Preparation method of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine

Abstract

The invention relates to a preparation method of a paroxetine main intermediate as shown in a formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The preparation method comprises the following steps: by taking methyl p-fluorobenzoylacetate as a raw material, carrying out asymmetric hydrogenation to obtain an intermediate shown in a formula II; reacting the intermediate shown in the formula II with sodium methoxide and methylamine hydrochloride to obtain an intermediate shown in a formula III; generating an intermediate IV from the intermediate III under the action of reducing agents such as lithium aluminum hydride; reacting the intermediate shown in the formula IV with malonic acid monoester at room temperature to obtain an amide intermediate shown in the formula V; reacting the intermediate formula V with various chlorophosphodiesters at room temperature to obtain an intermediate formula VI; generating an intermediate formula VII from the intermediate formula VI under an alkaline condition; the intermediate formula VII generates a formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine 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 methyl p-fluorobenzoyl acetate as a raw material, and obtains intermediate formula II through asymmetric hydrogenation; intermediate formula II reacts with trimethylaluminum and methylamine hydrochloride to obtain intermediate formula III; intermediate formula III generates intermediate formula IV under the action of a reducing agent such as lithium aluminum hydride; intermediate formula IV reacts to obtain amide intermediate formula V; intermediate formula V reacts with various chlorophosphate diesters at room temperature to obtain intermediate formula VI; intermediate formula VI generates intermediate formula VII under alkaline conditions; intermediate formula VII 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] First, the present invention provides a method of using methyl p-fluorobenzoyl acetate as a raw material and obtaining an intermediate of formula II through asymmetric hydrogenation;

[0007]

[0008] Then, the present invention provides the reaction of the intermediate formula II with sodium methoxide and methylamine hydrochloride to obtain the intermediate formula III;

[0009]

[0010] Secondly, the present invention provides an intermediate of formula III which is reduced to an amino alcohol intermediate of formula IV under the action of a reducing agent such as lithium aluminum hydride;

[0011]

[0012] Next, the present invention provides an intermediate of formula IV which is subjected to different reactions to obtain an amide intermediate of formula V;

[0013]

[0014] Where R 1 is methyl or ethyl;

[0015] Again, the present invention provides the reaction of the intermediate formula V with various chlorophosphate diesters at room temperature to obtain the intermediate formula VI;

[0016]

[0017] Where R 1 As mentioned above, R 2 is methyl or ethyl;

[0018] Then, the present invention provides the intermediate formula VI to generate the intermediate formula VII under alkaline conditions;

[0019]

[0020] Where R 1 As mentioned above;

[0021] Finally, the present invention provides an intermediate of formula VII 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.

[0022]

[0023] DETAILED DESCRIPTION

[0024] 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.

[0025]

[0026] The synthesis method of formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine comprises the following steps:

[0027] (1) Using methyl p-fluorobenzoyl acetate as the starting material, an intermediate of formula II is obtained by asymmetric hydrogenation reaction.

[0028]

[0029] 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 BF4, ClO4, SbF6, PF6, CF3SO3, RCOO or a mixture thereof;

[0030] 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;

[0031] In at least one specific embodiment of this step, the hydrogen pressure may be between 5 and 50 bar;

[0032] The reaction medium of the conversion is selected from one or more of dichloromethane, methanol, tetrahydrofuran, toluene, isopropanol and ethyl acetate; preferably methanol, dichloromethane 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.

[0033] (2) The intermediate II is reacted with sodium methoxide and methylamine to obtain the intermediate III.

[0034]

[0035] Among them, the molar ratio of intermediate formula II, methylamine hydrochloride and sodium methoxide is 1.0:2.0:(2.0-7.0), and the reaction medium can be selected from one or more of methanol, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether and toluene, preferably methanol.

[0036] (3) The intermediate III is reduced to an amide in the presence of a reducing agent such as lithium aluminum hydride to obtain the intermediate IV.

[0037]

[0038] Among them, the molar ratio of the intermediate formula III to the reducing agent is 1.0:(1.5-3.0), 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.

[0039] (4) The intermediate IV is reacted to obtain the amide intermediate V.

[0040] Method 1: The intermediate IV reacts with malonic acid monoester under the action of a condensing agent to generate the intermediate V;

[0041]

[0042] R 1 =Me,Et

[0043] Among them, the malonate monoester is preferably monomethyl malonate or monoethyl malonate, and the molar ratio of the intermediate formula IV, malonate monoester, condensation agent, and base is 1.0:(1.0-2.0):(1.0-2.0):(1.0-2.0), the condensation 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.

[0044] Method 2: Intermediate IV is reacted with malonate chloride under alkaline conditions at room temperature to generate intermediate V;

[0045]

[0046] R 1 =Me,Et

[0047] Among them, the malonate chloride is preferably methyl malonate chloride or ethyl malonate chloride, the molar ratio of the intermediate formula IV, 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.

[0048] Method 3: Intermediate Formula IV reacts with active ester to generate intermediate Formula V;

[0049]

[0050] R 1 =Me,Et;R 3 =Et,i-Bu

[0051] Among them, the malonate monoester is preferably monomethyl malonate or monoethyl malonate, the molar ratio of the intermediate formula IV, 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.

[0052] Method 4: Intermediate Formula IV is reacted with mixed acid anhydride to generate intermediate Formula V;

[0053]

[0054] R 1 =Me,Et

[0055] Among them, the potassium salt of monomalonate is preferably potassium salt of monomethyl malonate or potassium salt of monoethyl malonate, and the molar ratio of intermediate formula IV, potassium salt of monomalonate, pivaloyl chloride, base, and DMAP is 1.0:(1.0-1.5):(1.0-1.5):(1.0-2.0):0.1, the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine or DIPEA, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, and toluene.

[0056] (5) Under alkaline conditions, the intermediate V reacts with chlorophosphate diester at room temperature to generate the intermediate VI.

[0057]

[0058] R 1 =Me,Et;R 2=Me,Et

[0059] 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 V, 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.

[0060] (6) Under alkaline conditions, the intermediate VI undergoes intramolecular cyclization to generate the intermediate VII.

[0061]

[0062] R 1 =Me,Et

[0063] 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 VI 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.

[0064] (7) In a specific embodiment, the intermediate of formula VII 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.

[0065]

[0066] The molar ratio of the intermediate VII 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.

[0067] Example 1: Preparation of Intermediate Formula II

[0068]

[0069] Add 196 mg (1 mmol) of intermediate II, 10 mL of methanol and 1 mol% of Ru(COD)[(s)-Segphos] to a high-pressure reactor, add hydrogen to 30 bar, heat to 50°C, and react for 24 hours. After the reaction is completed, cool to room temperature, remove the solvent under reduced pressure, extract three times with 15 mL of dichloromethane (15 mL×3), wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 196 mg of a yellow oily liquid.

[0070] Example 2: Preparation of Intermediate Formula III

[0071]

[0072] Add 4.95g of intermediate formula II to a 250mL two-necked flask equipped with a stirrer, add 50mL of anhydrous methanol to dissolve, then add 3.38g of methylamine hydrochloride and 6.75g of sodium methoxide, protect with argon, and stir at room temperature for 30h. After the reaction is completed, remove the solvent under reduced pressure, add 75mL of water, extract three times with 100mL of ethyl acetate (100mL×3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 3.48g of solid, with a yield of 71%.

[0073] Example 3: Preparation of Intermediate Formula IV

[0074]

[0075] Add 1.9g of lithium aluminum hydride to a 100mL bottle equipped with a stirrer, protect with argon, add 50mL of anhydrous tetrahydrofuran, stir at -10℃, take 4.93g of intermediate III, add 40mL of anhydrous tetrahydrofuran to dissolve, slowly add dropwise to the reaction system, heat the reaction mixture to reflux, and stir for 15h. After the reaction is completed, cool to 0℃, slowly add dropwise water to quench until no bubbles are released, add 2mL of 4.0M NaOH solution and 50mL of water, stir for 30min, filter with a layer of diatomaceous earth, extract with 45mL of dichloromethane (45mL×3), wash with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 4.35g of white solid, with a yield of 95%.

[0076] 1 HNMR (400MHz, CDCl3): 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).

[0077] 13 CNMR (100MHz, CDCl3): δ161.99(d,JC-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.

[0078] LCMS(ESI)m / z calculation for C 10 H 15 FNO[M+H] + 184.1,Found:184.1.

[0079] Example 4: Preparation of Intermediate Formula V

[0080] Method 1: Preparation of intermediate formula V

[0081]

[0082] In a 250mL two-necked flask equipped with a stirrer, add 4.58g of intermediate IV, 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 transparent liquid, which is directly used in the next step without further purification.

[0083] Method 2: Preparation of intermediate formula V

[0084]

[0085] Add 4.58g of intermediate IV 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 transparent liquid, which is directly used in the next step without further purification.

[0086] Method 3: Preparation of intermediate formula V

[0087]

[0088] 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 IV, add 25mL of anhydrous dichloromethane to dissolve, slowly drop it into the reaction solution, and react overnight at room temperature. After the reaction is completed, add 75mL of saturated sodium bicarbonate solution, extract the reaction solution three times with 150mL of dichloromethane (150mL×3), wash once with 1.0M hydrochloric acid solution and saturated brine, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain a transparent liquid, which is directly used in the next step without further purification.

[0089] Method 4: Preparation of intermediate formula V

[0090]

[0091] Add 5.47g of potassium monomethyl malonate to a 250mL two-necked flask equipped with a stirrer, add 30mL of anhydrous dichloromethane, place at 0℃ and stir, take 3.62g of pivaloyl chloride and drop it into the reaction solution, stir at 0℃ for 4h, take 4.58g of intermediate formula IV and add 20mL of anhydrous dichloromethane to dissolve, drop it into the reaction solution at 0℃, take 3.03g of triethylamine and drop it into the reaction solution, take 366mg of DMAP and add a little dichloromethane to dissolve and drop it into the reaction solution, move to room temperature and stir for 35h after the addition is completed. 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, remove the solvent under reduced pressure, and obtain a transparent liquid, which is directly used in the next step without further purification.

[0092] Example 5: Preparation of Intermediate Formula VI

[0093]

[0094] The intermediate formula V obtained in Example 4 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.

[0095] 1 HNMR (400MHz, CDCl3): 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).

[0096] 13 CNMR (100MHz, CDCl3): 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.

[0097] LCMS(ESI)m / z calculation for C 18 H 28 FNNaO7P[M+Na] + 442.1,Found:442.1.

[0098] Example 6: Preparation of Intermediate Formula VII

[0099]

[0100] The intermediate VI obtained in Example 5 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 slurried to obtain 3.5 g of a white solid, and the three-step yield was 53%.

[0101] 1 HNMR (400MHz, CDCl3): 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).

[0102] 13 CNMR (100MHz, CDCl3): 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.

[0103] LCMS(ESI)m / z calculation for C 14 H 17 FNO3[M+H] + 266.1,Found:266.1.

[0104] Example 7: Preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine

[0105]

[0106] 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 -10 ° C, take 2.65 g of intermediate formula VII, dissolve it in 10 mL of anhydrous tetrahydrofuran, slowly add it dropwise into the reaction system, react at -10 ° C for 30 min, then slowly warm to room temperature, and react at room temperature for 3 h. After the reaction is completed, slowly add ethyl acetate dropwise 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 it once with saturated brine, dry it with 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%.

[0107] 1 HNMR (400MHz, CDCl3): δ7.16-7.12(m,2H),6.98-6.94(m,2H),3.38-3.34(m,1H),3.2 3-3.14(m,2H),2.94-2.92(m,1H),2.31(s,3H),2.27-2.23(m,1H),2.06-1.74(m,5H).

[0108] 13 CNMR (100MHz, CDCl3): 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.

[0109] LCMS(ESI)m / z calculation for C 13 H 19 FNO[M+H] + 224.1,Found:224.1.

[0110] 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.

[0111] 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 Features The following steps are involved: (1) Using methyl p-fluorobenzoyl acetate as the raw material, asymmetric hydrogenation is performed to obtain the intermediate of formula II; (2) the intermediate II is reacted with sodium methoxide and methylamine hydrochloride to obtain the intermediate III; (3) Intermediate Formula III is reacted with a reducing agent to generate Intermediate Formula IV; (4) The intermediate IV is subjected to various reactions to obtain the amide intermediate V; Wherein R1 is C1-C4 alkyl, preferably methyl or ethyl; (5) the intermediate of formula V reacts with various chlorophosphate diesters at room temperature to obtain the intermediate of formula VI; wherein R1 is as described above, R2 is a C1-C4 alkyl group, preferably a methyl group or an ethyl group; (6) the intermediate VI is subjected to alkaline conditions to generate the intermediate VII; Wherein R1 is as described above; (7) The intermediate VII is subjected to the action of a reducing agent to reduce the ester group and the amide to generate the formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine.

2. The synthesis method according to claim 1, characterized in that: The asymmetric hydrogenation is carried out under the action of a transition metal-chiral ligand catalyst, the general formula of which is: M(L)(N * )]X, wherein M is Rh, Ru, Ir or Fe; L = 1,5-cyclooctadiene or 2,5-norbornadiene; the reaction medium is dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent; the N * It is a chiral ligand compound, including 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, etc.; the temperature is 10-100oC.

3. The synthesis method according to claim 2, characterized in that: The transition metal-chiral ligand 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], [((S)-Cl-MeO-BIPHEP)Ru(p-cymene)Cl]Cl, etc.; or / and The temperature of the asymmetric hydrogenation reaction is 20-80°C; or / and The hydrogen pressure of the asymmetric hydrogenation reaction is 5 to 50 bar.

4. The synthesis method according to claim 1, characterized in that: The intermediate II is reacted with sodium methoxide and methylamine hydrochloride to obtain the intermediate III. The selected conditions are that the molar ratio of the intermediate II, methylamine hydrochloride and sodium methoxide is 1.0:2.0-3.0:(2.0-7.0), and the solvent can be selected from one or more of methanol, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether and toluene.

5. The synthesis method according to claim 1, characterized in that: The intermediate III is reduced to amide under the action of a reducing agent to obtain the intermediate IV. The selected conditions are that the molar ratio of the intermediate III to the reducing agent is 1.0:(1.5-3.0), the solvent can be selected from tetrahydrofuran, toluene, methanol, tert-butanol, and the reducing agent can be selected from lithium aluminum hydride, sodium borohydride, potassium borohydride, etc.

6. The synthesis method according to claim 1, characterized in that: The synthesis method of the amide intermediate formula V can be method one, method two, method three or method four: method one, the intermediate formula IV and malonic acid monoester are reacted at room temperature under the action of a condensing agent to generate the intermediate formula V; method two, the intermediate formula IV and malonic acid ester chloride are reacted at room temperature under alkaline conditions to generate the intermediate formula V; method three, the intermediate formula IV and active ester are reacted to generate the intermediate formula V; method four, the intermediate formula IV and mixed acid anhydride are reacted to generate the intermediate formula V.

7. The synthesis method according to claim 6, characterized in that: In method 1, the molar ratio of intermediate formula IV, malonic acid monoester, condensing agent, and 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 malonic acid monoester is preferably monomethyl malonate or monoethyl malonate, the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, ether, and toluene; or, In method 2, the molar ratio of intermediate formula IV, malonate chloride, and base is 1.0:(1.0-2.0):(1.0-2.0), malonate chloride is preferably methyl malonate chloride or ethyl malonate chloride, 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; or In method three, the molar ratio of intermediate formula IV, malonic acid monoester, acyl chloride and base is 1.0:(1.0-1.5):(1.0-1.5):(1.0-2.0), malonic acid monoester is preferably monomethyl malonate or monoethyl malonate, 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; or In method 4, the molar ratio of intermediate formula IV, malonate potassium salt, pivaloyl chloride, base, and DMAP is 1.0:(1.0-1.5):(1.0-1.5):(1.0-2.0):0.1, malonate potassium salt is preferably malonate monomethyl potassium salt or malonate monoethyl potassium salt, the base can be selected from triethylamine, DIPEA, pyridine, N-methylimidazole, N-methylmorpholine, preferably triethylamine or DIPEA, and the solvent can be selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, and toluene.

8. The synthesis method according to claim 1, characterized in that: The intermediate formula V reacts with various chlorophosphate diesters at room temperature to obtain the intermediate formula VI, the selected condition is that the molar ratio of the intermediate formula V to the various chlorophosphate diesters is 1.0:(1.0-1.5), and the solvent can be selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, and toluene.

9. The synthesis method according to claim 1, characterized in that: The intermediate VI is converted into the intermediate VII under alkaline conditions, the selected conditions are that the molar ratio of the intermediate VI to the base is 1.0:(1.5-2.0), the solvent can be selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, toluene, acetone, and dioxane, and the base can be selected from sodium hydride, cesium carbonate, potassium tert-butoxide, sodium methoxide, LDA, etc.; The reaction temperature is 20~100oC.

10. The synthesis method according to claim 1, characterized in that: The intermediate of formula VII is reduced to the ester group and the amide under the action of a reducing agent to generate formula I (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The selected conditions are that the molar ratio of the intermediate of formula VII to the reducing agent is 1.0:(2.0-3.0), the solvent can be selected from tetrahydrofuran, toluene, methanol, tert-butanol, and the reducing agent can be selected from lithium aluminum hydride, sodium borohydride, potassium borohydride, etc.

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