 3 ): δ7.16-7.12(m,2H),6.98-6.94(m,2H),3.38-3.34(m,1H),3.23-3.14(m, 2H),2.94-2.92(m,1H),2.31(s,3H),2.27-2.23(m,1H),2.06-1.74(m,5H).

[0093] 13 CNMR (100MHz, CDCl 3 ):δ161.64(d,J C-F =244.2Hz),139.92(d,J C-F =3.0Hz),128.93(d,J C-F =7.7Hz),115.54(d,J C-F =21.1Hz),63.63,59.61,56.27,46.46,44.38,43.78,34.34.

[0094] MS (ESI) m / z calcd for C 13 H 19 FNO[M+H] + 224.1,Found:224.1.

[0095] The invention describes in detail a preparation method of a main intermediate of paroxetine (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The preparation method has the characteristics of easy availability of raw materials, simple process, convenient operation, high yield, low cost, etc., has potential industrial value, and is in line with the development direction of green chemistry.

[0096] Although the present invention discloses the relevant preferred specific embodiments and methods of use, it should be understood that any replacement, modification and change of the technical solution of the present invention that does not violate the present invention is feasible. Therefore, all the above-mentioned feasible replacements, modifications and changes of the technical solution of the present invention that may be foreseen by those skilled in the art fall within the protection scope of the present invention.

Claims

1. A method for synthesizing (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine as shown in Formula I, It is characterized in that The following steps are involved: (1) Using 4-fluoroacetophenone as the raw material, an amine methylation reaction is performed to obtain the intermediate 1-(4-fluorophenyl)-3-methylamino-1-propanone hydrochloride of formula II; (2) the intermediate of formula II is reacted with a transition metal-chiral ligand complex catalyst to generate the intermediate of formula III, 1-(4-fluorophenyl)-3-methylamino-1-propanol; (3) the intermediate of formula III is subjected to amidation reaction to obtain the amide intermediate of formula IV; (4) reacting the intermediate of formula IV with a chlorophosphate diester compound to obtain the intermediate of formula V; (5) the intermediate of formula V is reacted under alkaline conditions to generate the intermediate of formula VI; (6) The intermediate of formula VI is reduced to the ester group and the amide group in the presence of a reducing agent to generate (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine of formula I; Among them, R 1 is a C1-C4 alkyl group; R 2 It is a C1~C4 alkyl group.

2. The synthesis method according to claim 1, wherein: In step (1), p-fluoroacetophenone, paraformaldehyde and methylamine hydrochloride are subjected to the aminomethylation reaction in an acid and alcohol solvent; The ratio of p-fluoroacetophenone, paraformaldehyde and methylamine hydrochloride is 1.0:(1.0-1.5):(1.0-2.0); the selected acid can be hydrochloric acid, p-toluenesulfonic acid, etc., preferably hydrochloric acid; the selected alcohol solvent is methanol or ethanol, preferably ethanol.

3. The synthesis method according to claim 1, wherein: In step (2), the intermediate of formula II is reacted with a transition metal-chiral ligand complex catalyst, acidic conditions and hydrogen pressure to generate 1-(4-fluorophenyl)-3-methylamino-1-propanol intermediate of formula III. The general formula of the transition metal-chiral ligand complex catalyst is: [M(L)(N * )]X, wherein M is Rh, Ru, Ir or Fe; L = 1,5-cyclooctadiene or 2,5-norbornadiene; the N * Chiral ligand compounds include ScRp-DuanPhos, RcSp-DuanPhos, SSRR-TangPhos, RRSS-TangPhos, (S)-Segphos, (S,S)-Ts-DPEN, (S)-BINAP, (R)-BINAP, (S)-DM-Segphos, (R)-DM-Segphos, (S)-MeO-BIPHEP, (S,S)-Ts-DPEN, (S,S)-Me-Duphos, (S,S)-teth-TsDPEN; The acidic conditions are formed by adding formic acid and triethylamine, with a molar ratio of formic acid:triethylamine = 5:(1-2); The reaction temperature is 10-100°C; The reaction medium of step (2) is dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent thereof.

4. The synthesis method according to claim 3, wherein: The catalyst includes RuBr2[(s)-segphos], Ru(p-cymene)[(s,s)-Ts-DPEN], Ru(COD)[(s)-segphos], Ru(Oac)2[(s)-(Binap)], (s,s)-TsDENEB, [RuCl(p-cymene)((s)-binap)]Cl, RuCl2[(R)-DM-Binap][(R)-DAIPEN], Rh(COD)[(s,s)-Me-Duphos], RuCl[(s,s)-teth-TsDPEN].

5. The synthesis method according to claim 3, wherein: The reaction temperature is 20-80°C.

6. The synthesis method according to claim 3, wherein: The hydrogen pressure is 10 to 50 bar.

7. The synthesis method according to claim 1, wherein: The synthesis method of the amide intermediate of formula IV is divided into method one, method two or method three: method one, the intermediate of formula III reacts with a malonic acid monoester under the action of a condensing agent and a base at room temperature to generate the intermediate of formula IV; method two, the intermediate of formula III reacts with a malonic acid ester chloride under alkaline conditions at room temperature to generate the intermediate of formula IV; method three, the intermediate of formula III reacts with an active ester under the action of a base to generate the intermediate of formula IV.

8. The synthesis method according to claim 7, wherein: In method 1, the molar ratio of the intermediate of formula III, malonate monoester, condensing agent, and base is 1.0:(1.0-2.0):(1.0-2.0):(1.0-2.0), the condensing agent is selected from DCC, EDCI, HATU, preferably EDCI; the malonate monoester is preferably monomethyl malonate or monoethyl malonate, and the base is selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine; the reaction is carried out in a solvent, and the solvent is selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether, and toluene.

9. The synthesis method according to claim 7, wherein: In method 2, the molar ratio of the intermediate of formula III, malonate chloride, and base is 1.0:(1.0-2.0):(1.0-2.0), the malonate chloride is preferably methyl malonate chloride or ethyl malonate chloride, and the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, and N-methylmorpholine; the reaction is carried out in a solvent, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, diethyl ether, and toluene.

10. The synthesis method according to claim 7, wherein: In method three, the molar ratio of the intermediate of formula III, malonate monoester, acyl chloride, and base is 1.0:(1.0-1.5):(1.0-1.5):(1.0-2.0), the malonate monoester is monomethyl malonate or monoethyl malonate, the acyl chloride is selected from ethyl chloroformate or isobutyl chloroformate, and the base is selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine or N-methylmorpholine; the reaction is carried out in a solvent, and the solvent is selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, and toluene.

11. The synthesis method according to claim 1, wherein: In step (4), the molar ratio of the intermediate of formula IV to the chlorophosphate diester compound is 1.0:(1.0-1.5), and the reaction is carried out in a solvent, which can be selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, and toluene; The reaction temperature is room temperature.

12. The synthesis method according to claim 1, wherein: In step (5), the molar ratio of the intermediate of formula V to the base is 1.0:(1.5-2.0); the reaction is carried out in a solvent, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, toluene, acetone, and dioxane, and the base is selected from one or more of sodium hydride, cesium carbonate, potassium tert-butoxide, sodium methoxide, and LDA.

13. The synthesis method according to claim 12, wherein: In step (5), the reaction temperature is 20-100°C.

14. The synthesis method according to claim 1, wherein: In step (6), the molar ratio of the intermediate of formula VI to the reducing agent is 1.0:(2.0-3.0); the reaction is carried out in a solvent, which can be selected from tetrahydrofuran, toluene, methanol, and tert-butanol, and the reducing agent is selected from one or more of lithium aluminum hydride, sodium borohydride, and potassium borohydride.

Images