WO2019165981A1 - Methods for synthesizing (r)-3-phenylpiperidine or/and (s)-3-phenylpiperidine and chiral intermediates of niraparib - Google Patents

Methods for synthesizing (r)-3-phenylpiperidine or/and (s)-3-phenylpiperidine and chiral intermediates of niraparib Download PDF

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WO2019165981A1
WO2019165981A1 PCT/CN2019/076351 CN2019076351W WO2019165981A1 WO 2019165981 A1 WO2019165981 A1 WO 2019165981A1 CN 2019076351 W CN2019076351 W CN 2019076351W WO 2019165981 A1 WO2019165981 A1 WO 2019165981A1
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phenylpiperidine
reaction
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刘振德
高河勇
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上海博邦医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, and also relates to the synthesis of chiral intermediates of nilapani method.
  • Niraparib 2- ⁇ 4-[(3S)-3-piperidinyl]phenyl ⁇ -2H-carbazole-7-carboxamide (11), its chemistry
  • the structure is as follows:
  • Niraparib MK-4827
  • PRP ADP-ribose polymerase
  • the drug is currently undergoing clinical trials in the United States for the treatment of different tumors, including two phase 3 clinical trials for the treatment of platinum-sensitive ovarian cancer (US Clinical Trial Registration No. NCT01847274); 2HER2 negative, BRCA1/2 positive Breast cancer (US Clinical Trial Registration No. NCT01905592).
  • Tesaro Biotech announced on June 11, 2014, two other Phase III clinical studies of Niraparib for first-line treatment of ovarian cancer and first-line treatment of small cell lung cancer.
  • the cyclization is continued under heating to obtain the intermediate 15, and the intermediate 15 is subjected to an ammonia exchange reaction in an ammonia methanol solution to obtain an amide intermediate 16, and finally the BOC protecting group is removed in the presence of HCl to obtain a nilapa. Nie 11.
  • the overall yield of the reaction of this route is not high, and the separation and purification of the product is difficult.
  • the starting material 3-pyridineboronic acid used in the route is not easy to prepare, has poor stability, high storage conditions and high price; uses expensive transition metals (palladium and platinum) in two successive steps, and performs chiral demolition in the last step. Also, about half of the enantiomers are not utilized, so if the intermediate 13 is produced on a large scale in accordance with this route, high production costs are incurred.
  • the production cost of nilapani in the prior art is too high, mainly due to the high synthesis cost of the chiral 3-phenylpiperidine side chain; the existing synthesis of the side chain group Several methods are not suitable for large-scale industrial production.
  • the present invention mainly aims to provide a new method for synthesizing (S)-3-phenylpiperidine.
  • the method uses a commonly used inexpensive reagent to carry out the reaction, and the reaction conditions are mild, and the reaction yield per step is high, so that the production cost of the piperidine side chain of nilapani can be effectively controlled;
  • (S)-3-phenylpiperidine It is possible to further synthesize various key chiral intermediates through simple chemical conversion, thus contributing to the production of the anticancer drug nilapani.
  • the first aspect of the present invention provides a method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route Scheme 1:
  • step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
  • step (b) is: 3-hydroxy-3-phenylpiperidine (3) undergoes alcoholic hydroxyl elimination reaction to form a mixture of compound (4) and compound (5);
  • step (c) is: under the catalysis of a transition metal catalyst, a mixture of compound (4) and compound (5) and a hydrogen source are hydrogenated to form N-protected 3-phenylpiperidine (6);
  • step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
  • step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
  • R 1 is selected from any one of the following: trityl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, tert-butyl, trimethyl Silicon-based, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
  • R 2 is selected from any one of the following: H, methoxy, ethoxy, isopropoxy, n-propoxy, allyloxy, n-butyloxy, Isobutyloxy, tert-butoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilylethoxy Oxylate, tert-butyldimethylsilylethoxymethoxy, trimethylsiloxy, triethylsiloxy, triisopropylsiloxy, tert-butyldimethylsiloxy, tert-Butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy, 2,4-dimethoxybenzyloxy.
  • the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
  • the transition metal catalyst is further preferably palladium carbon.
  • the chemical resolution solvent is selected from the combination of any one or more of the following: methanol, ethanol, isopropanol, n-propanol, n-butanol, Tetrahydrofuran, ethyl acetate, dichloromethane.
  • the chemical resolution solvent is further preferably selected from the combination of any one or more of the following: methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate.
  • the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoyl tartaric acid, malic acid, camphor Sulfonic acid, camphoric acid, mandelic acid, quinic acid.
  • the acidic resolving agent is further preferably any one of the following: tartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, malic acid, camphorsulfonic acid.
  • the synthesis method according to the first aspect of the present invention sequentially performs a Grignard reaction, an elimination reaction, a hydrogenation reduction reaction, a removal of a protecting group R 1 , and a chiral separation, and successfully obtains the target product (R)-3-benzene.
  • the yield of each step is higher in the piperidine or / and (S)-3-phenylpiperidine, wherein (S)-3-phenylpiperidine can be further used for the synthesis of nilapani. Chiral intermediates.
  • the second aspect of the present invention provides a method for synthesizing another (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route Scheme 1-1:
  • step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
  • step (f) is: 3-hydroxy-3-phenylpiperidine (3) is reacted with (C n H 2n+1 ) 3 SiH to directly form N-protected 3-phenylpiperidine (6); , n is an integer from 1 to 4;
  • step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
  • step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
  • the (C n H 2n+1 ) 3 SiH is selected from any one of the following: triethylsilane, tri-n-propylsilane, triisopropyl Silane.
  • the chemical resolution solvent is selected from any one or a combination of the following: methanol, ethanol, isopropanol, n-propanol, n-butanol, Tetrahydrofuran, ethyl acetate, dichloromethane.
  • the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoyl tartaric acid, malic acid, camphor Sulfonic acid, camphoric acid, mandelic acid, quinic acid.
  • the third aspect of the present invention provides a method for synthesizing a chiral intermediate ⁇ of nilapani, and the synthetic route thereof is as follows:
  • the nitrating agent is selected from any one of the following: nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, nitroxyl chloride, butyl nitrate, nitric acid Methyl ester, NO 2 BF 4 , NO 2 PF 6 .
  • the nitrating agent is selected from any one of the following: nitric acid, potassium nitrate, NO 2 BF 4 and methyl nitrate.
  • the reduction system is selected from any one of the following: ferric chloride/hydrated hydrazine, Fe/HCl, Zn/HCl, LiAlH 4 , Transition metal catalyst / hydrogen, sodium dithionite; wherein the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
  • the fourth aspect of the present invention also provides a method for synthesizing a chiral intermediate ⁇ of nilapani, and the synthetic route is as follows:
  • the protecting group PG is selected from any one of the following: an alkyl group, an acyl group, a sulfonyl group; for example, the protecting group PG is preferably an acetyl group, a propionyl group, a butyryl group, a benzenesulfonyl group;
  • the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
  • the bromination reagent is selected from any one of the following: NBS, Br 2 , HBr, pyridinium bromide hydrobromide, dibromide Hydanto, 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
  • the fifth aspect of the present invention also provides a method for synthesizing a chiral intermediate ⁇ of nilapani, and the synthetic route is as follows:
  • the protecting group PG is selected from any one of the following: an alkyl group, an acyl group, a sulfonyl group; for example, the protecting group PG is preferably an acetyl group, a propionyl group, a butyryl group, a benzenesulfonyl group;
  • R 2 is selected from any one of the following: according to the synthesis method of the first aspect or the second aspect of the invention: Oxyl, ethoxy, isopropoxy, n-propoxy, allyloxy, n-butyloxy, isobutyloxy, tert-butoxy, methoxymethoxy, ethoxy Methoxy, methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilylethoxymethoxy, tert-butyldimethylsilylethoxymethoxy, trimethyl Silyloxy, triethylsilyloxy, triisopropylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy , 2,4-dimethoxybenzyloxy;
  • P'4 The N-protected (S)-3-(4-hydroxyphenyl)-piperidine (9') is reacted with an active sulfonyl chloride or an active sulfonic anhydride to form an active ester (10'), ie Nila Pani's chiral intermediate ⁇ .
  • the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
  • the active sulfonyl chloride is selected from any one of the following: methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride; the active sulfonic acid anhydride It is trifluoromethanesulfonic anhydride.
  • the technical solution provided by the present invention has at least the following beneficial effects compared with the synthetic processes known in the prior art:
  • the synthesis method shown in Scheme 1 uses N-protected 3-piperidone as a starting material, followed by Grignard reaction, elimination reaction, hydrogenation reduction reaction, removal of protecting group R 1 and chiral resolution.
  • the target product (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine; the synthesis method shown by Scheme 1-1 is also based on N-protected 3-piperidone.
  • the Grignard reaction is first carried out, and the hydroxyl group is directly removed by using a silicone reagent, and then the protecting group R 1 is removed, and finally the target product (R)-3-phenylpiperidine or / is obtained by chiral resolution.
  • (S)-3-phenylpiperidine can also synthesize (S)-3-p-aminophenylpiperidine according to the route shown in Scheme 2, or synthesize (S)-3 according to the route shown in Scheme 3.
  • Phenylmagnesium bromide Grignard reagent (2mol/L in THF, 240mL), anhydrous tetrahydrofuran (300mL), added to the reaction flask, protected with nitrogen, cooled to 0 ° C in ice water bath, N-benzyl-3- Piperidone (2-1, 60.0 g, 317.0 mmol) was diluted with anhydrous tetrahydrofuran (300 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour.
  • the TLC was used to confirm that the starting material had been completely reacted, and a saturated aqueous solution of ammonium chloride (300 mL) was added thereto, and then extracted with ethyl acetate (200 mL ⁇ 3). After extracting three times, the organic layers were combined and added.
  • Phenylmagnesium bromide Grignard reagent (2mol/L in THF, 240mL), anhydrous ether (300mL), was added to the reaction flask, protected with nitrogen, cooled to 0 ° C in ice water bath, N-benzyl-3- Piperidone (2-1, 60.0 g, 317.0 mmol) was diluted with anhydrous diethyl ether (300 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour.
  • the TLC was used to confirm that the starting material had been completely reacted, and a saturated aqueous solution of ammonium chloride (300 mL) was added thereto, and then extracted with ethyl acetate (200 mL ⁇ 3), extracted three times, and then the organic layer was combined.
  • Phenylmagnesium chloride Grignard reagent (2mol/L in THF, 240mL), anhydrous tetrahydrofuran (300mL), added to the reaction flask, nitrogen protection, cooled to 0 ° C in ice water bath, N-benzyl-3-piperidine
  • the ketone (2,60.0 g, 317.0 mmol) was diluted with anhydrous tetrahydrofuran (300 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was controlled at 0-5 ° C, 50 min, and the addition was completed. The reaction was stirred for 1.5 hours, and the reaction was completed by TLC.
  • Phenylmagnesium chloride Grignard reagent (2mol/L in THF, 240mL), anhydrous ether (300mL), added to the reaction flask, nitrogen protection, cooled to 0 ° C in ice water bath, N-benzyl-3-piperidine
  • the ketone (2,60.0 g, 317.0 mmol) was diluted with anhydrous diethyl ether (300 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was controlled at 0-5 ° C, 30 min, and the addition was completed. The reaction was stirred for 1 hour, and the TLC was used to confirm that the starting material had been completely reacted.
  • 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in isopropanol (50 mL), and a solution of L-tartaric acid (93.16 g, 622.2 mmol) in isopropanol (200 mL) was added dropwise.
  • the solution of racemic 3-phenylpiperidine in isopropanol was stirred for 2 h and filtered to obtain the tartrate; then, methanol (10 L) was added to the tartrate, and after heating to complete dissolution, the stirring was stopped; the temperature was slowly lowered to room temperature.
  • the crystallization was carried out at -20 ° C for 7 days, and filtered to give a white crystals crystals crystals.
  • 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in methanol (50 mL) and a solution of L-(-)-dibenzoyltartaric acid (222.93 g, 622.2 mmol) in methanol (200 mL)
  • Add dropwise to a solution of racemic 3-phenylpiperidine in methanol stir for 2 h, and filter to obtain dibenzoyl tartrate; then, add ethanol (8 L) to the dibenzoyl tartrate and heat to dissolve completely.
  • Ethyl acetate (30. 200 mL) solution was added dropwise to a solution of racemic 3-phenylpiperidine in ethyl acetate, stirred for 2 h, filtered to give di-p-methylbenzoyl tartrate; then, to the di-p-methylbenzoyl tartaric acid
  • the salt was added to ethyl acetate (15 L), heated to complete dissolution, stirring was stopped; the temperature was slowly cooled to room temperature, crystallized at 0 ° C for 2 days, and filtered to give a crude white solid, 1N aqueous sodium hydroxide (50 mL) Ester extraction (25 mL x 2), EtOAc (EtOAc m.
  • 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in isopropanol (50 mL), and a solution of D-tartaric acid (93.16 g, 622.2 mmol) in isopropanol (200 mL) was added dropwise.
  • the solution of racemic 3-phenylpiperidine in isopropanol was stirred for 2 h and filtered to obtain the tartrate; then, methanol (10 L) was added to the tartrate, and after heating to complete dissolution, the stirring was stopped; the temperature was slowly lowered to room temperature.
  • the crystallization was carried out at -20 ° C for 7 days, and filtered to give a white crystals crystals crystals.
  • Ethyl acetate (30. 200 mL) solution was added dropwise to a solution of racemic 3-phenylpiperidine in ethyl acetate, stirred for 2 h, filtered to give di-p-methylbenzoyl tartrate; then, to the di-p-methylbenzoyl tartaric acid
  • the salt was added to ethyl acetate (15 L), heated to complete dissolution, stirring was stopped; the temperature was slowly cooled to room temperature, crystallized at 0 ° C for 2 days, and filtered to give a crude white solid, 1N aqueous sodium hydroxide (50 mL) Ester extraction (25 mL x 2), EtOAc (EtOAc m.
  • the layer was adjusted to pH 8-9 with a 10% aqueous sodium hydroxide solution, and then extracted with ethyl acetate (200 mL ⁇ 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • the aqueous layer was collected, the organic layer was discarded, and the pH of the aqueous layer was adjusted to 8-9 with a 10% aqueous sodium hydroxide solution, then extracted with ethyl acetate (200 mL ⁇ 3), and the organic layer was collected.
  • N-Benzyl-3-phenylpiperidine (6-2, 65 g, 258.96 mmol), palladium on carbon (12 g, 18%), absolute ethanol (300 mL), glacial acetic acid (11 mL), The hydrogen gas of 1 atm was introduced and heated to 60 ° C.
  • the starting material was completely reacted by TLC, quenched with saturated aqueous ammonium chloride (50 mL), and then ethyl acetate (20 mL ⁇ 3) After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give the crude product.
  • the crude product is purified by silica gel column chromatography (3-hydroxy-3-p-ethoxyphenyl) 1-tert-Butyldimethylsilylpiperidine (3-11)) 9.8 g, yield 91.2%; MS-ESI (m/z): 336.6 [(M+H) + ].
  • the starting material was completely reacted by TLC, quenched with saturated aqueous ammonium chloride (50 mL), and then ethyl acetate (20 mL ⁇ 3) After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, and filtered, and the solvent is evaporated to give a crude product.
  • the crude product is purified by silica gel column chromatography to give (3-hydroxy-3-p-t-butoxyphenyl) 1-1 Tert-butyldimethylsilylpiperidine (3-15)) 10.5 g, yield 90.2%; MS-ESI (m/z): 364.6 [(M+H) + ].
  • the TLC was used to confirm that the starting material had been completely reacted.
  • Saturated ammonium chloride aqueous solution 50 mL was added with stirring, and ethyl acetate (20 mL ⁇ 3) was used. After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give a crude product.
  • the crude product is purified by silica gel column chromatography (3-hydroxy-3-p-t-butyldimethylsilyl) Oxyphenyl-1-benzylpiperidine (3-20)) 12.1 g, yield 96.5%; MS-ESI (m/z): 398.6 [(M+H) + ].
  • Example 73 1-(2,4-Dimethoxybenzyl)-5-p-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-4) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-methoxyphenyl-1,2,3,4-tetrahydropyridine (5-4)
  • Example 74 1-tert-Butyl-5-p-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-5) and 1-tert-butyl-5-p-methoxyphenyl Synthesis of -1,2,3,4-tetrahydropyridine (5-5)
  • Example 77 1-Benzyl-5-p-ethoxyphenyl-1,2,3,6-tetrahydropyridine (4-6) and 1-benzyl-5-p-ethoxyphenyl-1 Synthesis of 2,3,4-tetrahydropyridine (5-6)
  • Example 78 1-(2,4-Dimethoxybenzyl)-5-p-ethoxyphenyl-1,2,3,6-tetrahydropyridine (4-7) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-ethoxyphenyl-1,2,3,4-tetrahydropyridine (5-7)
  • Example 80 1-(2,4-Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-9) and 1-(2,4- Synthesis of Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-9)
  • Example 82 1-Benzyl-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-8) and 1-benzyl-5-p-hydroxyphenyl-1,2,3 Synthesis of 4-tetrahydropyridine (5-8)
  • Example 83 1-(2,4-Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-9) and 1-(2,4- Synthesis of Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-9)
  • Example 84 1-Benzyl-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-8) and 1-benzyl-5-p-hydroxyphenyl-1,2,3 Synthesis of 4-tetrahydropyridine (5-8)
  • Example 87 1-(2,4-Dimethoxybenzyl)-5-p-benzyloxyphenyl-1,2,3,6-tetrahydropyridine (4-12) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-benzyloxyphenyl-1,2,3,4-tetrahydropyridine (5-12)
  • N-tert-butyl-3-p-methoxyphenylpiperidine (6-3) (7.6 g, 30.7 mmol) was added to a 100 mL glass flask, and then concentrated hydrochloric acid (40 mL). The mixture was heated under reflux for 24 hours with stirring. After the detection of the raw materials has been completed, the reaction is stopped. NaOH solution was added to the reaction solution, the pH was adjusted to 8-10, ethyl acetate was extracted (50 mL ⁇ 3), the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. 3-p-methoxyphenyl piperidine (1-2) 4.2g, yield 71.5%, MS-ESI (m / z): 192.3 (m + H) +.
  • 3-p-methoxyphenylpiperidine (1-2, 20.2 g, 105.6 mmol) was dissolved in isopropanol (30 mL) and isopropyl alcohol (40 mL) was dissolved in L-tartaric acid (15.91 g, 106.0 mmol).
  • the solution was added dropwise to a solution of racemic 3-p-methoxyphenylpiperidine in isopropanol, stirred for 2 h, filtered to give the tartrate; then, methanol (2 L) was added to the tartrate and heated to dissolve completely. After that, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -20 ° C for 7 days, and filtered to give a white solid.
  • 3-p-Ethoxyphenylpiperidine (1-3, 22.5 g, 109.6 mmol) was dissolved in isopropanol (30 mL), and isopropyl alcohol (40 mL) was dissolved in L-tartaric acid (17.3 g, 115.0 mmol). The solution was added dropwise to a solution of racemic 3-p-ethoxyphenylpiperidine in isopropanol, stirred for 2 h, filtered to give the tartrate; then, methanol (2 L) was added to the tartrate and heated to dissolve completely.
  • Triphenylphosphine (9.06 g, 34.53 mmol) was dissolved in acetonitrile (10 mL), cooled to 0 ° C in ice-water bath, and broth (5.52 g, 34. After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and stirred.
  • (S)-3-p-hydroxyphenylpiperidine ((S)-1-4, 5.1 g, 28.77 mmol) was added to the reaction solution, and the mixture was heated to 70 ° C for 30 minutes, and the solvent was evaporated to dryness. Heat to 250 ° C and react for 1 hour. After cooling to room temperature, the residue was dissolved with methylene chloride (m.hhhhhhhhhhhhhhhhhhhhhhhhh , ESI (m/z): 242.1, 240.1 (M+H) + .

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Abstract

The synthesis method provided by the first aspect of the invention successfully prepares the target product (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine using a N-protected 3-piperidone as a starting material. The synthesis method provided by the second aspect of the invention successfully prepares the target product (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine using the same starting raw material with the ingenious use of an organic silicon reagent. The (S)-3-phenylpiperidine can be used to synthesize the chiral intermediate α, β or γ of niraparib according to the third, the fourth or the fifth aspect of the invention, respectively. In general, the methods for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and the chiral intermediates α, β and γ of niraparib significantly reduces the production cost, favoring the large-scale industrial production of niraparib.

Description

(R)-3-苯基哌啶或/和(S)-3-苯基哌啶以及尼拉帕尼的手性中间体的合成方法Method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and chiral intermediate of nilapani 技术领域Technical field
本发明属于有机合成技术领域，特别涉及(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法，还涉及尼拉帕尼的手性中间体的合成方法。The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, and also relates to the synthesis of chiral intermediates of nilapani method.
背景技术Background technique
尼拉帕尼(Niraparib,MK-4827)的化学名为2-{4-[(3S)-3-哌啶基]苯基}-2H-吲唑-7-甲酰胺(11)，其化学结构式如下：The chemical name of Niraparib (MK-4827) is 2-{4-[(3S)-3-piperidinyl]phenyl}-2H-carbazole-7-carboxamide (11), its chemistry The structure is as follows:
Figure PCTCN2019076351-appb-000001
Figure PCTCN2019076351-appb-000001
众所周知，由Tesaro生物科技公司研制的的抗癌药物尼拉帕尼(Niraparib,MK-4827)是一种新型的口服的选择性聚腺苷二磷酸核糖聚合酶(PARP)抑制剂，该药物通过干扰细胞中DNA修复过程而发挥作用，这将使得肿瘤对DNA受损的化疗药物变得更加敏感。目前该药物正在美国进行临床试验用于不同肿瘤的治疗，其中包括两项3期临床试验，用于治疗①铂类敏感性卵巢癌(美国临床试验注册号NCT01847274)；②HER2阴性、BRCA1/2阳性乳腺癌(美国临床试验注册号NCT01905592)。此外，Tesaro生物科技公司于2014年6月11日宣布计划开展Niraparib用于卵巢癌一线治疗和小细胞肺癌一线治疗的另外两项Ⅲ期临床研究。It is well known that Niraparib (MK-4827), an anticancer drug developed by Tesaro Biotech, is a novel oral selective poly ADP-ribose polymerase (PARP) inhibitor that passes the drug. Interfering with DNA repair processes in cells, which will make tumors more sensitive to DNA-damaging chemotherapeutic drugs. The drug is currently undergoing clinical trials in the United States for the treatment of different tumors, including two phase 3 clinical trials for the treatment of platinum-sensitive ovarian cancer (US Clinical Trial Registration No. NCT01847274); 2HER2 negative, BRCA1/2 positive Breast cancer (US Clinical Trial Registration No. NCT01905592). In addition, Tesaro Biotech announced on June 11, 2014, two other Phase III clinical studies of Niraparib for first-line treatment of ovarian cancer and first-line treatment of small cell lung cancer.
根据相关文献报道，尼拉帕尼的合成路线目前主要有以下三种：According to relevant literature reports, there are three main synthetic routes for Nilapani:
一、路线1(Scheme 4)(参见WO2008084261，Journal of Medicinal Chemistry,2009,52(22),7170-7185)；Organic Process Research&Development,2011,15(4),831-840.)：使用BOC保护的(S)-3-对胺基苯基哌啶13与3-甲酰基-2-硝基苯甲酸甲12反应，形成亚胺化合物14，再与NaN 3/DMF 反应，硝基被叠氮基取代后，继续在加热条件下环化得到中间体15，中间体15在氨甲醇溶液中进行氨交换反应，得到酰胺中间体16，最后在HCl存在下脱除BOC保护基团，得到尼拉帕尼11。然而，该路线的反应总收率不高，且产物分离纯化较困难。 I. Scheme 4 (see WO2008084261, Journal of Medicinal Chemistry, 2009, 52(22), 7170-7185); Organic Process Research & Development, 2011, 15(4), 831-840.): Protected using BOC (S)-3-p-Aminophenylpiperidine 13 is reacted with 3-formyl-2-nitrobenzoic acid methyl 12 to form imine compound 14, which is then reacted with NaN 3 /DMF, and the nitro group is azide. After the substitution, the cyclization is continued under heating to obtain the intermediate 15, and the intermediate 15 is subjected to an ammonia exchange reaction in an ammonia methanol solution to obtain an amide intermediate 16, and finally the BOC protecting group is removed in the presence of HCl to obtain a nilapa. Nie 11. However, the overall yield of the reaction of this route is not high, and the separation and purification of the product is difficult.
Figure PCTCN2019076351-appb-000002
Figure PCTCN2019076351-appb-000002
二、路线2(Scheme 5)(参见WO2008084261)：将苯并吡唑中间体17与氟代苯18反应，得到中间体19，再将中间体19与3-吡啶硼酸发生Suzuki偶联反应，生成中间体20；中间体20的吡啶环还原得到外消旋的化合物21，进一步手性拆分得到手性的尼拉帕尼11。2. Scheme 5 (see WO2008084261): reacting benzopyrazole intermediate 17 with fluorobenzene 18 to give intermediate 19, and then subjecting intermediate 19 to 3-pyridine boronic acid to form a Suzuki coupling reaction. Intermediate 20; reduction of the pyridine ring of intermediate 20 afforded racemic compound 21 which was further chiral resolved to afford chiral Nilapani 11 .
Figure PCTCN2019076351-appb-000003
Figure PCTCN2019076351-appb-000003
在该路线中，Suzuki偶联反应和还原吡啶环这两步均使用了昂贵的过渡金属，成本较高；尤其是，在最后一步拆分得到手性产物，至少一半的对映异构体成为废弃物，从而导致收率降低，成本上升，不适合大规模工业化生产。In this route, both the Suzuki coupling reaction and the reduction of the pyridine ring use expensive transition metals, which are costly; in particular, in the final step, the chiral product is obtained, and at least half of the enantiomers become Waste, which leads to lower yields and higher costs, is not suitable for large-scale industrial production.
三、路线3(Scheme 6)(WO2018/088983，Org.Process Res.Dev.,2014,18(1),215–227)：采用了铜催化反应，将苯并吡唑中间体22和BOC保护的(S)-3-对溴苯基哌啶23进行偶联反应，得到中间体24，再在二甲苯溶剂中，甲磺酸脱除保护，得到最终产品尼拉帕尼11。通过分析可知，此路线所用催化剂便宜，反应条件温和，收率较高，因此，此路线是比较适合于工业化生产的路线。III. Scheme 6 (WO2018/088983, Org. Process Res. Dev., 2014, 18(1), 215–227): Protection of benzopyrazole intermediate 22 and BOC using a copper catalyzed reaction The (S)-3-p-bromophenylpiperidine 23 is subjected to a coupling reaction to obtain an intermediate 24, which is then deprotected with methanesulfonic acid in a solvent of xylene to give the final product of nilapani 11 . According to the analysis, the catalyst used in this route is cheap, the reaction conditions are mild, and the yield is high. Therefore, this route is more suitable for industrial production.
Figure PCTCN2019076351-appb-000004
Figure PCTCN2019076351-appb-000004
通过分析现有技术中的以上合成路线，可知苯基对位取代的S构型的3-苯基哌啶是合成尼拉帕尼的关键中间体之一。其中，路线一使用了BOC保护的(S)-3-对胺基苯基哌啶13作为反应物，路线三使用了BOC保护的(S)-3-对溴苯基哌啶23作为反应物；但是，文献中记载的两个侧链的合成方法并不经济，反应过程中使用贵重的过渡金属催化，或使用酶催化等反应效率很低的生产方式，都会导致生产成本居高不下。By analyzing the above synthetic routes in the prior art, it is known that the 3-phenylpiperidine of the phenyl para-substituted S configuration is one of the key intermediates for the synthesis of nilapani. Among them, Route 1 uses BOC-protected (S)-3-p-aminophenylpiperidine 13 as a reactant, and Route 3 uses BOC-protected (S)-3-p-bromophenylpiperidine 23 as a reactant. However, the synthesis method of the two side chains described in the literature is not economical, and the use of expensive transition metal catalysis in the reaction process or the use of a production method with low reaction efficiency such as enzymatic catalysis may result in high production costs.
此外，现有技术中还提供了BOC保护的(S)-3-对胺基苯基哌啶13的合成方法(参见WO2008084261，Journal of Medicinal Chemistry,2009,52(22),7170-7185)；Organic Process Research&Development,2011,15(4),831-840.)，其合成路线如Scheme 7所示。In addition, a method for synthesizing BOC-protected (S)-3-p-aminophenylpiperidine 13 is also provided in the prior art (see WO2008084261, Journal of Medicinal Chemistry, 2009, 52(22), 7170-7185); Organic Process Research & Development, 2011, 15(4), 831-840.), the synthetic route is shown as Scheme 7.
可见，该路线所使用的起始原料3-吡啶硼酸不易制备，且稳定性差，保存条件要求高，价格昂贵；连续两步使用昂贵的过渡金属(钯和铂)，在最后步骤进行手性拆分，同样有约一半的对映异构体得不到利用，因此若按照该该路线大 规模生产中间体13，会造成高昂的生产成本。It can be seen that the starting material 3-pyridineboronic acid used in the route is not easy to prepare, has poor stability, high storage conditions and high price; uses expensive transition metals (palladium and platinum) in two successive steps, and performs chiral demolition in the last step. Also, about half of the enantiomers are not utilized, so if the intermediate 13 is produced on a large scale in accordance with this route, high production costs are incurred.
Figure PCTCN2019076351-appb-000005
Figure PCTCN2019076351-appb-000005
现有技术中，BOC保护的(S)-3-对溴苯基哌啶23的合成使用了转氨酶(参见WO2018/088983，Org.Process Res.Dev.,2014,18(1),215–227.)，其合成采用了如Scheme 8或Scheme 9所示的路线：In the prior art, the conversion of BOC protected (S)-3-p-bromophenylpiperidine 23 uses a transaminase (see WO2018/088983, Org. Process Res. Dev., 2014, 18(1), 215-227 .), the synthesis uses a route as shown in Scheme 8 or Scheme 9:
Figure PCTCN2019076351-appb-000006
Figure PCTCN2019076351-appb-000006
然而，以上两条合成BOC保护的(S)-3-对溴苯基哌啶23的路线均须经过转 氨酶反应，生产效率低，显然成本过高。However, the above two routes for the synthesis of BOC-protected (S)-3-p-bromophenylpiperidine 23 are subjected to a transaminase reaction, which is inefficient in production and apparently cost prohibitive.
综上所述，现有技术中尼拉帕尼的生产成本过高，这主要是由于其手性的3-苯基哌啶侧链的合成成本高昂；现有的合成该侧链基团的几种方法，均无法适用于大规模工业化生产。因此，亟需提供一种尼拉帕尼关键中间体(S)-3-苯基哌啶的全新合成工艺，以期通过廉价的试剂与温和的反应条件获得较高的产物收率，便于将(S)-3-苯基哌啶用于合成各种关键手性中间体(例如，BOC保护的(S)-3-对胺基苯基哌啶13和BOC保护的(S)-3-对溴苯基哌啶23)，从而有利于最终实现尼拉帕尼的大规模工业化生产。In summary, the production cost of nilapani in the prior art is too high, mainly due to the high synthesis cost of the chiral 3-phenylpiperidine side chain; the existing synthesis of the side chain group Several methods are not suitable for large-scale industrial production. Therefore, there is an urgent need to provide a novel synthesis process for the key intermediate of nirapani (S)-3-phenylpiperidine, in order to obtain a higher product yield through inexpensive reagents and mild reaction conditions, which is convenient for S)-3-Phenylpiperidine for the synthesis of various key chiral intermediates (for example, BOC protected (S)-3-p-aminophenylpiperidine 13 and BOC protected (S)-3-pair Bromophenylpiperidine 23), which is conducive to the final realization of large-scale industrial production of nilapani.
发明内容Summary of the invention
为了促进抗癌药物尼拉帕尼的大规模工业化生产，克服现有合成工艺成本过高的技术缺陷，本发明主要旨在提供一种合成(S)-3-苯基哌啶的新方法，该方法使用常用的廉价试剂进行反应，且反应条件温和，每步反应收率较高，从而能够有效控制尼拉帕尼的哌啶侧链的生产成本；(S)-3-苯基哌啶可以经过简单的化学转化，进一步合成各种关键手性中间体，因此，有利于抗癌药物尼拉帕尼的生产。In order to promote the large-scale industrial production of the anticancer drug nilapani and overcome the technical defects of the excessive cost of the existing synthetic process, the present invention mainly aims to provide a new method for synthesizing (S)-3-phenylpiperidine. The method uses a commonly used inexpensive reagent to carry out the reaction, and the reaction conditions are mild, and the reaction yield per step is high, so that the production cost of the piperidine side chain of nilapani can be effectively controlled; (S)-3-phenylpiperidine It is possible to further synthesize various key chiral intermediates through simple chemical conversion, thus contributing to the production of the anticancer drug nilapani.
具体地，本发明第一方面提供了一种(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法，其包括如下合成路线Scheme 1：Specifically, the first aspect of the present invention provides a method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route Scheme 1:
Figure PCTCN2019076351-appb-000007
Figure PCTCN2019076351-appb-000007
其中，步骤(a)为：N保护的3-哌啶酮(2)与对位R 2取代的苯基卤化镁发生格氏反应，生成3-羟基-3-苯基哌啶(3)； Wherein step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
其中，步骤(b)为：3-羟基-3-苯基哌啶(3)发生醇羟基消去反应，生成化合物(4)和化合物(5)的混合物；Wherein step (b) is: 3-hydroxy-3-phenylpiperidine (3) undergoes alcoholic hydroxyl elimination reaction to form a mixture of compound (4) and compound (5);
其中，步骤(c)为：在过渡金属催化剂催化下，化合物(4)和化合物(5)的混合物与氢源发生加氢还原反应，生成N保护的3-苯基哌啶(6)；Wherein step (c) is: under the catalysis of a transition metal catalyst, a mixture of compound (4) and compound (5) and a hydrogen source are hydrogenated to form N-protected 3-phenylpiperidine (6);
其中，步骤(d)为：N保护的3-苯基哌啶(6)脱除保护基R 1，生成外消旋的3-苯基哌啶(1)； Wherein step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
其中，步骤(e)为：化学拆分溶剂中，使用酸性拆分剂对外消旋的3-苯基哌啶(1)进行拆分，得到(R)-3-苯基哌啶((R)-1)或/和(S)-3-苯基哌啶((S)-1)。Wherein step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
优选地，在上述合成方法中，R 1选自以下任一种：三苯甲基，苄基，对甲氧基苄基，2,4-二甲氧基苄基，叔丁基，三甲基硅基，三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基。 Preferably, in the above synthesis method, R 1 is selected from any one of the following: trityl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, tert-butyl, trimethyl Silicon-based, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
优选地，在上述合成方法中，R 2选自以下任一种：H，甲氧基，乙氧基，异丙氧基，正丙氧基，烯丙基氧基，正丁基氧基，异丁基氧基，叔丁氧基，甲氧基甲氧基，乙氧基甲氧基，甲氧基乙氧基，2-四氢吡喃氧基，三甲基硅基乙氧基甲氧基，叔丁基二甲基硅基乙氧基甲氧基，三甲基硅氧基，三乙基硅氧基，三异丙基硅氧基，叔丁基二甲基硅氧基，叔丁基二苯基硅氧基，苄氧基，对甲氧基苄氧基，2,4-二甲氧基苄氧基。 Preferably, in the above synthesis method, R 2 is selected from any one of the following: H, methoxy, ethoxy, isopropoxy, n-propoxy, allyloxy, n-butyloxy, Isobutyloxy, tert-butoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilylethoxy Oxylate, tert-butyldimethylsilylethoxymethoxy, trimethylsiloxy, triethylsiloxy, triisopropylsiloxy, tert-butyldimethylsiloxy, tert-Butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy, 2,4-dimethoxybenzyloxy.
优选地，在上述合成方法的所述步骤(c)中，所述过渡金属催化剂选自以下任一种：雷尼镍，钯碳，二氧化钯，铂黑，二氧化铂。所述过渡金属催化剂进一步优选为钯碳。Preferably, in the step (c) of the above synthesis method, the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide. The transition metal catalyst is further preferably palladium carbon.
优选地，在上述合成方法的所述步骤(e)中，所述化学拆分溶剂选自以下任一种或多种的组合：甲醇，乙醇，异丙醇，正丙醇，正丁醇，四氢呋喃，乙酸乙酯，二氯甲烷。所述化学拆分溶剂进一步优选自以下任一种或多种的组合：甲醇，乙醇，异丙醇，四氢呋喃，乙酸乙酯。Preferably, in the step (e) of the above synthetic method, the chemical resolution solvent is selected from the combination of any one or more of the following: methanol, ethanol, isopropanol, n-propanol, n-butanol, Tetrahydrofuran, ethyl acetate, dichloromethane. The chemical resolution solvent is further preferably selected from the combination of any one or more of the following: methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate.
优选地，在上述合成方法的所述步骤(e)中，所述酸性拆分剂选自以下任一种：酒石酸，二苯甲酰基酒石酸，二对甲基苯甲酰酒石酸，苹果酸，樟脑磺酸，樟脑酸，扁桃酸，奎宁酸。所述酸性拆分剂进一步优选自以下任一种：酒石酸，二苯甲酰基酒石酸，二对甲基苯甲酰酒石酸，苹果酸，樟脑磺酸。Preferably, in the step (e) of the above synthetic method, the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoyl tartaric acid, malic acid, camphor Sulfonic acid, camphoric acid, mandelic acid, quinic acid. The acidic resolving agent is further preferably any one of the following: tartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, malic acid, camphorsulfonic acid.
总之，本发明第一方面所述的合成方法依次进行格氏反应、消去反应、加氢还原反应、脱除保护基R 1、手性拆分，成功制得了目标产物(R)-3-苯基哌啶或/和(S)-3-苯基哌啶，各步反应收率均较高，其中，(S)-3-苯基哌啶还可被进一步用于合成尼拉帕尼的手性中间体。 In summary, the synthesis method according to the first aspect of the present invention sequentially performs a Grignard reaction, an elimination reaction, a hydrogenation reduction reaction, a removal of a protecting group R 1 , and a chiral separation, and successfully obtains the target product (R)-3-benzene. The yield of each step is higher in the piperidine or / and (S)-3-phenylpiperidine, wherein (S)-3-phenylpiperidine can be further used for the synthesis of nilapani. Chiral intermediates.
并且，本发明第二方面提供了另一种(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的 合成方法，其包括如下合成路线Scheme 1-1：Further, the second aspect of the present invention provides a method for synthesizing another (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route Scheme 1-1:
Figure PCTCN2019076351-appb-000008
Figure PCTCN2019076351-appb-000008
其中，步骤(a)为：N保护的3-哌啶酮(2)与对位R 2取代的苯基卤化镁发生格氏反应，生成3-羟基-3-苯基哌啶(3)； Wherein step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
其中，步骤(f)为：3-羟基-3-苯基哌啶(3)与(C nH 2n+1) 3SiH反应，直接生成N保护的3-苯基哌啶(6)；其中，n为1～4的整数； Wherein step (f) is: 3-hydroxy-3-phenylpiperidine (3) is reacted with (C n H 2n+1 ) 3 SiH to directly form N-protected 3-phenylpiperidine (6); , n is an integer from 1 to 4;
其中，步骤(d)为：N保护的3-苯基哌啶(6)脱除保护基R 1，生成外消旋的3-苯基哌啶(1)； Wherein step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
其中，步骤(e)为：化学拆分溶剂中，使用酸性拆分剂对外消旋的3-苯基哌啶(1)进行拆分，得到(R)-3-苯基哌啶((R)-1)或/和(S)-3-苯基哌啶((S)-1)。Wherein step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
可见，该另一种(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法合理利用了有机硅试剂(即(C nH 2n+1) 3SiH)，直接将3-羟基-3-苯基哌啶(3)中的羟基脱除，接着脱除保护基R 1，最终通过手性拆分制得目标产物(R)-3-苯基哌啶或/和(S)-3-苯基哌啶，其各步反应收率均较高，其中，(S)-3-苯基哌啶还可被进一步用于合成尼拉帕尼的手性中间体。 It can be seen that the synthesis method of the other (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine makes rational use of the silicone reagent (ie (C n H 2n+1 ) 3 SiH ), the hydroxyl group in 3-hydroxy-3-phenylpiperidine (3) is directly removed, followed by removal of the protecting group R 1 , and finally the desired product (R)-3-phenylpiperidyl is obtained by chiral resolution. Pyridine or / and (S)-3-phenylpiperidine, the reaction yield of each step is higher, wherein (S)-3-phenylpiperidine can be further used to synthesize the hand of nilapani Sexual intermediates.
优选地，在上述合成方法的所述步骤(f)中，所述(C nH 2n+1) 3SiH选自以下任一种：三乙基硅烷，三正丙基硅烷，三异丙基硅烷。 Preferably, in the step (f) of the above synthesis method, the (C n H 2n+1 ) 3 SiH is selected from any one of the following: triethylsilane, tri-n-propylsilane, triisopropyl Silane.
优选地，在上述合成方法的所述步骤(f)中，所述化学拆分溶剂选自以下任一种或多种的组合：甲醇，乙醇，异丙醇，正丙醇，正丁醇，四氢呋喃，乙酸乙酯，二氯甲烷。Preferably, in the step (f) of the above synthetic method, the chemical resolution solvent is selected from any one or a combination of the following: methanol, ethanol, isopropanol, n-propanol, n-butanol, Tetrahydrofuran, ethyl acetate, dichloromethane.
优选地，在上述合成方法的所述步骤(f)中，所述酸性拆分剂选自以下任一种：酒石酸，二苯甲酰基酒石酸，二对甲基苯甲酰酒石酸，苹果酸，樟脑磺酸，樟脑酸，扁桃酸，奎宁酸。Preferably, in the step (f) of the above synthetic method, the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoyl tartaric acid, malic acid, camphor Sulfonic acid, camphoric acid, mandelic acid, quinic acid.
同时，本发明第三方面提供了一种尼拉帕尼的手性中间体α的合成方法，其合成路线如下所示：Meanwhile, the third aspect of the present invention provides a method for synthesizing a chiral intermediate α of nilapani, and the synthetic route thereof is as follows:
Figure PCTCN2019076351-appb-000009
Figure PCTCN2019076351-appb-000009
并且，包括以下步骤：And, including the following steps:
S1：根据本发明第一方面或第二方面所述的合成方法制备(S)-3-苯基哌啶((S)-1)，其中，R 2为H； S1: (S)-3-phenylpiperidine ((S)-1), wherein R 2 is H, according to the synthesis method of the first aspect or the second aspect of the invention;
S2：将(S)-3-苯基哌啶((S)-1-1)与硝化剂发生硝化反应，生成(S)-3-对硝基苯基哌啶(6-1)；S2: nitration of (S)-3-phenylpiperidine ((S)-1-1) with a nitrating agent to form (S)-3-p-nitrophenyl piperidine (6-1);
S3：将(S)-3-对硝基苯基哌啶(6-1)与还原体系进行硝基还原反应，生成(S)-3-对胺基苯基哌啶(7)，即尼拉帕尼的手性中间体α。S3: nitro reduction reaction of (S)-3-p-nitrophenyl piperidine (6-1) with a reduction system to form (S)-3-p-aminophenyl piperidine (7), ie, Lappani's chiral intermediate alpha.
优选地，在上述尼拉帕尼的手性中间体α的合成方法中，所述硝化剂选自以下任一种：硝酸，硝酸钾，硝酸钠，硝酸铵，硝酰氯，硝酸丁酯，硝酸甲酯，NO 2BF 4，NO 2PF 6。进一步优选地，所述硝化剂选自以下任一种：硝酸，硝酸钾，NO 2BF 4和硝酸甲酯。 Preferably, in the above method for synthesizing the chiral intermediate α of nilapani, the nitrating agent is selected from any one of the following: nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, nitroxyl chloride, butyl nitrate, nitric acid Methyl ester, NO 2 BF 4 , NO 2 PF 6 . Further preferably, the nitrating agent is selected from any one of the following: nitric acid, potassium nitrate, NO 2 BF 4 and methyl nitrate.
优选地，在上述尼拉帕尼的手性中间体α的合成方法中，所述还原体系选自以下任一种：三氯化铁/水合肼，Fe/HCl，Zn/HCl，LiAlH 4，过渡金属催化剂/氢气，连二亚硫酸钠；其中，所述过渡金属催化剂选自以下任一种：雷尼镍，钯碳，二氧化钯，铂黑，二氧化铂。 Preferably, in the above synthesis method of the chiral intermediate α of nilapani, the reduction system is selected from any one of the following: ferric chloride/hydrated hydrazine, Fe/HCl, Zn/HCl, LiAlH 4 , Transition metal catalyst / hydrogen, sodium dithionite; wherein the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
此外，本发明第四方面还提供了一种尼拉帕尼的手性中间体β的合成方法，其合成路线如下所示：In addition, the fourth aspect of the present invention also provides a method for synthesizing a chiral intermediate β of nilapani, and the synthetic route is as follows:
Figure PCTCN2019076351-appb-000010
Figure PCTCN2019076351-appb-000010
其中，保护基PG选自以下任一种：烷基，酰基，磺酰基；例如，保护基PG优选为：乙酰基，丙酰基，丁酰基，苯磺酰基；Wherein the protecting group PG is selected from any one of the following: an alkyl group, an acyl group, a sulfonyl group; for example, the protecting group PG is preferably an acetyl group, a propionyl group, a butyryl group, a benzenesulfonyl group;
并且，包括以下步骤：And, including the following steps:
P1：根据本发明第一方面或第二方面所述的合成方法制备(S)-3-苯基哌啶((S)-1-1)，其中，R 2为H； P1: (S)-3-phenylpiperidine ((S)-1-1), wherein R 2 is H, according to the synthesis method of the first aspect or the second aspect of the invention;
P2：将(S)-3-苯基哌啶((S)-1)与N保护试剂发生反应，生成N-保护的(S)-3-苯基哌啶(8)；P2: reacting (S)-3-phenylpiperidine ((S)-1) with an N protecting reagent to form N-protected (S)-3-phenylpiperidine (8);
P3：将N-保护的(S)-3-苯基哌啶(8)与溴代试剂发生溴代反应，生成N-保护的(S)-3-对溴苯基哌啶(9)；P3: bromination of N-protected (S)-3-phenylpiperidine (8) with a bromination reagent to form N-protected (S)-3-p-bromophenylpiperidine (9);
P4：将N-保护的(S)-3-对溴苯基哌啶(9)进行脱保护反应，即脱去保护基PG，生成(S)-3-对溴苯基哌啶(10)，即尼拉帕尼的手性中间体β。P4: Deprotection of N-protected (S)-3-p-bromophenylpiperidine (9), ie removal of protecting group PG to give (S)-3-p-bromophenylpiperidine (10) , that is, the chiral intermediate β of Nilapani.
优选地，在上述尼拉帕尼的手性中间体β的合成方法中，所述N保护试剂选自以下任一种：乙酰氯，丙酰氯，丁酰氯，苯磺酰氯，BOC酸酐。Preferably, in the above method for synthesizing the chiral intermediate β of nilapani, the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
优选地，在上述尼拉帕尼的手性中间体β的合成方法中，所述溴代试剂选自以下任一种：NBS，Br 2，HBr，过溴化吡啶氢溴酸盐，二溴海因，2,4,4,6-四溴-2,5-环己二烯酮。 Preferably, in the above method for synthesizing the chiral intermediate β of nilapani, the bromination reagent is selected from any one of the following: NBS, Br 2 , HBr, pyridinium bromide hydrobromide, dibromide Hydanto, 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
最后，本发明第五方面还提供了一种尼拉帕尼的手性中间体γ的合成方法，其合成路线如下所示：Finally, the fifth aspect of the present invention also provides a method for synthesizing a chiral intermediate γ of nilapani, and the synthetic route is as follows:
Figure PCTCN2019076351-appb-000011
Figure PCTCN2019076351-appb-000011
其中，保护基PG选自以下任一种：烷基，酰基，磺酰基；例如，保护基PG优选为：乙酰基，丙酰基，丁酰基，苯磺酰基；Wherein the protecting group PG is selected from any one of the following: an alkyl group, an acyl group, a sulfonyl group; for example, the protecting group PG is preferably an acetyl group, a propionyl group, a butyryl group, a benzenesulfonyl group;
并且，包括以下步骤：And, including the following steps:
P'1：根据本发明第一方面或第二方面所述的合成方法制备(S)-3-苯基哌啶((S)-1)，其中，R 2选自以下任一种：甲氧基，乙氧基，异丙氧基，正丙氧基，烯丙基氧基，正丁基氧基，异丁基氧基，叔丁氧基，甲氧基甲氧基，乙氧基甲氧基，甲氧基乙氧基，2-四氢吡喃氧基，三甲基硅基乙氧基甲氧基，叔丁基二甲基硅基乙氧基甲氧基，三甲基硅氧基，三乙基硅氧基，三异丙基硅氧基，叔丁基二甲基硅氧基，叔丁基二苯基硅氧基，苄氧基，对甲氧基苄氧基，2,4-二甲氧基苄氧基； P'1: (S)-3-phenylpiperidine ((S)-1), wherein R 2 is selected from any one of the following: according to the synthesis method of the first aspect or the second aspect of the invention: Oxyl, ethoxy, isopropoxy, n-propoxy, allyloxy, n-butyloxy, isobutyloxy, tert-butoxy, methoxymethoxy, ethoxy Methoxy, methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilylethoxymethoxy, tert-butyldimethylsilylethoxymethoxy, trimethyl Silyloxy, triethylsilyloxy, triisopropylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy , 2,4-dimethoxybenzyloxy;
P'2：将(S)-3-苯基哌啶((S)-1)与N保护试剂发生反应，生成N-保护的(S)-3-苯基哌啶(8)；P'2: reacting (S)-3-phenylpiperidine ((S)-1) with an N protecting reagent to form N-protected (S)-3-phenylpiperidine (8);
P'3：将N-保护的(S)-3-苯基哌啶(8)脱除羟基保护基，生成N-保护的(S)-3-(4-羟基苯基)-哌啶(9’)；P'3: Deprotecting the N-protected (S)-3-phenylpiperidine (8) to form a N-protected (S)-3-(4-hydroxyphenyl)-piperidine ( 9');
P'4：将N-保护的(S)-3-(4-羟基苯基)-哌啶(9’)与活性磺酰氯或活性磺酸酐反应，生成活性酯(10’)，即尼拉帕尼的手性中间体γ。P'4: The N-protected (S)-3-(4-hydroxyphenyl)-piperidine (9') is reacted with an active sulfonyl chloride or an active sulfonic anhydride to form an active ester (10'), ie Nila Pani's chiral intermediate γ.
优选地，在上述尼拉帕尼的手性中间体γ的合成方法中，所述N保护试剂选自以下任一种：乙酰氯，丙酰氯，丁酰氯，苯磺酰氯，BOC酸酐。Preferably, in the above method for synthesizing the chiral intermediate γ of nilapani, the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
优选地，在上述尼拉帕尼的手性中间体γ的合成方法中，所述活性磺酰氯选自以下任一种：甲磺酰氯，对甲苯磺酰氯，苯磺酰氯；所述活性磺酸酐为三氟甲磺酸酐。Preferably, in the above method for synthesizing the chiral intermediate γ of nilapani, the active sulfonyl chloride is selected from any one of the following: methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride; the active sulfonic acid anhydride It is trifluoromethanesulfonic anhydride.
综上所述，与现有技术中已知的合成工艺相比，本发明所提供的技术方案至少具有以下有益效果：In summary, the technical solution provided by the present invention has at least the following beneficial effects compared with the synthetic processes known in the prior art:
Scheme 1所示的合成方法以N保护的3-哌啶酮为起始原料，依次进行格氏反应、消去反应、加氢还原反应、脱除保护基R 1、手性拆分，成功制得了目标产物(R)-3-苯基哌啶或/和(S)-3-苯基哌啶；Scheme 1-1所示的合成方法同样以N保护的3-哌啶酮为起始原料，先进行格氏反应，再巧妙地利用有机硅试剂直接将羟基脱除，然后脱除保护基R 1，并最终通过手性拆分制得目标产物(R)-3-苯基哌啶或/和(S)-3-苯基哌啶；并且，无论是Scheme 1所示的合成方法还是Scheme1-1所示的合成方法，其中所使用的反应试剂较廉价，各步反应收率较高，且反应条件温和，因此特别适用于大规模工业化生产。 The synthesis method shown in Scheme 1 uses N-protected 3-piperidone as a starting material, followed by Grignard reaction, elimination reaction, hydrogenation reduction reaction, removal of protecting group R 1 and chiral resolution. The target product (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine; the synthesis method shown by Scheme 1-1 is also based on N-protected 3-piperidone. The Grignard reaction is first carried out, and the hydroxyl group is directly removed by using a silicone reagent, and then the protecting group R 1 is removed, and finally the target product (R)-3-phenylpiperidine or / is obtained by chiral resolution. And (S)-3-phenylpiperidine; and, whether the synthesis method shown by Scheme 1 or the synthesis method shown by Scheme 1-1, the reaction reagent used is relatively inexpensive, and the reaction yield of each step is high. And the reaction conditions are mild, so it is particularly suitable for large-scale industrial production.
此外，(S)-3-苯基哌啶还可按照Scheme 2所示的路线合成(S)-3-对胺基苯基哌啶，或者按照Scheme 3所示的路线合成(S)-3-对溴苯基哌啶，亦或按照Scheme 3-1所示的路线合成活性酯；值得说明的是，本文所述的(S)-3-对胺基苯基哌啶、(S)-3-对溴苯基哌啶与活性酯均为制备尼拉帕尼的关键中间体。Further, (S)-3-phenylpiperidine can also synthesize (S)-3-p-aminophenylpiperidine according to the route shown in Scheme 2, or synthesize (S)-3 according to the route shown in Scheme 3. - p-bromophenylpiperidine, or an active ester according to the route shown in Scheme 3-1; it is worth noting that (S)-3-p-aminophenylpiperidine, (S)- described herein 3-P-Butylphenyl piperidine and the active ester are both key intermediates in the preparation of nilapani.
总之，本发明所提供的(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法与尼拉帕尼的手性中间体α、β、γ的合成方法均显著降低了生产成本，从而有利于尼拉帕尼药物的大规模工业化生产。In summary, the synthesis method of (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine provided by the present invention and the synthesis of the chiral intermediates α, β and γ of nilapani The methods all significantly reduce the production cost, which is beneficial to the large-scale industrial production of nirapani drugs.
具体实施方式Detailed ways
下面结合具体实施方式对本发明作进一步阐述，但本发明并不限于以下实施方式。The present invention will be further described below in conjunction with specific embodiments, but the invention is not limited to the following embodiments.
并且，下述实施例中的操作步骤，如无特殊说明，均为常规操作步骤；下述实施例中所用的仪器、材料、试剂等，如无特殊说明，均可从公开商业途径获得。Further, the operation steps in the following examples are routine operation steps unless otherwise specified; the instruments, materials, reagents and the like used in the following examples can be obtained from commercially available routes unless otherwise specified.
实施例1：3-羟基-3-苯基-1-苄基哌啶(3-1)的合成Example 1: Synthesis of 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)
Figure PCTCN2019076351-appb-000012
Figure PCTCN2019076351-appb-000012
将苯基溴化镁格氏试剂(2mol/L in THF，240mL)，无水四氢呋喃(300mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,60.0g,317.0mmol)用无水四氢呋喃(300mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(300mL)，再用乙酸乙酯(200mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品(3-羟基-3-苯基-1-苄基哌啶(3-1))76.5g，收率90.2％； 1H-NMR(400MHz,D 2O)δ:7.41(5H,s),7.32(5H,s),4.42(1H,d,J＝12.4Hz),4.21(1H,d,J＝13.2Hz),3.60(1H,d,J＝11.2Hz),3.28(1H,d,J＝12.4Hz),3.15-3.13(2H,m),2.22-2.19(1H,m),1.99-1.87(3H,m).MS-ESI(m/z)：268.3[(M+H) +]；该粗品可直接用于下一步反应。 Phenylmagnesium bromide Grignard reagent (2mol/L in THF, 240mL), anhydrous tetrahydrofuran (300mL), added to the reaction flask, protected with nitrogen, cooled to 0 ° C in ice water bath, N-benzyl-3- Piperidone (2-1, 60.0 g, 317.0 mmol) was diluted with anhydrous tetrahydrofuran (300 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and a saturated aqueous solution of ammonium chloride (300 mL) was added thereto, and then extracted with ethyl acetate (200 mL×3). After extracting three times, the organic layers were combined and added. Dry with an appropriate amount of anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product (3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)) 76.5 g, yield 90.2%; 1 H-NMR ( 400MHz, D 2 O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J = 12.4 Hz), 4.21 (1H, d, J = 13.2 Hz), 3.60 (1H, d, J = 11.2 Hz), 3.28 (1H, d, J = 12.4 Hz), 3.15-3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m). MS-ESI (m/z): 268.3 [(M+H) + ]; this crude product was used directly in the next step.
实施例2：3-羟基-3-苯基-1-苄基哌啶(3-1)的合成Example 2: Synthesis of 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)
Figure PCTCN2019076351-appb-000013
Figure PCTCN2019076351-appb-000013
将苯基溴化镁格氏试剂(2mol/L in THF，240mL)，无水乙醚(300mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,60.0g,317.0mmol)用无水乙醚(300mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC 检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(300mL)，再用乙酸乙酯(200mL×3)萃取，萃取三次后，合并有机层，再向合并的有机层中加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品(3-羟基-3-苯基-1-苄基哌啶(3-1))74.1g，收率87.4％； 1H-NMR(400MHz,D2O)δ:7.41(5H,s),7.32(5H,s),4.42(1H,d,J＝12.4Hz),4.21(1H,d,J＝13.2Hz),3.60(1H,d,J＝11.2Hz),3.28(1H,d,J＝12.4Hz),3.15-3.13(2H,m),2.22-2.19(1H,m),1.99-1.87(3H,m).MS-ESI(m/z)：268.3[(M+H) +]；该粗品可直接用于下一步反应。 Phenylmagnesium bromide Grignard reagent (2mol/L in THF, 240mL), anhydrous ether (300mL), was added to the reaction flask, protected with nitrogen, cooled to 0 ° C in ice water bath, N-benzyl-3- Piperidone (2-1, 60.0 g, 317.0 mmol) was diluted with anhydrous diethyl ether (300 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and a saturated aqueous solution of ammonium chloride (300 mL) was added thereto, and then extracted with ethyl acetate (200 mL×3), extracted three times, and then the organic layer was combined. The organic layer was added with an appropriate amount of anhydrous sodium sulfate and dried, filtered, and then evaporated to give the crude product (3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)) 74.1 g, 1 ; H-NMR (400MHz, D2O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J = 12.4 Hz), 4.21 (1H, d, J = 13.2 Hz) , 3.60 (1H, d, J = 11.2 Hz), 3.28 (1H, d, J = 12.4 Hz), 3.15-3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m MS-ESI (m/z): 268.3 [(M+H) + ];
实施例3：3-羟基-3-苯基-1-苄基哌啶(3-1)的合成Example 3: Synthesis of 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)
Figure PCTCN2019076351-appb-000014
Figure PCTCN2019076351-appb-000014
将苯基氯化镁格氏试剂(2mol/L in THF，240mL)，无水四氢呋喃(300mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2,60.0g,317.0mmol)用无水四氢呋喃(300mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，50min滴完，滴加完毕后继续搅拌反应1.5小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(300mL)，再用乙酸乙酯(200mL×3)萃取，萃取三次后，合并有机层，再向合并的有机层中加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品(3-羟基-3-苯基-1-苄基哌啶(3-1))75.5g，收率89.0％； 1H-NMR(400MHz,D 2O)δ:7.41(5H,s),7.32(5H,s),4.42(1H,d,J＝12.4Hz),4.21(1H,d,J＝13.2Hz),3.60(1H,d,J＝11.2Hz),3.28(1H,d,J＝12.4Hz),3.15-3.13(2H,m),2.22-2.19(1H,m),1.99-1.87(3H,m).MS-ESI(m/z)：268.3[(M+H) +]；该粗品可直接用于下一步反应。 Phenylmagnesium chloride Grignard reagent (2mol/L in THF, 240mL), anhydrous tetrahydrofuran (300mL), added to the reaction flask, nitrogen protection, cooled to 0 ° C in ice water bath, N-benzyl-3-piperidine The ketone (2,60.0 g, 317.0 mmol) was diluted with anhydrous tetrahydrofuran (300 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was controlled at 0-5 ° C, 50 min, and the addition was completed. The reaction was stirred for 1.5 hours, and the reaction was completed by TLC. A saturated aqueous solution of ammonium chloride (300 mL) was added, and then extracted with ethyl acetate (200 mL×3). After extraction three times, the organic layers were combined and then combined organic layer was added an appropriate amount of anhydrous sodium sulfate, filtered, rotary evaporation to give a crude product (3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)) 75.5g, yield 89.0%; 1 H NMR (400MHz, D 2 O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J = 12.4 Hz), 4.21 (1H, d, J = 13.2 Hz), 3.60 (1H, d, J = 11.2 Hz), 3.28 (1H, d, J = 12.4 Hz), 3.15-3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m). MS-ESI (m/z): 268.3 [(M+H) + ];
实施例4：3-羟基-3-苯基-1-苄基哌啶(3-1)的合成Example 4: Synthesis of 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)
Figure PCTCN2019076351-appb-000015
Figure PCTCN2019076351-appb-000015
将苯基氯化镁格氏试剂(2mol/L in THF，240mL)，无水乙醚(300mL)， 加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2,60.0g,317.0mmol)用无水乙醚(300mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，30min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(300mL)，再用乙酸乙酯(200mL×3)萃取，萃取三次后，合并有机层，再向合并的有机层中加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品(3-羟基-3-苯基-1-苄基哌啶(3-1))77.4g，收率91.3％； 1H-NMR(400MHz,D 2O)δ:7.41(5H,s),7.32(5H,s),4.42(1H,d,J＝12.4Hz),4.21(1H,d,J＝13.2Hz),3.60(1H,d,J＝11.2Hz),3.28(1H,d,J＝12.4Hz),3.15-3.13(2H,m),2.22-2.19(1H,m),1.99-1.87(3H,m).MS-ESI(m/z)：268.3[(M+H) +]；该粗品可直接用于下一步反应。 Phenylmagnesium chloride Grignard reagent (2mol/L in THF, 240mL), anhydrous ether (300mL), added to the reaction flask, nitrogen protection, cooled to 0 ° C in ice water bath, N-benzyl-3-piperidine The ketone (2,60.0 g, 317.0 mmol) was diluted with anhydrous diethyl ether (300 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was controlled at 0-5 ° C, 30 min, and the addition was completed. The reaction was stirred for 1 hour, and the TLC was used to confirm that the starting material had been completely reacted. Saturated aqueous ammonium chloride solution (300 mL) was added thereto, and extracted with ethyl acetate (200 mL×3). After extracting three times, the organic layers were combined and then combined organic The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product (3-hydroxy-3-phenyl-1-benzylpiperidine (3-1)) 77.4 g, yield 91.3%; 1 H NMR (400MHz, D 2 O) δ: 7.41 (5H, s), 7.32 (5H, s), 4.42 (1H, d, J = 12.4 Hz), 4.21 (1H, d, J = 13.2 Hz), 3.60 (1H, d, J = 11.2 Hz), 3.28 (1H, d, J = 12.4 Hz), 3.15-3.13 (2H, m), 2.22-2.19 (1H, m), 1.99-1.87 (3H, m). MS-ESI (m/z): 268.3 [(M+H) + ];
实施例5：化合物(4-1)和化合物(5-1)的合成Example 5: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000016
Figure PCTCN2019076351-appb-000016
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、冰乙酸(400mL,6.67mol)、乙酰氯(400mL,5.66mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(200mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品(化合物(4-1)和化合物(5-1)的混合物)64.7g，收率88.3％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 Add 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), glacial acetic acid (400 mL, 6.67 mol), acetyl chloride (400 mL, 5.66 mol) to the reaction flask After heating and refluxing for 90 min, TLC detects the reaction of the starting material completely, stops the reaction, and distills the acetic acid under reduced pressure. Then, a 20% aqueous sodium hydroxide solution is added to the residue to adjust the pH of the solution to 8-9, followed by extraction with ethyl acetate. (200 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude product (mixture of compound (4-1) and compound (5-1)) 64.7 g, yield 88.3% , used directly in the next reaction. MS-ESI (m / z) : 250.3 (M + H) +.
实施例6：化合物(4-1)和化合物(5-1)的合成Example 6: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000017
Figure PCTCN2019076351-appb-000017
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、甲酸(700mL,18.6mol)加入到反应瓶中，加热，回流反应3h后TLC检测原料反应完全，停止反应，将甲酸旋干，先加入水(250mL)，再加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(250mL×3)，收集有机层，用无水硫酸 钠进行干燥，过滤，将溶剂旋干得到粗品50.1g(化合物(4-1)和化合物(5-1)的混合物)，收率70.3％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), formic acid (700 mL, 18.6 mol) was added to the reaction flask, heated, refluxed for 3 h, and the material was detected by TLC. The reaction was completed, the reaction was stopped, the formic acid was spun dry, water (250 mL) was added first, then 20% aqueous sodium hydroxide solution was added, and the pH of the solution was adjusted to 8-9, followed by extraction with ethyl acetate (250 mL×3), and organic was collected. The layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to afford 50.1 g (yield of compound (4-1) and compound (5-1)). MS-ESI (m / z) : 250.3 (M + H) +.
实施例7：化合物(4-1)和化合物(5-1)的合成Example 7: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000018
Figure PCTCN2019076351-appb-000018
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、甲苯(700mL)、对甲苯磺酸(27g,142.1mmol)加入到反应瓶中，加热，回流反应12h后TLC检测原料反应完全，停止反应，旋蒸后，先加入水(100mL)，再加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(200mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品40.2g(化合物(4-1)和化合物(5-1)的混合物)，收率56.2％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), toluene (700 mL), p-toluenesulfonic acid (27 g, 142.1 mmol) was added to the reaction flask and heated. After refluxing for 12 h, TLC detected the reaction of the starting material completely, and stopped the reaction. After rotary evaporation, water (100 mL) was added first, then 20% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 8-9, followed by extraction with ethyl acetate ( 200 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give 40.2 g (yield of compound (4-1) and compound (5-1)). Used directly in the next step. MS-ESI (m / z) : 250.3 (M + H) +.
实施例8：化合物(4-1)和化合物(5-1)的合成Example 8: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000019
Figure PCTCN2019076351-appb-000019
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、乙酸(700mL,11.6mol)加入到反应瓶中，加热，回流反应2.5h后TLC检测原料反应完全，停止反应，将乙酸减压蒸出，先加入水(300mL)，再加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(200mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品50.2g(化合物(4-1)和化合物(5-1)的混合物)，收率70.3％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), acetic acid (700 mL, 11.6 mol) was added to the reaction flask, heated, refluxed for 2.5 h and then detected by TLC. The reaction of the starting material was completed, the reaction was stopped, acetic acid was distilled off under reduced pressure, water (300 mL) was added first, then 20% aqueous sodium hydroxide solution was added thereto, and the pH of the solution was adjusted to 8-9, followed by extraction with ethyl acetate (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give 50.2 g (yield of compound (4-1) and compound (5-1)). One step reaction. MS-ESI (m / z) : 250.3 (M + H) +.
实施例9：化合物(4-1)和化合物(5-1)的合成Example 9: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000020
Figure PCTCN2019076351-appb-000020
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、4M盐酸的1,4-二氧六环溶液(76.5mL)、1,4-二氧六环(200mL)加入到反应瓶中，加热，回流反应10h后TLC检测原料反应完全，停止反应，将1,4-二氧六环减压蒸出， 先加入水(200mL)，再加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(200mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品52.2g(化合物(4-1)和化合物(5-1)的混合物)，收率72.4％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), 4 M hydrochloric acid in 1,4-dioxane solution (76.5 mL), 1,4-di Oxyhexacyclohexane (200 mL) was added to the reaction flask, heated, and refluxed for 10 h. After TLC, the reaction of the starting material was complete, the reaction was stopped, and 1,4-dioxane was distilled off under reduced pressure. Water (200 mL) was added first, followed by addition. A 20% aqueous sodium hydroxide solution was adjusted to pH = 8-9, then extracted with ethyl acetate (200 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated. (A mixture of the compound (4-1) and the compound (5-1)), a yield of 72.4%, was used directly for the next reaction. MS-ESI (m / z) : 250.3 (M + H) +.
实施例10：化合物(4-1)和化合物(5-1)的合成Example 10: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000021
Figure PCTCN2019076351-appb-000021
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、4M盐酸的四氢呋喃溶液(700mL)加入到反应瓶中，加热，回流反应14h后TLC检测原料反应完全，停止反应，将四氢呋喃旋干，先加入水(100mL)，再加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(100mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品48.3g(化合物(4-1)和化合物(5-1)的混合物)，收率69.1％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), 4M hydrochloric acid in tetrahydrofuran (700 mL) was added to the reaction flask, heated, refluxed for 14 h and then detected by TLC The reaction of the starting material was completed, the reaction was stopped, the tetrahydrofuran was spun dry, water (100 mL) was added first, and then 20% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 8-9, followed by extraction with ethyl acetate (100 mL×3), and collected. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give 48.3 g (yield of compound (4-1) and compound (5-1)). . MS-ESI (m / z) : 250.3 (M + H) +.
实施例11：化合物(4-1)和化合物(5-1)的合成Example 11: Synthesis of Compound (4-1) and Compound (5-1)
Figure PCTCN2019076351-appb-000022
Figure PCTCN2019076351-appb-000022
将3-羟基-3-苯基-1-苄基哌啶(3-1,76.5g,286.5mmol)、三乙胺(70mL，503.1mmol)、二氯甲烷(DCM)(500mL)加入到反应瓶中，降温到0℃后，缓慢滴加甲基磺酰氯(30mL，392.8mmol)，30min滴加完毕，接着，升温到室温，继续搅拌反应1h，TLC检测原料反应完全，停止反应，将DCM旋干，再向残余物中加入500mL无水DMF，待残余物溶清后，投加钠氢(60％，14g,0.35mol)，加热到75℃，反应2h，TLC检测原料反应完毕，停止反应，将反应液倒入冰水(100mL)中；用乙酸乙酯萃取(100mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品60.3g(化合物(4-1)和化合物(5-1)的混合物)，收率85.6％，直接用于下一步反应。MS-ESI(m/z)：250.3(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 76.5 g, 286.5 mmol), triethylamine (70 mL, 503.1 mmol), dichloromethane (DCM) (500 mL) In the bottle, after cooling to 0 ° C, methylsulfonyl chloride (30 mL, 392.8 mmol) was slowly added dropwise, and the addition was completed in 30 min. Then, the temperature was raised to room temperature, and the reaction was further stirred for 1 h. The reaction of the starting material was completely confirmed by TLC, and the reaction was stopped. The mixture was spun dry, and 500 mL of anhydrous DMF was added to the residue. After the residue was dissolved, sodium hydrogen (60%, 14 g, 0.35 mol) was added, and the mixture was heated to 75 ° C for 2 h. The reaction of TLC was completed and stopped. The reaction mixture was poured into ice water (100 mL); EtOAc (EtOAc m. 4-1) and a mixture of the compound (5-1), the yield was 85.6%, and it was used directly for the next reaction. MS-ESI (m / z) : 250.3 (M + H) +.
实施例12：3-苯基哌啶(1-1)的合成Example 12: Synthesis of 3-phenylpiperidine (1-1)
Figure PCTCN2019076351-appb-000023
Figure PCTCN2019076351-appb-000023
将化合物(4-1)和化合物(5-1)的混合物(64.7g,259.8mmol)、钯碳(13g,20％)、无水甲醇(300mL)、冰乙酸(12mL)加入到高压釜中，并通入1atm的氢气，加热到60℃，反应16h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(200mL)，并用乙酸乙酯进行萃取(200mL×3)，收集有机层，用无水硫酸钠干燥，过滤，将溶剂旋干得到产物3-苯基哌啶(1-1)35.1g，收率88.3％，直接用于下一步反应。 1H-NMR(400MHz，DMSO-d6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +。 A mixture of the compound (4-1) and the compound (5-1) (64.7 g, 259.8 mmol), palladium carbon (13 g, 20%), anhydrous methanol (300 mL), glacial acetic acid (12 mL) was placed in the autoclave. And pass 1 atm of hydrogen, heat to 60 ° C, react for 16 h, TLC detection of the reaction of the starting material is complete, stop the reaction, filter the palladium on carbon, spin the solvent, add water (200 mL), and extract with ethyl acetate (200 mL × 3 The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give the product 3-phenylpiperidine (1-1) (35.1 g, yield: 88.3%). 1 H-NMR (400MHz, DMSO -d6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67 - 1.46 (3H, m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI (m/z): 162.2 ( M+H) + .
实施例13：(S)-3-苯基哌啶((S)-1-1)的制备Example 13: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000024
Figure PCTCN2019076351-appb-000024
将3-苯基哌啶(1-1,100g,621.1mmol)溶于异丙醇(50mL)，将溶有L-酒石酸(93.16g,622.2mmol)的异丙醇(200mL)溶液滴加到外消旋3-苯基哌啶的异丙醇溶液中，搅拌2h，过滤，得到酒石酸盐；然后，向该酒石酸盐加入甲醇(10L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-20℃析晶7天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体30.1g，即(S)-3-苯基哌啶，收率30.1％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝95.39％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in isopropanol (50 mL), and a solution of L-tartaric acid (93.16 g, 622.2 mmol) in isopropanol (200 mL) was added dropwise. The solution of racemic 3-phenylpiperidine in isopropanol was stirred for 2 h and filtered to obtain the tartrate; then, methanol (10 L) was added to the tartrate, and after heating to complete dissolution, the stirring was stopped; the temperature was slowly lowered to room temperature. The crystallization was carried out at -20 ° C for 7 days, and filtered to give a white crystals crystals crystals. 30.1 g of a white waxy solid, (S)-3-phenylpiperidine, yield 30.1%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 95.39%.
实施例14：(S)-3-苯基哌啶((S)-1-1)的制备Example 14: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000025
Figure PCTCN2019076351-appb-000025
将3-苯基哌啶(1-1,100g,621.1mmol)溶于甲醇(50mL)，将溶有L-(-)-二苯甲酰酒石酸(222.93g,622.2mmol)的甲醇(200mL)溶液滴加到外消旋3-苯基哌啶的甲醇溶液中，搅拌2h，过滤，得到二苯甲酰酒石酸盐；然后，向该二苯甲酰酒石酸盐加入乙醇(8L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-10℃析晶5天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体28.3g，即(S)-3-苯基哌啶，收率28.3％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝92.41％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in methanol (50 mL) and a solution of L-(-)-dibenzoyltartaric acid (222.93 g, 622.2 mmol) in methanol (200 mL) Add dropwise to a solution of racemic 3-phenylpiperidine in methanol, stir for 2 h, and filter to obtain dibenzoyl tartrate; then, add ethanol (8 L) to the dibenzoyl tartrate and heat to dissolve completely. After that, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -10 ° C for 5 days, and filtered to give a white solid (yield: EtOAc (EtOAc) Dry over anhydrous sodium sulfate, filtered and concentrated to give a white white solid (2,3 g), (S)-3-phenylpiperidine, yield: 28.3%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 92.41%.
实施例15：(S)-3-苯基哌啶((S)-1-1)的制备Example 15: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000026
Figure PCTCN2019076351-appb-000026
将3-苯基哌啶(1-1,100g,621.1mmol)溶于乙酸乙酯(50mL)，将溶有L-(-)-二苯甲酰酒石酸(222.93g,622.2mmol)的乙酸乙酯(200mL)溶液滴加到外消旋3-苯基哌啶的乙酸乙酯溶液中，搅拌2h，过滤，得到二苯甲酰酒石酸盐；然后，向该二苯甲酰酒石酸盐加入甲醇(10L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-20℃析晶7天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(100mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体25.3g，即(S)-3-苯基哌啶，收率25.3％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝93.21％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in ethyl acetate (50 mL) and ethyl acetate ethyl acetate (222.93 g, 622.2 (200 mL) solution was added dropwise to a solution of racemic 3-phenylpiperidine in ethyl acetate, stirred for 2 h, filtered to give dibenzoyl tartrate; then, methanol (10 L) was added to the dibenzoyl tartrate. After heating to complete dissolution, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -20 ° C for 7 days, and filtered to give a crude white solid. EtOAc (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated.]]]] 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 93.21%.
实施例16：(S)-3-苯基哌啶((S)-1-1)的制备Example 16: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000027
Figure PCTCN2019076351-appb-000027
将3-苯基哌啶(1-1,100g,621.1mmol)溶于乙酸乙酯(30mL)，将溶有L-二对甲基苯甲酰酒石酸(205.53g,622.2mmol)的乙酸乙酯(200mL)溶液滴加到外消旋3-苯基哌啶的乙酸乙酯溶液中，搅拌2h，过滤，得到二对甲基苯甲酰酒石酸盐；然后，向该二对甲基苯甲酰酒石酸盐加入乙酸乙酯(15L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，0℃析晶2天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体20.5g，即(S)-3-苯基哌啶，收率20.5％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝93.82％。 Ethyl acetate (30. 200 mL) solution was added dropwise to a solution of racemic 3-phenylpiperidine in ethyl acetate, stirred for 2 h, filtered to give di-p-methylbenzoyl tartrate; then, to the di-p-methylbenzoyl tartaric acid The salt was added to ethyl acetate (15 L), heated to complete dissolution, stirring was stopped; the temperature was slowly cooled to room temperature, crystallized at 0 ° C for 2 days, and filtered to give a crude white solid, 1N aqueous sodium hydroxide (50 mL) Ester extraction (25 mL x 2), EtOAc (EtOAc m. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 93.82%.
实施例17：(S)-3-苯基哌啶((S)-1-1)的制备Example 17: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000028
Figure PCTCN2019076351-appb-000028
将3-苯基哌啶(1-1,100g,621.1mmol)溶于四氢呋喃(60mL)，将溶有L-苹果酸(83.43g,622.2mmol)的四氢呋喃(250mL)溶液滴加到外消旋3-苯基哌啶的四氢呋喃溶液中，搅拌2h，过滤，得到苹果酸盐；然后，向该苹果酸盐加入四氢呋喃(8L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-10℃析晶3天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体18.7g，即(S)-3-苯基哌啶，收率18.7％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝92.49％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in tetrahydrofuran (60 mL), and a solution of L-malic acid (83.43 g, 622.2 mmol) in tetrahydrofuran (250 mL) was added dropwise to the racemic 3 -Phenylpiperidine in tetrahydrofuran solution, stirring for 2 h, filtering to obtain malate; then, adding tetrahydrofuran (8 L) to the malate, heating to complete dissolution, stirring was stopped; slowly cooling to room temperature, -10 ° C The crystallization was carried out for 3 days, and filtered to give a white crystals crystals crystals crystals crystals 18.7 g of solid, namely (S)-3-phenylpiperidine, yield 18.7%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 92.49%.
实施例18：(S)-3-苯基哌啶((S)-1-1)的制备Example 18: Preparation of (S)-3-phenylpiperidine ((S)-1-1)
Figure PCTCN2019076351-appb-000029
Figure PCTCN2019076351-appb-000029
将3-苯基哌啶(1-1,100g,621.1mmol)溶于乙醇(50mL)，将溶有L-樟脑磺酸(145.8g,622.2mmol)的乙醇(150mL)溶液滴加到外消旋3-苯基哌啶的乙醇溶液中，搅拌2h，过滤，得到樟脑磺酸盐；然后，向该樟脑磺酸盐加入甲醇(5L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，0℃析晶2天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体18.1g，即(S)-3-苯基哌啶，收率18.1％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；Mp＝14.5-15.5℃，ee＝89.19％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in ethanol (50 mL), and a solution of L-camphorsulfonic acid (145.8 g, 622.2 mmol) in ethanol (150 mL) was added dropwise to the racemic 3-phenylpiperidine in ethanol solution, stirred for 2 h, filtered to obtain camphor sulfonate; then, methanol (5 L) was added to the camphor sulfonate, heated to complete dissolution, stirring was stopped; slowly cooled to room temperature, After crystallization at 0 ° C for 2 days, EtOAc (EtOAc)EtOAc. 18.1 g of a waxy solid, namely (S)-3-phenylpiperidine, yield 18.1%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; Mp = 14.5-15.5 ° C, ee = 89.19%.
实施例19：(R)-3-苯基哌啶((R)-1-1)的制备Example 19: Preparation of (R)-3-phenylpiperidine ((R)-1-1)
Figure PCTCN2019076351-appb-000030
Figure PCTCN2019076351-appb-000030
将3-苯基哌啶(1-1,100g,621.1mmol)溶于异丙醇(50mL)，将溶有D-酒石酸(93.16g,622.2mmol)的异丙醇(200mL)溶液滴加到外消旋3-苯基哌啶的异丙醇溶液中，搅拌2h，过滤，得到酒石酸盐；然后，向该酒石酸盐加入甲醇(10L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-20℃析晶7天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体29.7g，即(R)-3-苯基哌啶，收率29.7％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；ee 94.85％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in isopropanol (50 mL), and a solution of D-tartaric acid (93.16 g, 622.2 mmol) in isopropanol (200 mL) was added dropwise. The solution of racemic 3-phenylpiperidine in isopropanol was stirred for 2 h and filtered to obtain the tartrate; then, methanol (10 L) was added to the tartrate, and after heating to complete dissolution, the stirring was stopped; the temperature was slowly lowered to room temperature. The crystallization was carried out at -20 ° C for 7 days, and filtered to give a white crystals crystals crystals. 29.7 g of a white waxy solid, (R)-3-phenylpiperidine, yield 29.7%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; ee 94.85%.
实施例20：(R)-3-苯基哌啶((R)-1-1)的制备Example 20: Preparation of (R)-3-phenylpiperidine ((R)-1-1)
Figure PCTCN2019076351-appb-000031
Figure PCTCN2019076351-appb-000031
将3-苯基哌啶(1-1,100g,621.1mmol)溶于甲醇(50mL)，将溶有D-(+)-二苯甲酰酒石酸(222.93g,622.2mmol)的甲醇(200mL)溶液滴加到外消旋3-苯基哌啶的甲醇溶液中，搅拌2h，过滤，得到二苯甲酰酒石酸盐；然后，向该二苯甲酰酒石酸盐加入乙醇(8L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-10℃析晶5天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体28.3g，即(R)-3-苯基哌啶，收率28.3％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；ee＝93.64％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in methanol (50 mL) and a solution of D-(+)-dibenzoyltartaric acid (222.93 g, 622.2 mmol) in methanol (200 mL) Add dropwise to a solution of racemic 3-phenylpiperidine in methanol, stir for 2 h, and filter to obtain dibenzoyl tartrate; then, add ethanol (8 L) to the dibenzoyl tartrate and heat to dissolve completely. After that, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -10 ° C for 5 days, and filtered to give a white solid (yield: EtOAc (EtOAc) Dry over anhydrous sodium sulfate, filtered and concentrated to give a white crystals. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; ee=93.64%.
实施例21：(R)-3-苯基哌啶((R)-1-1)的制备Example 21: Preparation of (R)-3-phenylpiperidine ((R)-1-1)
Figure PCTCN2019076351-appb-000032
Figure PCTCN2019076351-appb-000032
将3-苯基哌啶(1-1,100g,621.1mmol)溶于乙酸乙酯(30mL)，将溶有D-二对甲基苯甲酰酒石酸(205.53g,622.2mmol)的乙酸乙酯(200mL)溶液滴加到外消旋3-苯基哌啶的乙酸乙酯溶液中，搅拌2h，过滤，得到二对甲基苯甲酰酒石酸盐；然后，向该二对甲基苯甲酰酒石酸盐加入乙酸乙酯(15L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，0℃析晶2天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体23.5g，即(R)-3-苯基哌啶，收率23.5％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92, 43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；ee＝95.32％。 Ethyl acetate (30. 200 mL) solution was added dropwise to a solution of racemic 3-phenylpiperidine in ethyl acetate, stirred for 2 h, filtered to give di-p-methylbenzoyl tartrate; then, to the di-p-methylbenzoyl tartaric acid The salt was added to ethyl acetate (15 L), heated to complete dissolution, stirring was stopped; the temperature was slowly cooled to room temperature, crystallized at 0 ° C for 2 days, and filtered to give a crude white solid, 1N aqueous sodium hydroxide (50 mL) Ester extraction (25 mL x 2), EtOAc (EtOAc m. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; ee = 95.32%.
实施例22：(R)-3-苯基哌啶((R)-1-1)的制备Example 22: Preparation of (R)-3-phenylpiperidine ((R)-1-1)
Figure PCTCN2019076351-appb-000033
Figure PCTCN2019076351-appb-000033
将3-苯基哌啶(1-1,100g,621.1mmol)溶于四氢呋喃(60mL)，将溶有D-苹果酸(83.43g,622.2mmol)的四氢呋喃(250mL)溶液滴加到外消旋3-苯基哌啶的四氢呋喃溶液中，搅拌2h，过滤，得到苹果酸盐；然后，向该苹果酸盐加入四氢呋喃(8L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-10℃析晶3天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体17.9g，即(R)-3-苯基哌啶，收率17.9％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；ee＝90.20％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in tetrahydrofuran (60 mL), and a solution of D-malic acid (83.43 g, 622.2 mmol) in tetrahydrofuran (250 mL) was added dropwise to the racemic 3 -Phenylpiperidine in tetrahydrofuran solution, stirring for 2 h, filtering to obtain malate; then, adding tetrahydrofuran (8 L) to the malate, heating to complete dissolution, stirring was stopped; slowly cooling to room temperature, -10 ° C The crystallization was carried out for 3 days, and filtered to give a white crystals crystals crystals crystals crystals 17.9 g of solid, i.e., (R)-3-phenylpiperidine, yield 17.9%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; ee = 90.20%.
实施例23：(R)-3-苯基哌啶((R)-1-1)的制备Example 23: Preparation of (R)-3-phenylpiperidine ((R)-1-1)
Figure PCTCN2019076351-appb-000034
Figure PCTCN2019076351-appb-000034
将3-苯基哌啶(1-1,100g,621.1mmol)溶于乙醇(50mL)，将溶有D-樟脑磺酸(145.8g,622.2mmol)的乙醇(150mL)溶液滴加到外消旋3-苯基哌啶的乙醇溶液中，搅拌2h，过滤，得到樟脑磺酸盐；然后，向该樟脑磺酸盐加入甲醇(5L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，0℃析晶2天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到白色蜡状固体19.3g，即(R)-3-苯基哌啶，收率19.3％。 1H-NMR(400MHz，DMSO-d 6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08, 126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +；ee＝87.31％。 3-Phenylpiperidine (1-1, 100 g, 621.1 mmol) was dissolved in ethanol (50 mL), and a solution of D-camphorsulfonic acid (145.8 g, 622.2 mmol) in ethanol (150 mL) was added dropwise to the racemic 3-phenylpiperidine in ethanol solution, stirred for 2 h, filtered to obtain camphor sulfonate; then, methanol (5 L) was added to the camphor sulfonate, heated to complete dissolution, stirring was stopped; slowly cooled to room temperature, After crystallization at 0 ° C for 2 days, EtOAc (EtOAc)EtOAc. The waxy solid was 19.3 g, i.e., (R)-3-phenylpiperidine, yield 19.3%. 1 H-NMR (400MHz, DMSO -d 6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67-1.46(3H,m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI(m/z):162.2 (M+H) + ; ee = 87.31%.
实施例24：(S)-3-对硝基苯基哌啶(6-1)的合成Example 24: Synthesis of (S)-3-p-nitrophenyl piperidine (6-1)
Figure PCTCN2019076351-appb-000035
Figure PCTCN2019076351-appb-000035
将(S)-3-苯基哌啶((S)-1-1,35.1g,218.0mmol)、冰乙酸(300mL)加入到反应瓶中，接着缓慢滴加浓硫酸(12mL)，搅拌10min后，降温到0℃，再缓慢滴入发烟硝酸(9.6mL,218.2mmol)，继续搅拌10min，然后缓慢滴加浓硫酸(180mL)，滴加完毕后，0℃搅拌反应7h，TLC检测原料反应完全，停止反应；用20％的氢氧化钠溶液，调节反应溶液pH＝10-12，然后用乙酸乙酯萃取(200mL×2)，收集有机层，加入无水硫酸钠干燥，过滤，旋干溶剂得到产物(S)-3-对硝基苯基哌啶(6-1)31.9g，收率71.0％；MS-ESI(m/z)：207.2(M+H) +。 (S)-3-Phenylpiperidine ((S)-1-1, 35.1 g, 218.0 mmol), glacial acetic acid (300 mL) was added to the reaction flask, followed by dropwise addition of concentrated sulfuric acid (12 mL) and stirring for 10 min. After that, the temperature was lowered to 0 ° C, and then the fuming nitric acid (9.6 mL, 218.2 mmol) was slowly added dropwise, and stirring was continued for 10 min, then concentrated sulfuric acid (180 mL) was slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at 0 ° C for 7 h, and the material was detected by TLC. The reaction was completed, the reaction was stopped; the reaction solution was adjusted to pH = 10-12 with 20% sodium hydroxide solution, and then extracted with ethyl acetate (200 mL × 2). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, dry the solvent to give the product (S) -3- nitrophenyl piperidine (6-1) 31.9g, yield 71.0%; MS-ESI (m / z): 207.2 (m + H) +.
实施例25：(S)-3-对硝基苯基哌啶(6-1)的合成Example 25: Synthesis of (S)-3-p-nitrophenyl piperidine (6-1)
Figure PCTCN2019076351-appb-000036
Figure PCTCN2019076351-appb-000036
将(S)-3-苯基哌啶((S)-1-1,35.1g,218.0mmol)、硝酸钾(25.7g,254.45mmol)、浓硫酸(180mL)加入到反应瓶中，升温到58℃反应8h，TLC检测原料反应完全，停止反应；用20％的氢氧化钠溶液，调节反应溶液pH＝10-12，然后用乙酸乙酯萃取(250mL×2)，收集有机层，加入无水硫酸钠干燥，过滤，旋干溶剂得到产物(S)-3-对硝基苯基哌啶(6-1)32.9g，收率73.2％；MS-ESI(m/z)：207.2(M+H) +。 (S)-3-Phenylpiperidine ((S)-1-1, 35.1 g, 218.0 mmol), potassium nitrate (25.7 g, 254.45 mmol), concentrated sulfuric acid (180 mL) was added to the reaction flask, and the temperature was raised. After reacting at 58 ° C for 8 h, the reaction of the starting material was completely detected by TLC, and the reaction was stopped. The pH of the reaction solution was adjusted to 10-12 with 20% sodium hydroxide solution, and then extracted with ethyl acetate (250 mL×2), and the organic layer was collected and added. The aqueous solution was dried over sodium sulfate, filtered, and then evaporated to dryness crystalssssssssssssssssssssssssss +H) + .
实施例26：(S)-3-对硝基苯基哌啶(6-1)的合成Example 26: Synthesis of (S)-3-p-nitrophenyl piperidine (6-1)
Figure PCTCN2019076351-appb-000037
Figure PCTCN2019076351-appb-000037
将(S)-3-苯基哌啶((S)-1-1,31.9g,197.84mmol)、硝基甲烷(150mL)加入反应瓶中，反应液冷却至0℃，先加入三氟化硼乙醚络合物(32.96g,232.28mmol)，再滴加硝酸甲酯(35.77g,464.55mmol)，滴加完毕后，升温至25℃反应。反应结束后，加入二氯甲烷(300mL)，用饱和碳酸氢钠水溶液洗涤(3×100 mL)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，过柱分纯得到28.8g产物(S)-3-对硝基苯基哌啶(6-1)，产物为浅棕色固体，收率70.6％。MS-ESI(m/z)：207.2(M+H) +。 (S)-3-Phenylpiperidine ((S)-1-1, 31.9g, 197.84mmol), nitromethane (150mL) was added to the reaction flask, the reaction solution was cooled to 0 ° C, first added to the trifluoride The boryl ether complex (32.96 g, 232.28 mmol) was further added dropwise with methyl nitrate (35.77 g, 464.55 mmol). After the dropwise addition was completed, the mixture was warmed to 25 ° C. After completion of the reaction, methylene chloride (300 mL) was added and washed with aq. (S)-3-p-Nitrophenylpiperidine (6-1), product was a light brown solid, yield 70.6%. MS-ESI (m / z) : 207.2 (M + H) +.
实施例27：(S)-3-对硝基苯基哌啶(6-1)的合成Example 27: Synthesis of (S)-3-p-nitrophenyl piperidine (6-1)
Figure PCTCN2019076351-appb-000038
Figure PCTCN2019076351-appb-000038
将(S)-3-苯基哌啶((S)-1-1,31.9g,197.84mmol)溶于二氯甲烷(200mL)中，反应液冷却至0℃，分批加入NO 2BF 4(27.6g,207.73mmol)，加入完毕后，缓慢升温至25℃反应。反应结束后，用饱和碳酸氢钠水溶液洗涤(3×50mL)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，过柱分纯得到36.00g产物(S)-3-对硝基苯基哌啶(6-1)，产物为浅棕色固体，收率88.2％。MS-ESI(m/z)：207.2(M+H) +。 The (S) -3- phenyl-piperidine ((S) -1-1,31.9g, 197.84mmol) was dissolved in dichloromethane (200mL), the reaction was cooled to 0 deg.] C, was added portionwise NO 2 BF 4 (27.6 g, 207.73 mmol), after the addition was completed, the temperature was slowly raised to 25 ° C to react. After completion of the reaction, the mixture was washed with aq.hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh Phenylpiperidine (6-1), product was a light brown solid, yield 88.2%. MS-ESI (m / z) : 207.2 (M + H) +.
实施例28：(S)-3-对胺基苯基哌啶(7)的合成Example 28: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000039
Figure PCTCN2019076351-appb-000039
将(S)-3-对硝基苯基哌啶(6-1,30g,145.6mmol)，活性炭(3g,10％)，三氯化铁(1.335g,3.5％)，80％水合肼(19mL,2.18mol)，无水乙醇(300mL)加入到反应瓶中，加热，回流反应20h后，停止反应；过滤，浓缩溶剂，先加入水(100mL)，再用乙酸乙酯提取(200mL×3)，合并有机层，无水硫酸钠干燥，过滤，浓缩得到固体粗品，硅胶柱层析，得到(S)-3-对胺基苯基哌啶(7)15.2g，收率65.0％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H) +。 13C-NMR(100MHz,CDCl 3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI(m/z)：177.2(M+H) +。 (S)-3-p-Nitrophenylpiperidine (6-1, 30 g, 145.6 mmol), activated carbon (3 g, 10%), ferric chloride (1.335 g, 3.5%), 80% hydrazine hydrate ( 19mL, 2.18mol), anhydrous ethanol (300mL) was added to the reaction flask, heated, reflux reaction for 20h, the reaction was stopped; filtered, concentrated solvent, first added water (100mL), and then extracted with ethyl acetate (200mL × 3 The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and evaporated tolulululululujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj =96-98 ° C, 1 H-NMR (400 MHz, CD 3 OD) δ: 7.04 (2H, d, J = 8.4 Hz), 6.72 (2H, d, J = 8.4 Hz), 3.44 - 3.33 (2H, m ), 3.05-2.97 (2H, m), 2.88-2.84 (1H, m), 2.07-1.98 (2H, m), 1.88-1.75 (2H, m). MS-ESI (m/z): 177 (M +H) + . 13 C-NMR (100 MHz, CDCl 3 ) δ: 144.60, 135.20, 127.84, 115.19, 54.47, 46.73, 43.73, 32.36, 27.29. MS-ESI (m/z): 177.2 (M+H) + .
实施例29：(S)-3-对胺基苯基哌啶(7)的合成Example 29: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000040
Figure PCTCN2019076351-appb-000040
向反应瓶中加入水(200mL)，搅拌情况下，分批撒入60-80目的铁粉(24.46g,436.80mmol)，加入盐酸，调节反应液pH值为4-5左右后，加热至微沸，再将(S)-3-(4-硝基)苯基哌啶(6-1,30g,145.6mmol)慢慢滴入，滴加完毕后，延长反应时间，至原料反应完。停止反应，用饱和碳酸钠水溶液调节溶液pH＝9-10，用乙酸乙酯萃取(100mL×3)，合并有机层，无水硫酸钠干燥，过滤，浓缩得到固体粗品，硅胶柱层析，得到(S)-3-对胺基苯基哌啶(7)14.0g，收率55.0％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H) +。 13C-NMR(100MHz,CDCl 3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI(m/z)：177.2(M+H) +。 Water (200 mL) was added to the reaction flask. Under stirring, 60-80 mesh iron powder (24.46 g, 436.80 mmol) was sprinkled in portions, hydrochloric acid was added, and the pH of the reaction solution was adjusted to about 4-5, and then heated to micro. After boiling, (S)-3-(4-nitro)phenylpiperidine (6-1, 30 g, 145.6 mmol) was slowly added dropwise, and after the completion of the dropwise addition, the reaction time was extended until the starting of the reaction. The reaction was stopped, the solution was adjusted to pH = 9-10 with a saturated aqueous solution of sodium carbonate, and ethyl acetate (100 mL × 3) was evaporated. (S)-3-p-aminophenylpiperidine (7) 14.0 g, yield 55.0%; Mp = 96-98 ° C, 1 H-NMR (400 MHz, CD 3 OD) δ: 7.04 (2H, d, J = 8.4 Hz), 6.72 (2H, d, J = 8.4 Hz), 3.44 - 3.33 (2H, m), 3.05 - 2.97 (2H, m), 2.88 - 2.84 (1H, m), 2.07-1.98 (2H , m), 1.88-1.75 (2H, m). MS-ESI (m/z): 177 (M+H) + . 13 C-NMR (100 MHz, CDCl 3 ) δ: 144.60, 135.20, 127.84, 115.19, 54.47, 46.73, 43.73, 32.36, 27.29. MS-ESI (m/z): 177.2 (M+H) + .
实施例30：(S)-3-对胺基苯基哌啶(7)的合成Example 30: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000041
Figure PCTCN2019076351-appb-000041
将(S)-3-(4-硝基)苯基哌啶(6-1,31.9g,154.85mmol)，无水四氢呋喃(300mL)加入到反应瓶中中，分批加入四氢铝锂(5.9g,154.95mmol)，反应3h后，TLC检测原料反应完全，停止反应，降温到0℃，缓慢滴加水(6mL)，再用15％的氢氧化钠水溶液将水层pH调到8-9，然后滴加水(18mL)，室温搅拌1h。加入无水硫酸镁(50g)搅拌15，min，过滤，浓缩除去THF，再用乙酸乙酯萃取(200mL×3)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到13.6g产物(S)-3-对胺基苯基哌啶(7)，收率50.2％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H) +. 13C-NMR(100MHz,CDCl3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI (m/z)：177.2(M+H) +。 (S)-3-(4-Nitro)phenylpiperidine (6-1, 31.9 g, 154.85 mmol), anhydrous tetrahydrofuran (300 mL) was added to a reaction flask, and lithium tetrahydroaluminum was added in portions ( 5.9g, 154.95mmol), after 3h reaction, TLC detected the reaction of the starting material completely, stopped the reaction, cooled to 0 ° C, slowly added water (6mL), and then adjusted the pH of the water layer to 8-9 with 15% sodium hydroxide aqueous solution. Then, water (18 mL) was added dropwise and stirred at room temperature for 1 h. Anhydrous magnesium sulfate (50 g) was added, and the mixture was stirred for 15 min, filtered, evaporated, evaporated, evaporated, evaporated. Analysis gave 13.6 g of the product (S)-3-p-aminophenylpiperidine (7) in a yield of 50.2%; Mp = 96-98 ° C, 1 H-NMR (400 MHz, CD 3 OD) δ: 7.04 ( 2H,d,J=8.4Hz), 6.72(2H,d,J=8.4Hz), 3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07 - 1.98 (2H, m), 1.88-1.75 (2H, m). MS-ESI (m/z): 177 (M+H) + . 13 C-NMR (100 MHz, CDCl3) δ: 144.60, 135.20, 127.84 , 115.19, 54.47, 46.73, 43.73, 32.36, 27.29. MS-ESI (m/z): 177.2 (M+H) + .
实施例31：(S)-3-对胺基苯基哌啶(7)的合成Example 31: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000042
Figure PCTCN2019076351-appb-000042
将(S)-3-(4-硝基)苯基哌啶(6-1,31.9g,154.85mmol)、钯碳(1.6g,5％)、无水甲醇(300mL)加入到高压釜中，通入1atm氢气，反应2h后，TLC检测原料反应完全，停止反应，过滤，将溶剂旋干，加入1N盐酸(100mL)，再用乙酸乙酯萃取(100mL)，收集水层，弃去有机层，再用10％的氢氧化钠水溶液将水层pH调到8-9，然后用乙酸乙酯萃取(200mL×3)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到17.3g产物(S)-3-对胺基苯基哌啶(7)，收率63.2％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H) +. 13C-NMR(100MHz,CDCl3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI(m/z)：177.2(M+H) +。 (S)-3-(4-Nitro)phenylpiperidine (6-1, 31.9 g, 154.85 mmol), palladium on carbon (1.6 g, 5%), anhydrous methanol (300 mL) was added to the autoclave After 1 hour of hydrogen gas was introduced, the reaction was completed for 2 hours, and the reaction was completed by TLC. The reaction was stopped, filtered, and the solvent was evaporated to dryness. 1N hydrochloric acid (100 mL) was added, and then ethyl acetate (100 mL) was used to collect the aqueous layer, and the organic layer was discarded. The layer was adjusted to pH 8-9 with a 10% aqueous sodium hydroxide solution, and then extracted with ethyl acetate (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated. Column chromatography gave 17.3 g of the product (S)-3-p-aminophenylpiperidine (7) in a yield of 63.2%; Mp = 96-98 ° C, 1 H-NMR (400 MHz, CD 3 OD) δ: 7.04(2H,d,J=8.4Hz), 6.72(2H,d,J=8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m) , 2.07-1.98 (2H, m), 1.88-1.75 (2H, m). MS-ESI (m/z): 177 (M+H) + . 13 C-NMR (100MHz, CDCl3) δ: 144.60, 135.20 , 127.84, 115.19, 54.47, 46.73, 43.73, 32.36, 27.29. MS-ESI (m/z): 177.2 (M+H) + .
实施例32：(S)-3-对胺基苯基哌啶(7)的合成Example 32: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000043
Figure PCTCN2019076351-appb-000043
将(S)-3-(4-硝基)苯基哌啶(6-1,31.9g,154.85mmol)、二氧化铂(1.6g,5％)、无水甲醇(250mL)加入到高压釜中，通入1atm氢气，反应1.5h后，TLC检测原料反应完全，停止反应，过滤，将溶剂旋干，加入1N盐酸(100mL)，再用乙酸乙酯萃取(100mL)，收集水层，弃去有机层，再用10％的氢氧化钠水溶液将水层pH调到8-9，然后用乙酸乙酯萃取(200mL×3)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到17.8g产物(S)-3-对胺基苯基哌啶(7)，收率65.2％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177 (M+H) +. 13C-NMR(100MHz,CDCl3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI(m/z)：177.2(M+H) +。 Add (S)-3-(4-nitro)phenylpiperidine (6-1, 31.9 g, 154.85 mmol), platinum dioxide (1.6 g, 5%), anhydrous methanol (250 mL) to the autoclave After the reaction was carried out for 1 hour, hydrogen was reacted for 1.5 h, and the reaction of the starting material was completed by TLC. The reaction was stopped, filtered, and the solvent was evaporated to dryness, and then 1N hydrochloric acid (100 mL) was added, and then ethyl acetate (100 mL) was used to collect the aqueous layer. The organic layer was removed, and the pH of the aqueous layer was adjusted to 8-9 with 10% aqueous sodium hydroxide, and then extracted with ethyl acetate (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated Silica gel column chromatography gave 17.8 g of product (S)-3-p-aminophenylpiperidine (7) in a yield of 65.2%; Mp = 96-98 ° C, 1 H-NMR (400 MHz, CD 3 OD) δ: 7.04 (2H, d, J = 8.4 Hz), 6.72 (2H, d, J = 8.4 Hz), 3.44 - 3.33 (2H, m), 3.05 - 2.97 (2H, m), 2.88 - 2.84 (1H, m), 2.07-1.98 (2H, m), 1.88-1.75 (2H, m). MS-ESI (m/z): 177 (M+H) + . 13 C-NMR (100 MHz, CDCl3) δ: 144.60 , 135.20, 127.84, 115.19, 54.47, 46.73, 43.73, 32.36, 27.29. MS-ESI (m/z): 177.2 (M+H) + .
实施例33：(S)-3-对胺基苯基哌啶(7)的合成Example 33: Synthesis of (S)-3-p-aminophenylpiperidine (7)
Figure PCTCN2019076351-appb-000044
Figure PCTCN2019076351-appb-000044
将(S)-3-(4-硝基)苯基哌啶(6-1,31.9g,154.85mmol)、雷尼镍(0.957g,3％)、80％水合肼(20mL,2.32mol)、无水乙醇(320mL)加入到反应瓶中，反应8h后，TLC检测原料反应完全，停止反应，过滤，将溶剂旋干，先加入稀盐酸(100mL)，搅拌30min，再加入乙酸乙酯萃取(200mL)，收集水层，弃去有机层，再用10％的氢氧化钠水溶液将水层pH调到8-9，然后用乙酸乙酯萃取(200mL×3)，收集有机层，无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到17.7g产物(S)-3-对胺基苯基哌啶(7)，收率65.2％；Mp＝96-98℃， 1H-NMR(400MHz,CD 3OD)δ:7.04(2H,d,J＝8.4Hz),6.72(2H,d,J＝8.4Hz),3.44-3.33(2H,m),3.05-2.97(2H,m),2.88-2.84(1H,m),2.07-1.98(2H,m),1.88-1.75(2H,m).MS-ESI(m/z):177(M+H) +； 13C-NMR(100MHz,CDCl 3)δ:144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI(m/z)：177.2(M+H) +。 (S)-3-(4-Nitro)phenylpiperidine (6-1, 31.9 g, 154.85 mmol), Raney nickel (0.957 g, 3%), 80% hydrazine hydrate (20 mL, 2.32 mol) Anhydrous ethanol (320 mL) was added to the reaction flask. After 8 h of reaction, TLC detected the reaction of the starting material completely, stopped the reaction, filtered, and the solvent was spun dry. First, dilute hydrochloric acid (100 mL) was added, stirred for 30 min, and then extracted with ethyl acetate. (200 mL), the aqueous layer was collected, the organic layer was discarded, and the pH of the aqueous layer was adjusted to 8-9 with a 10% aqueous sodium hydroxide solution, then extracted with ethyl acetate (200 mL×3), and the organic layer was collected. over sodium sulfate, filtered, rotary evaporation, silica gel column chromatography, to give 17.7g product (S) -3- amino-phenyl piperidine to (7), a yield of 65.2%; Mp = 96-98 ℃, 1 H - NMR (400 MHz, CD 3 OD) δ: 7.04 (2H, d, J = 8.4 Hz), 6.72 (2H, d, J = 8.4 Hz), 3.44 - 3.33 (2H, m), 3.05 - 2.97 (2H, m), 2.88-2.84 (1H, m ), 2.07-1.98 (2H, m), 1.88-1.75 (2H, m) .MS-ESI (m / z): 177 (m + H) +; 13 C- NMR (100MHz, CDCl 3) δ : 144.60,135.20,127.84,115.19,54.47,46.73,43.73,32.36,27.29.MS-ESI (m / z): 177.2 (m + H) +.
实施例34：N-苄基-3-苯基哌啶(6-2)的合成Example 34: Synthesis of N-benzyl-3-phenylpiperidine (6-2)
Figure PCTCN2019076351-appb-000045
Figure PCTCN2019076351-appb-000045
室温条件下，将3-羟基-3-苯基-1-苄基哌啶(3-1,75g,279.85mmol)、DCM(500mL)、三氟化硼乙醚(38mL)加入到反应瓶中，冰水浴冷却到0℃，缓慢滴加三乙基硅烷(75mL，474.78mmol)，30min滴加完毕，升温到室温，反应3h，TLC检测原料反应完全，停止反应，缓慢加入水(200mL)，再加入NaOH溶液调节水层为碱性，搅拌20min，分液，将有机层用无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到产物N-苄基-3-苯基哌啶(6-2)56.4g，收率80.3％；MS-ESI(m/z)：252.4(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 75 g, 279.85 mmol), DCM (500 mL), boron trifluoride diethyl ether (38 mL) was added to the reaction flask at room temperature. The ice water bath was cooled to 0 ° C, and triethylsilane (75 mL, 474.78 mmol) was slowly added dropwise. After 30 min, the mixture was warmed to room temperature and reacted for 3 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, and water (200 mL) was slowly added. The NaOH solution was added to adjust the aqueous layer to be alkaline, stirred for 20 min, and the organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to silica gel column chromatography to afford product N-benzyl-3-phenylpiperidine. (6-2) 56.4g, yield 80.3%; MS-ESI (m / z): 252.4 (m + H) +.
实施例35：N-苄基-3-苯基哌啶(6-2)的合成Example 35: Synthesis of N-benzyl-3-phenylpiperidine (6-2)
Figure PCTCN2019076351-appb-000046
Figure PCTCN2019076351-appb-000046
室温条件下，将3-羟基-3-苯基-1-苄基哌啶(3-1,75g,279.85mmol)、DCM(500mL)、三氟乙酸(32mL)加入到反应瓶中，冰水浴冷却到0℃，缓慢滴加三乙基硅烷(75mL，474.78mmol)，30min滴加完毕，升温到室温，反应2.5h，TLC检测原料反应完全，停止反应，缓慢加入水(200mL)，再加入NaOH溶液调节水层为碱性，搅拌20min，分液，将有机层用无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到产物N-苄基-3-苯基哌啶(6-2)50.1g，收率71.2％；MS-ESI(m/z)：252.4(M+H) +。 Add 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1, 75g, 279.85mmol), DCM (500mL), trifluoroacetic acid (32mL) to the reaction flask at room temperature, ice water bath Cool to 0 ° C, slowly add triethylsilane (75 mL, 474.78 mmol), add dropwise after 30 min, warm to room temperature, reaction for 2.5 h, TLC detection of the reaction of the starting material is complete, stop the reaction, slowly add water (200 mL), then add The aqueous layer was adjusted to be alkaline with NaOH solution, stirred for 20 min, and the organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to silica gel column chromatography to afford product N-benzyl-3-phenylpiperidine ( 6-2) 50.1 g, yield 71.2%; MS-ESI (m/z): 252.4 (M+H) + .
实施例36：N-苄基-3-苯基哌啶(6-2)的合成Example 36: Synthesis of N-benzyl-3-phenylpiperidine (6-2)
Figure PCTCN2019076351-appb-000047
Figure PCTCN2019076351-appb-000047
室温条件下，将3-羟基-3-苯基-1-苄基哌啶(3-1,75g,279.85mmol)、THF(500mL)、三氟化硼乙醚(38mL)加入到反应瓶中，冰水浴冷却到0℃，缓慢滴加三乙基硅烷(75mL，474.78mmol)，30min滴加完毕，升温到室温，反应3h，TLC检测原料反应完全，停止反应，缓慢加入水(200mL)，再加入NaOH溶液调节水层为碱性，搅拌20min，分液，将有机层用无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到产物N-苄基-3-苯基哌啶(6-2)55.4g，收率79.2％；MS-ESI(m/z)：252.4(M+H) +。 3-Hydroxy-3-phenyl-1-benzylpiperidine (3-1, 75 g, 279.85 mmol), THF (500 mL), boron trifluoride diethyl ether (38 mL) was added to the reaction flask at room temperature. The ice water bath was cooled to 0 ° C, and triethylsilane (75 mL, 474.78 mmol) was slowly added dropwise. After 30 min, the mixture was warmed to room temperature and reacted for 3 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, and water (200 mL) was slowly added. The NaOH solution was added to adjust the aqueous layer to be alkaline, stirred for 20 min, and the organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated to silica gel column chromatography to afford product N-benzyl-3-phenylpiperidine. (6-2) 55.4g, yield 79.2%; MS-ESI (m / z): 252.4 (m + H) +.
实施例37：N-苄基-3-苯基哌啶(6-2)的合成Example 37: Synthesis of N-benzyl-3-phenylpiperidine (6-2)
Figure PCTCN2019076351-appb-000048
Figure PCTCN2019076351-appb-000048
室温条件下，将3-羟基-3-苯基-1-苄基哌啶(3-1,75g,279.85mmol)、THF (500mL)、三氟乙酸(32mL)加入到反应瓶中，冰水浴冷却到0℃，缓慢滴加三乙基硅烷(75mL，474.78mmol)，30min滴加完毕，升温到室温，反应2.5h，TLC检测原料反应完全，停止反应，缓慢加入水(200mL)，再加入NaOH溶液调节水层pH＝8，搅拌20min，分液，将有机层用无水硫酸钠干燥，过滤，旋干溶剂，硅胶柱层析，得到产物N-苄基-3-苯基哌啶(6-2)49.4g，收率70.3％；MS-ESI(m/z)：252.4(M+H) +。 Add 3-hydroxy-3-phenyl-1-benzylpiperidine (3-1, 75g, 279.85mmol), THF (500mL), trifluoroacetic acid (32mL) to the reaction flask at room temperature, ice water bath Cool to 0 ° C, slowly add triethylsilane (75 mL, 474.78 mmol), add dropwise after 30 min, warm to room temperature, reaction for 2.5 h, TLC detection of the reaction of the starting material is complete, stop the reaction, slowly add water (200 mL), then add The pH of the aqueous layer was adjusted to pH=8, and the mixture was stirred for 20 min, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to silica gel column chromatography to give the product N-benzyl-3-phenylpiperidine ( 6-2) 49.4 g, yield 70.3%; MS-ESI (m/z): 252.4 (M+H) + .
实施例38：3-苯基哌啶(1)的合成Example 38: Synthesis of 3-phenylpiperidine (1)
Figure PCTCN2019076351-appb-000049
Figure PCTCN2019076351-appb-000049
将N-苄基-3-苯基哌啶(6-2,65g,258.96mmol)、钯碳(12g,18％)、无水乙醇(300mL)、冰乙酸(11mL)加入到反应瓶中，通入1atm的氢气，加热到60℃，反应12h后，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干，然后加入水(250mL)，并用乙酸乙酯萃取(250mL×3)，收集有机层，用无水硫酸钠干燥，过滤，将溶剂旋干，硅胶柱层析，得到产物3-苯基哌啶(1)35.2g，收率89.3％，直接用于下一步反应； 1H-NMR(400MHz，DMSO-d6)δ：7.30-7.16(5H,m),3.13-2.95(4H,m),2.51-2.50(1H,m),1.87-1.84(1H,m),1.67-1.46(3H,m). 13C-NMR(100MHz,D 2O)δ:144.23,128.45,127.08,126.43,52.96,45.92,43.32,31.80,26.21.MS-ESI(m/z):162.2(M+H) +。 N-Benzyl-3-phenylpiperidine (6-2, 65 g, 258.96 mmol), palladium on carbon (12 g, 18%), absolute ethanol (300 mL), glacial acetic acid (11 mL), The hydrogen gas of 1 atm was introduced and heated to 60 ° C. After 12 h of reaction, the reaction of the starting material was completed by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was dried, then water (250 mL) was added and extracted with ethyl acetate (250 mL×3) The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to silica gel column chromatography to give the product 3-phenylpiperidine (1) 35.2 g, yield 89.3%, directly used for the next reaction; 1 H-NMR (400MHz, DMSO -d6) δ: 7.30-7.16 (5H, m), 3.13-2.95 (4H, m), 2.51-2.50 (1H, m), 1.87-1.84 (1H, m), 1.67 - 1.46 (3H, m). 13 C-NMR (100MHz, D 2 O) δ: 144.23, 128.45, 127.08, 126.43, 52.96, 45.92, 43.32, 31.80, 26.21. MS-ESI (m/z): 162.2 ( M+H) + .
实施例39：(S)-N-乙酰基-3-苯基哌啶(8-1)的合成Example 39: Synthesis of (S)-N-acetyl-3-phenylpiperidine (8-1)
Figure PCTCN2019076351-appb-000050
Figure PCTCN2019076351-appb-000050
将(S)-3-苯基哌啶((S)-1-1,50g,310.55mmol)、DCM(100mL)、三乙胺(43.8g,315.1mmol)加入反应瓶中，冰盐浴降温到0℃后，缓慢滴加乙酰氯(24.7g,315.1mmol)，30min滴加完毕，停止反应；加入饱和碳酸氢钠水溶液(100mL)萃取，收集有机相，无水硫酸钠干燥，浓缩溶剂，硅胶柱层析，得到无色油状液体58.2g，即(S)-N-乙酰基-3-苯基哌啶(8-1)，收率92.1％；MS-ESI (m/z)：204.3(M+H) +。 (S)-3-Phenylpiperidine ((S)-1-1, 50g, 310.55mmol), DCM (100mL), triethylamine (43.8g, 315.1mmol) was added to the reaction flask, and the ice bath was cooled. After 0 °C, acetyl chloride (24.7 g, 315.1 mmol) was slowly added dropwise, and the reaction was stopped after 30 min, and the reaction was stopped. The mixture was extracted with saturated aqueous sodium hydrogen sulfate (100 mL). Silica gel column chromatography gave 58.2 g of a colorless oily liquid, (S)-N-acetyl-3-phenylpiperidine (8-1), yield 92.1%; MS-ESI (m/z): 204.3 (M+H) + .
实施例40：(S)-N-苯磺酰基-3-苯基哌啶(8-2)的合成Example 40: Synthesis of (S)-N-benzenesulfonyl-3-phenylpiperidine (8-2)
Figure PCTCN2019076351-appb-000051
Figure PCTCN2019076351-appb-000051
将(S)-3-苯基哌啶((S)-1-1,50g,310.55mmol)、二氯甲烷(300mL)、三乙胺(62.7g,621.10mmol)加入反应瓶中，滴加苯磺酰氯(55.65g,315.1mmol)，滴加完毕，25℃反应3h，反应完毕；反应液用水洗涤(100mLx3)，收集有机相，无水硫酸钠干燥，浓缩溶剂，得到产物88.1g，即(S)-N-苯磺酰基-3-苯基哌啶(8-2)，收率94.1％；MS-ESI(m/z)：302.4(M+H) +。 (S)-3-Phenylpiperidine ((S)-1-1, 50g, 310.55mmol), dichloromethane (300mL), triethylamine (62.7g, 621.10mmol) was added to the reaction flask, and added dropwise The benzenesulfonyl chloride (55.65 g, 315.1 mmol) was added dropwise, and the reaction was completed at 25 ° C for 3 h. The reaction was completed. The reaction mixture was washed with water (100 mL×3), and the organic phase was collected and dried over anhydrous sodium sulfate (S) -N- benzenesulfonyl-3-phenyl-piperidine (8-2), 94.1% yield; MS-ESI (m / z ): 302.4 (m + H) +.
实施例41：(S)-N-乙酰基-3-(4-溴-苯基)哌啶(9-1)的合成Example 41: Synthesis of (S)-N-acetyl-3-(4-bromo-phenyl)piperidine (9-1)
Figure PCTCN2019076351-appb-000052
Figure PCTCN2019076351-appb-000052
将(S)-N-乙酰基-3-苯基哌啶(8-1,147.78mmol)、冰乙酸(60mL)、NBS(26.3g,147.75mmol)加入反应瓶中，加热到65℃，反应2h，停止反应；减压蒸馏除去乙酸，然后加入饱和碳酸氢钠水溶液(100mL)，并用乙酸乙酯提取(30mL×3)，合并有机相，无水硫酸钠干燥，浓缩，粗品用硅胶柱层析，得到无色油状液体35.1g，即(S)-N-乙酰基-3-(4-溴-苯基)哌啶(9-1)，收率85.3％；MS-ESI(m/z)：282.2，284.2(M+H) +。 (S)-N-Acetyl-3-phenylpiperidine (8-1,147.78 mmol), glacial acetic acid (60 mL), NBS (26.3 g, 147.75 mmol) was added to the reaction flask, heated to 65 ° C, and reacted for 2 h. The reaction was quenched; the acetic acid was evaporated under reduced pressure. EtOAc (EtOAc m. 35.1 g of a colorless oily liquid, (S)-N-acetyl-3-(4-bromo-phenyl)piperidine (9-1), yield: 85.3%; MS-ESI (m/z): 282.2, 284.2 (M+H) + .
实施例42：(S)-N-苯磺酰基-3-(4-溴-苯基)哌啶(9-2)的合成Example 42: Synthesis of (S)-N-benzenesulfonyl-3-(4-bromo-phenyl)piperidine (9-2)
Figure PCTCN2019076351-appb-000053
Figure PCTCN2019076351-appb-000053
将(S)-N-苯磺酰基-3-苯基哌啶(8-2,147.78mmol)、二氯甲烷(120mL)加入反应瓶，将溴素(24.8g,155.17mmol)用二氯甲烷(180mL)稀释缓慢滴加到反应瓶中，滴毕，室温反应10h，停止反应。将反应液用水(80mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品用硅胶柱层析，得到无色油状液体 50.7g，即(S)-N-苯磺酰基-3-(4-溴-苯基)哌啶(9-2)，收率90.3％；MS-ESI(m/z)：380.1,382.1(M+H) +。 (S)-N-Benzenesulfonyl-3-phenylpiperidine (8-2,147.78 mmol), dichloromethane (120 mL) was added to a reaction flask, and bromine (24.8 g, 155.17 mmol). The dilution was slowly added dropwise to the reaction flask, and the reaction was carried out for 10 hours at room temperature to stop the reaction. The reaction mixture was washed with EtOAcq. 4-bromo-phenyl) - piperidine (9-2), a yield of 90.3%; MS-ESI (m / z): 380.1,382.1 (m + H) +.
实施例43：(S)-3-对溴苯基哌啶(10)的合成Example 43: Synthesis of (S)-3-p-bromophenylpiperidine (10)
Figure PCTCN2019076351-appb-000054
Figure PCTCN2019076351-appb-000054
将(S)-N-乙酰基-3-(4-溴-苯基)哌啶(9-1,106.76mmol)、6N的盐酸水溶液(150mL)加入到反应瓶中，加热，回流反应12h，停止反应；滴加2N氢氧化钠水溶液，调节反应液pH＝9，再用乙酸乙酯提取(35mL×3)，合并有机相，无水硫酸钠干燥，浓缩，粗品用硅胶柱层析，得无色油状液体20.1g，即(S)-3-对溴苯基哌啶(10)，收率78.4％；MS-ESI(m/z)：240.1，242.1(M+H) +。 (S)-N-Acetyl-3-(4-bromo-phenyl)piperidine (9-1,106.76 mmol), 6N aqueous hydrochloric acid (150 mL) was added to the reaction flask, heated, refluxed for 12 h, and the reaction was stopped. 2N sodium hydroxide aqueous solution was added dropwise, and the reaction mixture was adjusted to pH=9, and then extracted with ethyl acetate (35 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated. 20.1 g of an oily liquid, (S)-3-p-bromophenylpiperidine (10), yield 78.4%; MS-ESI (m/z): 240.1, 242.1 (M+H) + .
实施例44：(S)-3-对溴苯基哌啶(10)的合成Example 44: Synthesis of (S)-3-p-bromophenylpiperidine (10)
Figure PCTCN2019076351-appb-000055
Figure PCTCN2019076351-appb-000055
将(S)-N-苯磺酰基-3-(4-溴-苯基)哌啶(9-2,106.76mmol)、40％的HBr溶液(100mL)与冰醋酸(100mL)加入到反应瓶中，缓慢升温至70℃反应。反应结束后，减压浓缩溶剂。残余物用水溶解，NaOH溶液调节pH为10-12，然后用DCM萃取(100mLx3)，合并有机层，无水硫酸钠干燥，浓缩，粗品用硅胶柱层析，得无色油状液体15.1g，即(S)-3-对溴苯基哌啶(10)，收率58.4％；MS-ESI(m/z)：240.1，242.1(M+H) +。 (S)-N-Benzenesulfonyl-3-(4-bromo-phenyl)piperidine (9-2, 106.76 mmol), 40% HBr solution (100 mL) and glacial acetic acid (100 mL) were added to the reaction flask. Slowly warm to 70 ° C reaction. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was dissolved in water, and the NaOH solution was adjusted to pH 10-12, then extracted with DCM (100 mL×3). (S)-3-p-Bromophenylpiperidine (10), yield 58.4%; MS-ESI (m/z): 240.1, 242.1 (M+H) + .
实施例45：3-羟基-3-对甲氧基苯基-1-苄基哌啶(3-2)的合成Example 45: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-benzylpiperidine (3-2)
Figure PCTCN2019076351-appb-000056
Figure PCTCN2019076351-appb-000056
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗 中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-苄基哌啶(3-2))8.7g，收率92.2％；MS-ESI(m/z)：298.3[(M+H) +]。 P-methoxyphenylmagnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), was added to the reaction flask, nitrogen protection, cooling to 0 ° C in ice water bath, N-benzyl Base-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask at a temperature of 0-5 ° C. After the completion of the dropwise addition for 60 minutes, the reaction was stirred for 1 hour. The TLC was used to detect the starting material. The saturated aqueous ammonium chloride solution (50 mL) was added and extracted with ethyl acetate (20 mL×3). The organic layer was dried over anhydrous sodium sulfate (MgSO4) -2)) 8.7 g, yield 92.2%; MS-ESI (m/z): 298.3 [(M+H) + ].
实施例46：3-羟基-3-对甲氧基苯基-1-三苯甲基哌啶(3-3)的合成Example 46: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-tritylmethylpiperidine (3-3)
Figure PCTCN2019076351-appb-000057
Figure PCTCN2019076351-appb-000057
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-三苯甲基哌啶(3-3))14.1g，收率98.3％；MS-ESI(m/z)：450.6[(M+H) +]。 Add p-methoxyphenyl magnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, nitrogen protection, ice water bath cooling to 0 ° C, N-three Benzyl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and saturated aqueous ammonium chloride (50 mL) was added thereto, and then extracted with ethyl acetate (20 mL×3), and extracted three times. The organic layer was combined, dried (MgSO4) Piperidine (3-3)) 14.1 g, yield 98.3%; MS-ESI (m/z): 450.6 [(M+H) + ].
实施例47：3-羟基-3-对甲氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-4)的合成Example 47: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-4)
Figure PCTCN2019076351-appb-000058
Figure PCTCN2019076351-appb-000058
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完 毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-4))11.0g，收率96.1％；MS-ESI(m/z)：358.5[(M+H) +]。 P-methoxyphenylmagnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, N- ( 2,4-Dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. In the middle, the temperature is controlled at 0-5 ° C, 60 min, and the reaction is stirred for 1 hour after the completion of the dropwise addition. The TLC test material has been completely reacted, and saturated aqueous ammonium chloride solution (50 mL) is added with stirring, and then ethyl acetate (20 mL) is used. ×3) Extraction, extraction three times, the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product. 1 - 1 g of -1-(2,4-dimethoxy)benzylpiperidine (3-4)), yield 96.1%; MS-ESI (m/z): 358.5 [(M+H) + ] .
实施例48：3-羟基-3-对甲氧基苯基-1-叔丁基哌啶(3-5)的合成Example 48: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-tert-butylpiperidine (3-5)
Figure PCTCN2019076351-appb-000059
Figure PCTCN2019076351-appb-000059
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁基-3-哌啶酮(2-4,5.0g,32.2mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-叔丁基哌啶(3-5))7.9g，收率93.2％；MS-ESI(m/z)：264.3[(M+H) +]。 Add p-methoxyphenyl magnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, nitrogen protection, cool to 0 ° C in ice water bath, N-un Butyl-3-piperidone (2-4, 5.0 g, 32.2 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5 ° C. After the completion of the dropwise addition, the reaction was stirred for 1 hour. After the completion of the dropwise addition, the reaction was completed. TLC was used to confirm that the starting material was completely reacted, and the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (20 mL×3) and extracted three times. Then, the organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness Piperidine (3-5)) 7.9 g, yield 93.2%; MS-ESI (m/z): 264.3 [(M+H) + ].
实施例49：3-羟基-3-对甲氧基苯基-1-三甲基硅基哌啶(3-6)的合成Example 49: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-trimethylsilylpiperidine (3-6)
Figure PCTCN2019076351-appb-000060
Figure PCTCN2019076351-appb-000060
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三甲基硅基-3-哌啶酮(2-5,5.5g,32.1mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继 续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-三甲基硅基哌啶(3-6))8.2g，收率91.4％；MS-ESI(m/z)：280.4[(M+H) +]。 Add p-methoxyphenyl magnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, nitrogen protection, ice water bath cooling to 0 ° C, N-three Methylsilyl-3-piperidone (2-5, 5.5 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0- After the completion of the dropwise addition, the reaction was continued for 5 hours. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The starting material was completely reacted by TLC, quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (20 mL×3). After extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product. Methylsilylpiperidine (3-6)) 8.2 g, yield 91.4%; MS-ESI (m/z): 280.4 [(M+H) + ].
实施例50：3-羟基-3-对甲氧基苯基-1-叔丁基二甲基硅基哌啶(3-7)的合成Example 50: Synthesis of 3-hydroxy-3-p-methoxyphenyl-1-tert-butyldimethylsilylpiperidine (3-7)
Figure PCTCN2019076351-appb-000061
Figure PCTCN2019076351-appb-000061
将对甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基苯基-1-叔丁基二甲基硅基哌啶(3-7))9.8g，收率95.8％；MS-ESI(m/z)：322.5[(M+H) +]。 Add p-methoxyphenyl magnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, nitrogen protection, cool to 0 ° C in ice water bath, N-un Butyl-3-piperidone (2-6, 6.8g, 31.9mmol) was diluted with anhydrous tetrahydrofuran (30mL), added to the dropping funnel, slowly added dropwise to the reaction flask, temperature control at 0-5 ° C After the completion of the dropwise addition, the reaction was stirred for 1 hour. After the completion of the dropwise addition, the reaction was completed. TLC was used to confirm that the starting material was completely reacted, and the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (20 mL×3) and extracted three times. Then, the organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness Dimethylsilylpiperidine (3-7)) 9.8 g, yield 95.8%; MS-ESI (m/z): 322.5 [(M+H) + ].
实施例51：3-羟基-3-对乙氧基苯基-1-苄基哌啶(3-8)的合成Example 51: Synthesis of 3-hydroxy-3-p-ethoxyphenyl-1-benzylpiperidine (3-8)
Figure PCTCN2019076351-appb-000062
Figure PCTCN2019076351-appb-000062
将对乙氧基苯基溴化镁格氏试剂(1.8mol/L in THF，20mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50 mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对乙氧基苯基-1-苄基哌啶(3-8))9.2g，收率93.2％；MS-ESI(m/z)：312.4[(M+H) +]。 P-ethoxyphenylmagnesium bromide Grignard reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, cooling in ice water bath to 0 ° C, N- Benzyl-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask at a temperature of 0-5 ° C. After the completion of the dropwise addition, the reaction was stirred for 1 hour, and the reaction was completed by TLC. The saturated aqueous solution of ammonium chloride (50 mL) was added and then extracted with ethyl acetate (20 mL×3) and extracted three times. The organic layer was combined, dried (MgSO4) (3-8)) 9.2 g, yield 93.2%; MS-ESI (m/z): 312.4 [(M+H) + ].
实施例52：3-羟基-3-对乙氧基苯基-1-三苯甲基哌啶(3-9)的合成Example 52: Synthesis of 3-hydroxy-3-p-ethoxyphenyl-1-tritylmethylpiperidine (3-9)
Figure PCTCN2019076351-appb-000063
Figure PCTCN2019076351-appb-000063
将对乙氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对乙氧基苯基-1-三苯甲基哌啶(3-9))13.8g，收率93.2％；MS-ESI(m/z)：464.6[(M+H) +]。 P-ethoxyphenyl magnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, N-three Benzyl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and saturated aqueous ammonium chloride (50 mL) was added thereto, and then extracted with ethyl acetate (20 mL×3), and extracted three times. The organic layer was combined, dried (MgSO4) Piperidine (3-9)) 13.8 g, yield 93.2%; MS-ESI (m/z): 464.6 [(M+H) + ].
实施例53：3-羟基-3-对乙氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-10)的合成Example 53: Synthesis of 3-hydroxy-3-p-ethoxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-10)
Figure PCTCN2019076351-appb-000064
Figure PCTCN2019076351-appb-000064
将对乙氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完 毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对乙氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-10))11.2g，收率94.3％；MS-ESI(m/z)：372.5[(M+H) +]。 P-ethoxyphenylmagnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, N- ( 2,4-Dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. In the middle, the temperature is controlled at 0-5 ° C, 60 min, and the reaction is stirred for 1 hour after the completion of the dropwise addition. The TLC test material has been completely reacted, and saturated aqueous ammonium chloride solution (50 mL) is added with stirring, and then ethyl acetate (20 mL) is used. ×3) After extraction and extraction three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to give a crude product. Base-1-(2,4-dimethoxy)benzylpiperidine (3-10)) 11.2 g, yield 94.3%; MS-ESI (m/z): 372.5 [(M+H) + ] .
实施例54：3-羟基-3-对乙氧基苯基-1-叔丁基二甲基硅基哌啶(3-11)的合成Example 54: Synthesis of 3-hydroxy-3-p-ethoxyphenyl-1-tert-butyldimethylsilylpiperidine (3-11)
Figure PCTCN2019076351-appb-000065
Figure PCTCN2019076351-appb-000065
将对乙氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁基二甲基硅基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对乙氧基苯基-1-叔丁基二甲基硅基哌啶(3-11))9.8g，收率91.2％；MS-ESI(m/z)：336.6[(M+H) +]。 P-ethoxyphenylmagnesium bromide Grignard reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooling to 0 ° C, N-un Butyldimethylsilyl-3-piperidone (2-6, 6.8g, 31.9mmol) was diluted with anhydrous tetrahydrofuran (30mL), added to the dropping funnel, slowly added dropwise to the reaction flask, temperature control After the dropwise addition was completed at 0-5 ° C for 60 min, the reaction was stirred for 1 hour after completion of the dropwise addition. The starting material was completely reacted by TLC, quenched with saturated aqueous ammonium chloride (50 mL), and then ethyl acetate (20 mL×3) After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give the crude product. The crude product is purified by silica gel column chromatography (3-hydroxy-3-p-ethoxyphenyl) 1-tert-Butyldimethylsilylpiperidine (3-11)) 9.8 g, yield 91.2%; MS-ESI (m/z): 336.6 [(M+H) + ].
实施例55：3-羟基-3-对叔丁氧基苯基-1-苄基哌啶(3-12)的合成Example 55: Synthesis of 3-hydroxy-3-p-tert-butoxyphenyl-1-benzylpiperidine (3-12)
Figure PCTCN2019076351-appb-000066
Figure PCTCN2019076351-appb-000066
将对叔丁氧基苯基溴化镁格氏试剂(1.8mol/L in THF，20mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续 搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁氧基苯基-1-苄基哌啶(3-12))10.4g，收率96.5％；MS-ESI(m/z)：343.5[(M+H) +]。 Add p-tert-butoxyphenylmagnesium bromide reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N -Benzyl-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and saturated aqueous ammonium chloride (50 mL) was added thereto, and then extracted with ethyl acetate (20 mL×3), and extracted three times. The organic layer was combined, dried (MgSO4) Acridine (3-12)) 10.4 g, yield 96.5%; MS-ESI (m/z): 343.5 [(M+H) + ].
实施例56：3-羟基-3-对叔丁氧基苯基-1-三苯甲基哌啶(3-13)的合成Example 56: Synthesis of 3-hydroxy-3-p-tert-butoxyphenyl-1-tritylmethylpiperidine (3-13)
Figure PCTCN2019076351-appb-000067
Figure PCTCN2019076351-appb-000067
将对叔丁氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁氧基苯基-1-三苯甲基哌啶(3-13))14.6g，收率92.9％；MS-ESI(m/z)：492.6[(M+H) +]。 Add p-tert-butoxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N- Trityl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0- After 5 ° C, 60 min, the reaction was stirred for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The starting material was completely reacted by TLC. A saturated aqueous solution of ammonium chloride (50 mL) was added and then extracted with ethyl acetate (20 mL×3) and extracted three times. Then, the organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness Methylpiperidine (3-13)) 14.6 g, yield 92.9%; MS-ESI (m/z): 492.6 [(M+H) + ].
实施例57：3-羟基-3-对叔丁氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-14)的合成Example 57: Synthesis of 3-hydroxy-3-p-tert-butoxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-14)
Figure PCTCN2019076351-appb-000068
Figure PCTCN2019076351-appb-000068
将对叔丁氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30mL)稀释， 加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-14))12.2g，收率95.2％；MS-ESI(m/z)：400.5[(M+H) +]。 Add p-tert-butoxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N- (2,4-Dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction In the bottle, the temperature control was carried out at 0-5 ° C, 60 min, and the reaction was stirred for 1 hour after the completion of the dropwise addition. The TLC test was carried out to complete the reaction, and saturated aqueous ammonium chloride solution (50 mL) was added thereto, followed by ethyl acetate ( 20mL×3) extraction, after extracting three times, the organic layer is combined, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the solvent is evaporated to give a crude product, which is obtained by silica gel column chromatography to give (3-hydroxy-3-tert-butoxy Phenyl-1-(2,4-dimethoxy)benzylpiperidine (3-14)) 12.2 g, yield 95.2%; MS-ESI (m/z): 400.5 [(M+H) + ].
实施例58：3-羟基-3-对叔丁氧基苯基-1-叔丁基二甲基硅基哌啶(3-15)的合成Example 58: Synthesis of 3-hydroxy-3-p-tert-butoxyphenyl-1-tert-butyldimethylsilylpiperidine (3-15)
Figure PCTCN2019076351-appb-000069
Figure PCTCN2019076351-appb-000069
将对叔丁氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁二甲基硅基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁氧基苯基-1-叔丁二甲基硅基哌啶(3-15))10.5g，收率90.2％；MS-ESI(m/z)：364.6[(M+H) +]。 Add p-tert-butoxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N- tert-Butyldimethylsilyl-3-piperidone (2-6, 6.8g, 31.9mmol) was diluted with anhydrous tetrahydrofuran (30mL), added to the dropping funnel, slowly added dropwise to the reaction flask, temperature control After the dropwise addition was completed at 0-5 ° C for 60 min, the reaction was stirred for 1 hour after completion of the dropwise addition. The starting material was completely reacted by TLC, quenched with saturated aqueous ammonium chloride (50 mL), and then ethyl acetate (20 mL×3) After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, and filtered, and the solvent is evaporated to give a crude product. The crude product is purified by silica gel column chromatography to give (3-hydroxy-3-p-t-butoxyphenyl) 1-1 Tert-butyldimethylsilylpiperidine (3-15)) 10.5 g, yield 90.2%; MS-ESI (m/z): 364.6 [(M+H) + ].
实施例59：3-羟基-3-对甲氧基甲氧基苯基-1-苄基哌啶(3-16)的合成Example 59: Synthesis of 3-hydroxy-3-p-methoxymethoxyphenyl-1-benzylpiperidine (3-16)
Figure PCTCN2019076351-appb-000070
Figure PCTCN2019076351-appb-000070
将对甲氧基甲氧基苯基溴化镁格氏试剂(1.8mol/L in THF，20mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继 续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基甲氧基苯基-1-苄基哌啶(3-16))9.9g，收率95.2％；MS-ESI(m/z)：328.5[(M+H) +]。 P-methoxymethoxyphenylmagnesium bromide reagent (1.8 mol / L in THF, 20 mL), anhydrous tetrahydrofuran (30 mL), was added to the reaction flask, protected with nitrogen, and cooled to 0 ° C in an ice water bath. N-Benzyl-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The starting material was completely reacted by TLC, and a saturated aqueous solution of ammonium chloride (50 mL) was added thereto, and extracted with ethyl acetate (20 mL×3). After three times, the organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness - benzyl piperidine (3-16)) 9.9 g, yield 95.2%; MS-ESI (m/z): 328.5 [(M+H) + ].
实施例60：3-羟基-3-对甲氧基甲氧基苯基-1-三苯甲基哌啶(3-17)的合成Example 60: Synthesis of 3-hydroxy-3-p-methoxymethoxyphenyl-1-tritylmethylpiperidine (3-17)
Figure PCTCN2019076351-appb-000071
Figure PCTCN2019076351-appb-000071
将对甲氧基甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基甲氧基苯基-1-三苯甲基哌啶(3-17))14.5g，收率94.6％；MS-ESI(m/z)：480.6[(M+H) +]。 P-methoxymethoxyphenylmagnesium bromide reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, will N-trityl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The starting material was completely reacted by TLC, and saturated aqueous ammonium chloride (50 mL) was added thereto, and then extracted with ethyl acetate (20 mL×3). After extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness 1-Tritylpiperidine (3-17)) 14.5 g, yield 94.6%; MS-ESI (m/z): 480.6 [(M+H) + ].
实施例61：3-羟基-3-对甲氧基甲氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-18)的合成Example 61: Synthesis of 3-hydroxy-3-p-methoxymethoxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-18)
Figure PCTCN2019076351-appb-000072
Figure PCTCN2019076351-appb-000072
将对甲氧基甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30mL) 稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基甲氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-18))11.8g，收率94.8％；MS-ESI(m/z)：388.5[(M+H) +]。 P-methoxymethoxyphenylmagnesium bromide reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, will N-(2,4-dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise In the reaction flask, the temperature is controlled at 0-5 ° C, 60 min, and the reaction is continued for 1 hour after the completion of the dropwise addition. The TLC test material has been completely reacted, and saturated aqueous ammonium chloride solution (50 mL) is added under stirring, and then acetic acid B is added. The ester (20 mL×3) was extracted, and after extracting three times, the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product. Oxymethoxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-18)) 11.8 g, yield 94.8%; MS-ESI (m/z): 388.5 [ M+H) + ].
实施例62：3-羟基-3-对甲氧基甲氧基苯基-1-叔丁基二甲基硅基哌啶(3-19)的合成Example 62: Synthesis of 3-hydroxy-3-p-methoxymethoxyphenyl-1-tert-butyldimethylsilylpiperidine (3-19)
Figure PCTCN2019076351-appb-000073
Figure PCTCN2019076351-appb-000073
将对甲氧基甲氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁二甲基硅基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对甲氧基甲氧基苯基-1-叔丁二甲基硅基哌啶(3-19))10.2g，收率91.1％；MS-ESI(m/z)：352.6[(M+H) +]。 P-methoxymethoxyphenylmagnesium bromide reagent (2mol / L in THF, 18mL), anhydrous tetrahydrofuran (30mL), added to the reaction flask, nitrogen protection, ice water bath cooled to 0 ° C, will N-tert-butyldimethylsilyl-3-piperidone (2-6, 6.8 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was controlled at 0-5 ° C, 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to detect the starting material. The mixture was quenched with saturated aqueous ammonium chloride (50 mL) and then ethyl acetate (20 mL) ×3) Extraction, extraction three times, the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product. Oxyphenyl-1-tert-butyldimethylsilylpiperidine (3-19)) 10.2 g, yield 91.1%; MS-ESI (m/z): 352.6 [(M+H) + ].
实施例63：3-羟基-3-对叔丁基二甲基硅氧基苯基-1-苄基哌啶(3-20)的合成Example 63: Synthesis of 3-hydroxy-3-p-tert-butyldimethylsilyloxyphenyl-1-benzylpiperidine (3-20)
Figure PCTCN2019076351-appb-000074
Figure PCTCN2019076351-appb-000074
将对叔丁基二甲基硅氧基苯基溴化镁格氏试剂(1.8mol/L in THF，20mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕 后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁基二甲基硅氧基苯基-1-苄基哌啶(3-20))12.1g，收率96.5％；MS-ESI(m/z)：398.6[(M+H) +]。 Add p-tert-butyldimethylsilyloxyphenylmagnesium bromide reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool in ice water bath N-benzyl-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL) at 0 ° C, added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature was dropped at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted. Saturated ammonium chloride aqueous solution (50 mL) was added with stirring, and ethyl acetate (20 mL×3) was used. After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give a crude product. The crude product is purified by silica gel column chromatography (3-hydroxy-3-p-t-butyldimethylsilyl) Oxyphenyl-1-benzylpiperidine (3-20)) 12.1 g, yield 96.5%; MS-ESI (m/z): 398.6 [(M+H) + ].
实施例64：3-羟基-3-对叔丁基二甲基硅氧基苯基-1-三苯甲基哌啶(3-21)的合成Example 64: Synthesis of 3-hydroxy-3-p-tert-butyldimethylsilyloxyphenyl-1-tritylmethylpiperidine (3-21)
Figure PCTCN2019076351-appb-000075
Figure PCTCN2019076351-appb-000075
将对叔丁基二甲基硅氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁基二甲基硅氧基苯基-1-三苯甲基哌啶(3-21))16.7g，收率95.1％；MS-ESI(m/z)：550.8[(M+H) +]。 Add p-tert-butyldimethylsilyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 in ice water bath N-trityl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. The temperature control was carried out at 0-5 ° C for 60 min. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted. Saturated ammonium chloride aqueous solution (50 mL) was added with stirring, and ethyl acetate (20 mL×3) was used. After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give the crude product. The crude product is purified by silica gel column chromatography to give (3-hydroxy-3-p-t-butyl dimethyl Siloxyphenyl-1-tritylpiperidine (3-21)) 16.7 g, yield 95.1%; MS-ESI (m/z): 550.8 [(M+H) + ].
实施例65：3-羟基-3-对叔丁基二甲基硅氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-22)的合成Example 65: Synthesis of 3-hydroxy-3-p-tert-butyldimethylsilyloxy-1-(2,4-dimethoxy)benzylpiperidine (3-22)
Figure PCTCN2019076351-appb-000076
Figure PCTCN2019076351-appb-000076
将对叔丁基二甲基硅氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30 mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁基二甲基硅氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-22))13.6g，收率92.5％；MS-ESI(m/z)：458.7[(M+H) +]。 Add p-tert-butyldimethylsilyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 in ice water bath N-(2,4-dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL) and added to a dropping funnel. Slowly drip into the reaction flask, the temperature control was carried out at 0-5 ° C, 60 min, and the reaction was stirred for 1 hour after the completion of the dropwise addition. The TLC test was completed and the saturated ammonium chloride aqueous solution (50 mL) was added under stirring. After extracting with ethyl acetate (20 mL×3), the organic layer was combined, and then dried and evaporated. 1-p-butyldimethylsilyloxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-22)) 13.6 g, yield 92.5%; MS-ESI (m /z): 458.7 [(M + H) + ].
实施例66：3-羟基-3-对叔丁基二甲基硅氧基苯基-1-叔丁基二甲基硅基哌啶(3-23)的合成Example 66: Synthesis of 3-hydroxy-3-p-tert-butyldimethylsilyloxyphenyl-1-tert-butyldimethylsilylpiperidine (3-23)
Figure PCTCN2019076351-appb-000077
Figure PCTCN2019076351-appb-000077
将对叔丁基二甲基硅氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁二甲基硅基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对叔丁基二甲基硅基苯基-1-叔丁二甲基硅氧基哌啶(3-23))12.5g，收率93.0％；MS-ESI(m/z)：422.8[(M+H) +]。 Add p-tert-butyldimethylsilyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 in ice water bath N-tert-Butyldimethylsilyl-3-piperidone (2-6, 6.8 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction. In the bottle, the temperature is controlled at 0-5 ° C, 60 min, and the reaction is continued for 1 hour after the completion of the dropwise addition. The TLC test material has been completely reacted, and the mixture is quenched with saturated aqueous ammonium chloride solution (50 mL), and then acetic acid B is added. The ester (20 mL×3) was extracted, and after extracting three times, the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product. Butyldimethylsilylphenyl-1-tert-butyldimethylsilylpiperidine (3-23)) 12.5 g, yield 93.0%; MS-ESI (m/z): 422.8 [(M+ H) + ].
实施例67：3-羟基-3-对苄氧基苯基-1-苄基哌啶(3-24)的合成Example 67: Synthesis of 3-hydroxy-3-p-benzyloxyphenyl-1-benzylpiperidine (3-24)
Figure PCTCN2019076351-appb-000078
Figure PCTCN2019076351-appb-000078
将对苄氧基苯基溴化镁格氏试剂(1.8mol/L in THF，20mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-苄基-3-哌啶酮(2-1,6.0g,31.7mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗 中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对苄氧基苯基-1-苄基哌啶(3-24))11.2g，收率94.8％；MS-ESI(m/z)：374.5[(M+H) +]。 Add p-benzyloxyphenylmagnesium bromide reagent (1.8mol/L in THF, 20mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N- Benzyl-3-piperidone (2-1, 6.0 g, 31.7 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask at a temperature of 0-5 ° C. After the completion of the dropwise addition, the reaction was stirred for 1 hour, and the reaction was completed by TLC. The mixture was stirred and evaporated to ethyl acetate (20 mL×3) and extracted three times. The organic layer was combined, dried (MgSO4) 3-24)) 11.2 g, yield 94.8%; MS-ESI (m/z): 374.5 [(M+H) + ].
实施例68：3-羟基-3-对苄氧基苯基-1-三苯甲基哌啶(3-25)的合成Example 68: Synthesis of 3-hydroxy-3-p-benzyloxyphenyl-1-tritylmethylpiperidine (3-25)
Figure PCTCN2019076351-appb-000079
Figure PCTCN2019076351-appb-000079
将对苄氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-三苯甲基-3-哌啶酮(2-2,10.9g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对苄氧基苯基-1-三苯甲基哌啶(3-25))16.0g，收率95.1％；MS-ESI(m/z)：526.7[(M+H) +]。 Add p-benzyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N-three Benzyl-3-piperidone (2-2, 10.9 g, 31.9 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5. After the completion of the dropwise addition, the reaction was continued for 1 hour. After the completion of the dropwise addition, the reaction was stirred for 1 hour. The TLC was used to confirm that the starting material had been completely reacted, and saturated aqueous ammonium chloride (50 mL) was added thereto, and then extracted with ethyl acetate (20 mL×3), and extracted three times. The organic layer was combined, dried (MgSO4) Piperidine (3-25)) 16.0 g, yield 95.1%; MS-ESI (m/z): 526.7 [(M+H) + ].
实施例69：3-羟基-3-对苄氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-26)的合成Example 69: Synthesis of 3-hydroxy-3-p-benzyloxyphenyl-1-(2,4-dimethoxy)benzylpiperidine (3-26)
Figure PCTCN2019076351-appb-000080
Figure PCTCN2019076351-appb-000080
将对苄氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-(2,4-二甲氧 基)苄基-3-哌啶酮(2-3,8.0g,32.1mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对苄氧基苯基-1-(2,4-二甲氧基)苄基哌啶(3-26))13.5g，收率97.2％；MS-ESI(m/z)：434.5[(M+H) +]。 Add p-benzyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 ° C in ice water bath, N-( 2,4-Dimethoxy)benzyl-3-piperidone (2-3, 8.0 g, 32.1 mmol) was diluted with anhydrous tetrahydrofuran (30 mL), added to a dropping funnel, and slowly added dropwise to the reaction flask. In the middle, the temperature is controlled at 0-5 ° C, 60 min, and the reaction is stirred for 1 hour after the completion of the dropwise addition. The TLC test material has been completely reacted, and saturated aqueous ammonium chloride solution (50 mL) is added with stirring, and then ethyl acetate (20 mL) is used. ×3) After extraction and extraction three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give the crude product. 1-(2,4-dimethoxy)benzylpiperidine (3-26)) 13.5 g, yield 97.2%; MS-ESI (m/z): 434.5 [(M+H) + ] .
实施例70：3-羟基-3-对苄氧基苯基-1-叔丁基二甲基硅基哌啶(3-27)的合成Example 70: Synthesis of 3-hydroxy-3-p-benzyloxyphenyl-1-tert-butyldimethylsilylpiperidine (3-27)
Figure PCTCN2019076351-appb-000081
Figure PCTCN2019076351-appb-000081
将对苄氧基苯基溴化镁格氏试剂(2mol/L in THF，18mL)，无水四氢呋喃(30mL)，加入到反应瓶中，氮气保护，冰水浴冷却到0℃，将N-叔丁二甲基硅基-3-哌啶酮(2-6,6.8g,31.9mmol)用无水四氢呋喃(30mL)稀释，加入到滴液漏斗中，缓慢滴加到反应瓶中，控温在0-5℃，60min滴完，滴加完毕后继续搅拌反应1小时，TLC检测原料已经反应完全，搅拌下加入饱和氯化铵水溶液(50mL)猝灭，再用乙酸乙酯(20mL×3)萃取，萃取三次后，合并有机层，加入适量无水硫酸钠干燥，过滤，旋干溶剂得到产物粗品，粗品用硅胶柱层析，得(3-羟基-3-对苄氧基苯基-1-叔丁二甲基硅基哌啶(3-27))11.7g，收率92.6％；MS-ESI(m/z)：398.6[(M+H) +]。 Add p-benzyloxyphenylmagnesium bromide reagent (2mol/L in THF, 18mL), anhydrous tetrahydrofuran (30mL), add to the reaction flask, protect with nitrogen, cool to 0 °C in ice water bath, N-un Dibutylsilyl-3-piperidone (2-6, 6.8g, 31.9mmol) was diluted with anhydrous tetrahydrofuran (30mL), added to the dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled. 0-5 ° C, 60 min after the completion of the dropwise addition, the reaction was continued for 1 hour after the completion of the dropwise addition. The TLC was used to detect the starting material. The mixture was quenched with saturated aqueous ammonium chloride (50 mL) and then ethyl acetate (20 mL×3). After extracting and extracting three times, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give a crude product. The crude product is purified by silica gel column chromatography (3-hydroxy-3-p-benzyloxyphenyl-1) - tert-butyldimethylsilylpiperidine (3-27)) 11.7 g, yield 92.6%; MS-ESI (m/z): 398.6 [(M+H) + ].
实施例71：1-苄基-5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-2)和1-苄基-5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-2)的合成Example 71:1-Benzyl-5-p-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-2) and 1-benzyl-5-p-methoxyphenyl-1 Synthesis of 2,3,4-tetrahydropyridine (5-2)
Figure PCTCN2019076351-appb-000082
Figure PCTCN2019076351-appb-000082
将3-羟基-3-对甲氧基苯基-1-苄基哌啶(3-2,8.0g,26.9mmol)、冰乙酸(40mL,0.67mol)、乙酰氯(40mL,0.56mol)加入到反应瓶中，加热，回流反应 90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-2)和化合物(5-2)的混合物)6.5g，收率86.8％；MS-ESI(m/z)：280.4(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-benzylpiperidine (3-2, 8.0 g, 26.9 mmol), glacial acetic acid (40 mL, 0.67 mol), acetyl chloride (40 mL, 0.56 mol) Into the reaction flask, heating, reflux reaction for 90 min, TLC detection of the raw material reaction is complete, stop the reaction, acetic acid is distilled under reduced pressure, and then the residue is added 20% aqueous sodium hydroxide solution, adjust the solution pH = 8-9, then use The organic layer was extracted with ethyl acetate (20 mL×3), and dried over anhydrous sodium sulfate. -2) mixture 6.5 g, yield 86.8%; MS-ESI (m/z): 280.4 (M+H) + .
实施例72：5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-3)和5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-3)的合成Example 72: 5-P-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-3) and 5-p-methoxyphenyl-1,2,3,4-tetrahydropyridine Synthesis of (5-3)
Figure PCTCN2019076351-appb-000083
Figure PCTCN2019076351-appb-000083
将3-羟基-3-对甲氧基苯基-1-三苯甲基哌啶(3-3,12.0g,26.7mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品(化合物(4-3)和化合物(5-3)的混合物)，将所得粗品用硅胶柱层析，得到化合物(4-3)和化合物(5-3)的混合物4.2g，收率83.9％，MS-ESI(m/z)：189.3(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-tritylpiperidine (3-3, 12.0 g, 26.7 mmol), glacial acetic acid (60 mL, 1.00 mol), acetyl chloride (60 mL, 0.84 mol) Adding to the reaction flask, heating, refluxing reaction for 90 min, TLC detection of the raw material reaction is complete, stop the reaction, acetic acid is distilled under reduced pressure, and then the residue is added with 20% aqueous sodium hydroxide solution to adjust the solution pH = 8-9, The organic layer was extracted with ethyl acetate (20 mL×3) the resulting crude product was purified by silica gel column chromatography to give compound (4-3) and compound (5-3) 4.2 g of mixture, yield 83.9%, MS-ESI (m / z): 189.3 (m + H) +.
实施例73：1-(2,4-二甲氧基苄基)-5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-4)和1-(2,4-二甲氧基苄基)-5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-4)的合成Example 73: 1-(2,4-Dimethoxybenzyl)-5-p-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-4) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-methoxyphenyl-1,2,3,4-tetrahydropyridine (5-4)
Figure PCTCN2019076351-appb-000084
Figure PCTCN2019076351-appb-000084
将3-羟基-3-对甲氧基苯基-1-(2,4-二甲氧基苄基)-哌啶(3-4,10.0g,28.0mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行 减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-4)和化合物(5-4)的混合物)8.1g，收率85.6％；MS-ESI(m/z)：340.4(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-(2,4-dimethoxybenzyl)-piperidine (3-4, 10.0 g, 28.0 mmol), glacial acetic acid (50 mL, 0.84 mol) ), acetyl chloride (50mL, 0.70mol) was added to the reaction flask, heated, refluxed for 90 minutes, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then 20% aqueous sodium hydroxide solution was added to the residue. The solution was adjusted to pH = 8-9, then extracted with ethyl acetate (20 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness (a mixture of compound (4-4) and compound (5-4) a) 8.1g, yield 85.6%; MS-ESI (m / z): 340.4 (m + H) +.
实施例74：1-叔丁基-5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-5)和1-叔丁基-5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-5)的合成Example 74: 1-tert-Butyl-5-p-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-5) and 1-tert-butyl-5-p-methoxyphenyl Synthesis of -1,2,3,4-tetrahydropyridine (5-5)
Figure PCTCN2019076351-appb-000085
Figure PCTCN2019076351-appb-000085
将3-羟基-3-对甲氧基苯基-1-叔丁基-哌啶(3-5,7.8g,29.6mmol)、冰乙酸(40mL,0.67mol)、乙酰氯(40mL,0.56mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-5)和化合物(5-5)的混合物)6.3g，收率86.7％；MS-ESI(m/z)：246.4(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-tert-butyl-piperidine (3-5, 7.8 g, 29.6 mmol), glacial acetic acid (40 mL, 0.67 mol), acetyl chloride (40 mL, 0.56 mol) Adding to the reaction flask, heating, refluxing reaction for 90 min, TLC detection of the raw material reaction is complete, stop the reaction, acetic acid is distilled under reduced pressure, and then the residue is added with 20% aqueous sodium hydroxide solution to adjust the solution pH = 8-9, The organic layer was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to dryness (5-5) mixture 6.3 g, yield 86.7%; MS-ESI (m/z): 246.4 (M+H) + .
实施例75：5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-3)和5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-3)的合成Example 75: 5-P-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-3) and 5-p-methoxyphenyl-1,2,3,4-tetrahydropyridine Synthesis of (5-3)
Figure PCTCN2019076351-appb-000086
Figure PCTCN2019076351-appb-000086
将3-羟基-3-对甲氧基苯基-1-三甲基硅基哌啶(3-6,8.0g,28.6mmol)、冰乙酸(40mL,0.67mol)、乙酰氯(40mL,0.56mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品(化合物(4-3)和化合物(5-3)的混合物)，将所得粗品用硅胶柱层析， 得到化合物(4-3)和化合物(5-3)的混合物4.5g，收率83.3％，MS-ESI(m/z)：189.3(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-trimethylsilylpiperidine (3-6, 8.0 g, 28.6 mmol), glacial acetic acid (40 mL, 0.67 mol), acetyl chloride (40 mL, 0.56) Mol) was added to the reaction flask, heated, refluxed for 90 min, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous solution of sodium hydroxide was added to the residue to adjust the pH of the solution to 8-9. Then, it was extracted with ethyl acetate (20 mL × 3), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude product (the mixture of compound (4-3) and compound (5-3)) The obtained crude product was subjected to silica gel column chromatography to give a mixture of compound (4-3) and compound (5-3): 4.5 g, yield: 83.3%, MS-ESI (m/z): 189.3 (M+H) + .
实施例76：5-对甲氧基苯基-1,2,3,6-四氢吡啶(4-3)和5-对甲氧基苯基-1,2,3,4-四氢吡啶(5-3)的合成Example 76: 5-P-methoxyphenyl-1,2,3,6-tetrahydropyridine (4-3) and 5-p-methoxyphenyl-1,2,3,4-tetrahydropyridine Synthesis of (5-3)
Figure PCTCN2019076351-appb-000087
Figure PCTCN2019076351-appb-000087
将3-羟基-3-对甲氧基苯基-1-叔丁基二甲基硅基哌啶(3-7,8.8g,27.4mmol)、冰乙酸(40mL,0.67mol)、乙酰氯(40mL,0.56mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品(化合物(4-3)和化合物(5-3)的混合物)，将所得粗品用硅胶柱纯化，得到化合物(4-3)和化合物(5-3)的混合物4.5g，收率86.6％。MS-ESI(m/z)：189.3(M+H) +。 3-Hydroxy-3-p-methoxyphenyl-1-tert-butyldimethylsilylpiperidine (3-7, 8.8 g, 27.4 mmol), glacial acetic acid (40 mL, 0.67 mol), acetyl chloride ( 40 mL, 0.56 mol) was added to the reaction flask, heated, and refluxed for 90 min. After TLC, the reaction of the starting material was completely completed, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous sodium hydroxide solution was added to the residue to adjust the pH of the solution. 8-9, followed by extraction with ethyl acetate (20 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude product (Compound (4-3) and Compound (5-3) The obtained crude product was purified by a silica gel column to give 4.5 g of a mixture of compound (4-3) and compound (5-3), yield 86.6%. MS-ESI (m / z) : 189.3 (M + H) +.
实施例77：1-苄基-5-对乙氧基苯基-1,2,3,6-四氢吡啶(4-6)和1-苄基-5-对乙氧基苯基-1,2,3,4-四氢吡啶(5-6)的合成Example 77: 1-Benzyl-5-p-ethoxyphenyl-1,2,3,6-tetrahydropyridine (4-6) and 1-benzyl-5-p-ethoxyphenyl-1 Synthesis of 2,3,4-tetrahydropyridine (5-6)
Figure PCTCN2019076351-appb-000088
Figure PCTCN2019076351-appb-000088
将3-羟基-3-对乙氧基苯基-1-苄基哌啶(3-8,9.0g,28.9mmol)、冰乙酸(40mL,0.67mol)、乙酰氯(40mL,0.56mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-6)和化合物(5-6)的混合物)7.2g，收率85.0％，MS-ESI(m/z)：294.4(M+H) +。 3-Hydroxy-3-p-ethoxyphenyl-1-benzylpiperidine (3-8, 9.0 g, 28.9 mmol), glacial acetic acid (40 mL, 0.67 mol), acetyl chloride (40 mL, 0.56 mol) Into the reaction flask, heating, reflux reaction for 90 min, TLC detection of the raw material reaction is complete, stop the reaction, acetic acid is distilled under reduced pressure, and then the residue is added 20% aqueous sodium hydroxide solution, adjust the solution pH = 8-9, then use The organic layer was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated to dryness -6) mixture) 7.2g, yield 85.0%, MS-ESI (m / z): 294.4 (m + H) +.
实施例78：1-(2,4-二甲氧基苄基)-5-对乙氧基苯基-1,2,3,6-四氢吡啶(4-7)和 1-(2,4-二甲氧基苄基)-5-对乙氧基苯基-1,2,3,4-四氢吡啶(5-7)的合成Example 78: 1-(2,4-Dimethoxybenzyl)-5-p-ethoxyphenyl-1,2,3,6-tetrahydropyridine (4-7) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-ethoxyphenyl-1,2,3,4-tetrahydropyridine (5-7)
Figure PCTCN2019076351-appb-000089
Figure PCTCN2019076351-appb-000089
将3-羟基-3-对乙氧基苯基-1-(2,4-二甲氧基苄基)-哌啶(3-10,10.0g,26.92mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-7)和化合物(5-7)的混合物)8.2g，收率86.3％。MS-ESI(m/z)：354.4(M+H) +。 3-Hydroxy-3-p-ethoxyphenyl-1-(2,4-dimethoxybenzyl)-piperidine (3-10, 10.0 g, 26.92 mmol), glacial acetic acid (50 mL, 0.84 mol) ), acetyl chloride (50mL, 0.70mol) was added to the reaction flask, heated, refluxed for 90 minutes, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then 20% aqueous sodium hydroxide solution was added to the residue. The solution was adjusted to pH = 8-9, then extracted with ethyl acetate (20 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness (A mixture of the compound (4-7) and the compound (5-7)) 8.2 g, a yield of 86.3%. MS-ESI (m/z): 354.4 (M+H) + .
实施例79：1-苄基-5-对羟基苯基-1,2,3,6-四氢吡啶(4-8)和1-苄基-5-对羟基苯基-1,2,3,4-四氢吡啶(5-8)的合成Example 79: 1-Benzyl-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-8) and 1-benzyl-5-p-hydroxyphenyl-1,2,3 Synthesis of 4-tetrahydropyridine (5-8)
Figure PCTCN2019076351-appb-000090
Figure PCTCN2019076351-appb-000090
将3-羟基-3-对叔丁氧基苯基-1-苄基哌啶(3-12,10.0g,29.5mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-8)和化合物(5-8)的混合物)6.4g，收率81.4％，MS-ESI(m/z)：266.4(M+H) +。 3-Hydroxy-3-p-tert-butoxyphenyl-1-benzylpiperidine (3-12, 10.0 g, 29.5 mmol), glacial acetic acid (50 mL, 0.84 mol), acetyl chloride (50 mL, 0.70 mol) Adding to the reaction flask, heating, refluxing reaction for 90 min, TLC detection of the raw material reaction is complete, the reaction is stopped, acetic acid is distilled under reduced pressure, and then a 20% aqueous sodium hydroxide solution is added to the residue to adjust the pH of the solution to 8-9, followed by The organic layer was extracted with ethyl acetate (20 mL×3). Mixture 5-8) 6.4 g, yield 81.4%, MS-ESI (m/z): 266.4 (M+H) + .
实施例80：1-(2,4-二甲氧基苄基)-5-对羟基苯基-1,2,3,6-四氢吡啶(4-9)和1-(2,4-二甲氧基苄基)-5-对羟基苯基-1,2,3,4-四氢吡啶(5-9)的合成Example 80: 1-(2,4-Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-9) and 1-(2,4- Synthesis of Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-9)
Figure PCTCN2019076351-appb-000091
Figure PCTCN2019076351-appb-000091
将3-羟基-3-对叔丁氧基苯基-1-(2,4-二甲氧基苄基)-哌啶(3-14,12.0g,30.0mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-9)和化合物(5-9)的混合物)8.2g，收率84.2％，MS-ESI(m/z)：326.4(M+H) +。 3-Hydroxy-3-p-tert-butoxyphenyl-1-(2,4-dimethoxybenzyl)-piperidine (3-14, 12.0 g, 30.0 mmol), glacial acetic acid (60 mL, 1.00 Mol), acetyl chloride (60mL, 0.84mol) was added to the reaction flask, heated, refluxed for 90min, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then 20% sodium hydroxide was added to the residue. The aqueous solution was adjusted to pH=8-9, then extracted with ethyl acetate (20 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate. to give (a mixture of compound (4-9) and compound (5-9) a) 8.2g, yield 84.2%, MS-ESI (m / z): 326.4 (m + H) +.
实施例81：5-对羟基苯基-1,2,3,6-四氢吡啶(4-10)和5-对羟基苯基-1,2,3,4-四氢吡啶(5-10)的合成Example 81: 5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-10) and 5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-10) )Synthesis
Figure PCTCN2019076351-appb-000092
Figure PCTCN2019076351-appb-000092
将3-羟基-3-对叔丁氧基苯基-1-叔丁基二甲基硅基-哌啶(3-15,10.0g,27.5mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×5)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-10)和化合物(5-10)的混合物)4.0g，收率83.9％，MS-ESI(m/z)：176.2(M+H) +。 3-Hydroxy-3-p-tert-butoxyphenyl-1-tert-butyldimethylsilyl-piperidine (3-15, 10.0 g, 27.5 mmol), glacial acetic acid (50 mL, 0.84 mol), B The acid chloride (50 mL, 0.70 mol) was added to the reaction flask, heated, refluxed for 90 min, and the reaction of the starting material was completely detected by TLC, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous sodium hydroxide solution was added to the residue to adjust the solution. The mixture was extracted with ethyl acetate (20 mL×5), and the organic layer was evaporated. 4-10) and a mixture of the compound (5-10)) 4.0 g, yield 83.9%, MS-ESI (m/z): 176.2 (M+H) + .
实施例82：1-苄基-5-对羟基苯基-1,2,3,6-四氢吡啶(4-8)和1-苄基-5-对羟基苯基-1,2,3,4-四氢吡啶(5-8)的合成Example 82: 1-Benzyl-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-8) and 1-benzyl-5-p-hydroxyphenyl-1,2,3 Synthesis of 4-tetrahydropyridine (5-8)
Figure PCTCN2019076351-appb-000093
Figure PCTCN2019076351-appb-000093
将3-羟基-3-对甲氧基甲氧基苯基-1-苄基哌啶(3-16,9.5g,29.0mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯 萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-8)和化合物(5-8)的混合物)7.2g，收率85.0％，MS-ESI(m/z)：266.4(M+H) +。 3-Hydroxy-3-p-methoxymethoxyphenyl-1-benzylpiperidine (3-16, 9.5 g, 29.0 mmol), glacial acetic acid (50 mL, 0.84 mol), acetyl chloride (50 mL, 0.70) Mol) was added to the reaction flask, heated, refluxed for 90 min, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous solution of sodium hydroxide was added to the residue to adjust the pH of the solution to 8-9. Then, it is extracted with ethyl acetate (20 mL × 3), and the organic layer is collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness mixture of compound (5-8) a) 7.2g, yield 85.0%, MS-ESI (m / z): 266.4 (m + H) +.
实施例83：1-(2,4-二甲氧基苄基)-5-对羟基苯基-1,2,3,6-四氢吡啶(4-9)和1-(2,4-二甲氧基苄基)-5-对羟基苯基-1,2,3,4-四氢吡啶(5-9)的合成Example 83: 1-(2,4-Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-9) and 1-(2,4- Synthesis of Dimethoxybenzyl)-5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-9)
Figure PCTCN2019076351-appb-000094
Figure PCTCN2019076351-appb-000094
将3-羟基-3-对甲氧基甲氧基苯基-1-(2,4-二甲氧基苄基)-哌啶(3-18,11.5g,29.7mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-9)和化合物(5-9)的混合物)7.9g，收率82.3％，MS-ESI(m/z)：326.4(M+H) +。 3-Hydroxy-3-p-methoxymethoxyphenyl-1-(2,4-dimethoxybenzyl)-piperidine (3-18, 11.5 g, 29.7 mmol), glacial acetic acid (60 mL) , 1.00mol), acetyl chloride (60mL, 0.84mol) was added to the reaction flask, heated, reflux reaction for 90min, TLC detection of the raw material reaction was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then 20% hydrogen was added to the residue. The sodium hydroxide aqueous solution was adjusted to pH=8-9, and then extracted with ethyl acetate (20 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness analysis, to give (a mixture of compound (4-9) and compound (5-9) a) 7.9 g of, a yield of 82.3%, MS-ESI (m / z): 326.4 (m + H) +.
实施例84：1-苄基-5-对羟基苯基-1,2,3,6-四氢吡啶(4-8)和1-苄基-5-对羟基苯基-1,2,3,4-四氢吡啶(5-8)的合成Example 84: 1-Benzyl-5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-8) and 1-benzyl-5-p-hydroxyphenyl-1,2,3 Synthesis of 4-tetrahydropyridine (5-8)
Figure PCTCN2019076351-appb-000095
Figure PCTCN2019076351-appb-000095
将3-羟基-3-对叔丁基二甲基硅氧基苯基-1-苄基哌啶(3-20,11.8g,29.7mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-8)和化合物(5-8)的混合物)6.3g，收率79.8％，MS-ESI(m/z)：266.4(M+H) +。 3-Hydroxy-3-p-tert-butyldimethylsilyloxyphenyl-1-benzylpiperidine (3-20, 11.8 g, 29.7 mmol), glacial acetic acid (60 mL, 1.00 mol), acetyl chloride ( 60 mL, 0.84 mol) was added to the reaction flask, heated, refluxed for 90 min, and the reaction of the starting material was completely detected by TLC. The reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous sodium hydroxide solution was added to the residue to adjust the pH of the solution. The mixture was extracted with ethyl acetate (20 mL×3). 8) and a mixture of the compound (5-8)) 6.3 g, yield 79.8%, MS-ESI (m/z): 266.4 (M+H) + .
实施例85：5-对羟基苯基-1,2,3,6-四氢吡啶(4-10)和5-对羟基苯基-1,2,3,4- 四氢吡啶(5-10)的合成Example 85: 5-p-hydroxyphenyl-1,2,3,6-tetrahydropyridine (4-10) and 5-p-hydroxyphenyl-1,2,3,4-tetrahydropyridine (5-10) )Synthesis
Figure PCTCN2019076351-appb-000096
Figure PCTCN2019076351-appb-000096
将3-羟基-3-对叔丁基二甲基硅氧基苯基-1-叔丁基二甲基硅基哌啶(3-23,12.2g,28.9mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×5)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-10)和化合物(5-10)的混合物)4.1g，收率80.8％，MS-ESI(m/z)：176.2(M+H) +。 3-Hydroxy-3-p-tert-butyldimethylsilyloxyphenyl-1-tert-butyldimethylsilylpiperidine (3-23, 12.2 g, 28.9 mmol), glacial acetic acid (60 mL, 1.00) Mol), acetyl chloride (60mL, 0.84mol) was added to the reaction flask, heated, refluxed for 90min, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then 20% sodium hydroxide was added to the residue. The aqueous solution was adjusted to pH=8-9, then extracted with ethyl acetate (20 mL×5), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. (Compound of compound (4-10) and compound (5-10)) 4.1 g, yield 80.8%, MS-ESI (m/z): 176.2 (M+H) + .
实施例86：1-苄基-5-对苄氧基苯基-1,2,3,6-四氢吡啶(4-11)和1-苄基-5-对苄氧基苯基-1,2,3,4-四氢吡啶(5-11)的合成Example 86: 1-Benzyl-5-p-benzyloxyphenyl-1,2,3,6-tetrahydropyridine (4-11) and 1-benzyl-5-p-benzyloxyphenyl-1 Synthesis of 2,3,4-tetrahydropyridine (5-11)
Figure PCTCN2019076351-appb-000097
Figure PCTCN2019076351-appb-000097
将3-羟基-3-对苄氧基苯基-1-苄基哌啶(3-24,11.0g,29.4mmol)、冰乙酸(50mL,0.84mol)、乙酰氯(50mL,0.70mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-11)和化合物(5-11)的混合物)8.6g，收率81.9％，MS-ESI(m/z)：356.5(M+H) +。 3-Hydroxy-3-p-benzyloxyphenyl-1-benzylpiperidine (3-24, 11.0 g, 29.4 mmol), glacial acetic acid (50 mL, 0.84 mol), acetyl chloride (50 mL, 0.70 mol) Into the reaction flask, heating, reflux reaction for 90 min, TLC detection of the raw material reaction is complete, stop the reaction, acetic acid is distilled under reduced pressure, and then the residue is added 20% aqueous sodium hydroxide solution, adjust the solution pH = 8-9, then use The organic layer was extracted with ethyl acetate (20 mL×3), EtOAcjjjjjjjjjjj </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt;
实施例87：1-(2,4-二甲氧基苄基)-5-对苄氧基苯基-1,2,3,6-四氢吡啶(4-12)和1-(2,4-二甲氧基苄基)-5-对苄氧基苯基-1,2,3,4-四氢吡啶(5-12)的合成Example 87: 1-(2,4-Dimethoxybenzyl)-5-p-benzyloxyphenyl-1,2,3,6-tetrahydropyridine (4-12) and 1-(2, Synthesis of 4-dimethoxybenzyl)-5-p-benzyloxyphenyl-1,2,3,4-tetrahydropyridine (5-12)
Figure PCTCN2019076351-appb-000098
Figure PCTCN2019076351-appb-000098
将3-羟基-3-对苄氧基苯基-1-(2,4-二甲氧基苄基)-哌啶(3-26,12.8g,29.5mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得到粗品，粗品用硅胶柱层析，得(化合物(4-12)和化合物(5-12)的混合物)10.1g，收率82.7％。MS-ESI(m/z)：416.5(M+H) +。 3-Hydroxy-3-p-benzyloxyphenyl-1-(2,4-dimethoxybenzyl)-piperidine (3-26, 12.8 g, 29.5 mmol), glacial acetic acid (60 mL, 1.00 mol) ), acetyl chloride (60 mL, 0.84 mol) was added to the reaction flask, heated, refluxed for 90 min, and the reaction of the starting material was completely detected by TLC, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous sodium hydroxide solution was added to the residue. The solution was adjusted to pH = 8-9, then extracted with ethyl acetate (20 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness (A mixture of the compound (4-12) and the compound (5-12)) 10.1 g, a yield of 82.7%. MS-ESI (m / z) : 416.5 (M + H) +.
实施例88：5-对苄氧基苯基-1,2,3,6-四氢吡啶(4-13)和5-对苄氧基苯基-1,2,3,4-四氢吡啶(5-13)的合成Example 88: 5-p-benzyloxyphenyl-1,2,3,6-tetrahydropyridine (4-13) and 5-p-benzyloxyphenyl-1,2,3,4-tetrahydropyridine Synthesis of (5-13)
Figure PCTCN2019076351-appb-000099
Figure PCTCN2019076351-appb-000099
将3-羟基-3-对苄氧基苯基-1-叔丁基二甲基硅基-哌啶(3-27,11.0g,27.7mmol)、冰乙酸(60mL,1.00mol)、乙酰氯(60mL,0.84mol)加入到反应瓶中，加热，回流反应90min后TLC检测原料反应完全，停止反应，将乙酸进行减压蒸馏，然后向残余物加入20％的氢氧化钠水溶液，调节溶液pH＝8-9，接着用乙酸乙酯萃取(20mL×3)，收集有机层，用无水硫酸钠进行干燥，过滤，将溶剂旋干得粗品，粗品用硅胶柱层析，得产物(化合物(4-13)和化合物(5-13)的混合物)5.9g，收率79.8％，MS-ESI(m/z)：266.4(M+H) +。 3-Hydroxy-3-p-benzyloxyphenyl-1-tert-butyldimethylsilyl-piperidine (3-27, 11.0 g, 27.7 mmol), glacial acetic acid (60 mL, 1.00 mol), acetyl chloride (60mL, 0.84mol) was added to the reaction flask, heated, refluxed for 90 minutes, TLC detected the reaction of the starting material was complete, the reaction was stopped, acetic acid was distilled under reduced pressure, and then a 20% aqueous solution of sodium hydroxide was added to the residue to adjust the pH of the solution. After extraction with ethyl acetate (20 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness 4-13) and a mixture of the compound (5-13)) 5.9 g, yield 79.8%, MS-ESI (m/z): 266.4 (M+H) + .
实施例89：3-对甲氧基苯基哌啶(1-2)的合成Example 89: Synthesis of 3-p-methoxyphenylpiperidine (1-2)
Figure PCTCN2019076351-appb-000100
Figure PCTCN2019076351-appb-000100
将化合物(4-2)和化合物(5-2)的混合物(8.0g,28.6mmol)、钯碳(1.6g,20％)、无水甲醇(40mL)、冰乙酸(1.6mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应16h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，并用乙酸乙酯进行萃取(50 mL×3)，收集有机层，用无水硫酸钠干燥，过滤，将溶剂旋干，粗品用硅胶柱层析，得到产物3-对甲氧基苯基哌啶(1-2)4.9g，收率89.5％，MS-ESI(m/z)：192.3(M+H) +。 Mixture of compound (4-2) and compound (5-2) (8.0 g, 28.6 mmol), palladium on carbon (1.6 g, 20%), anhydrous methanol (40 mL), glacial acetic acid (1.6 mL) In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 60 ° C, and reacted for 16 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was sparged, water (50 mL) was added, and extracted with ethyl acetate. (50 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. g, yield 89.5%, MS-ESI (m / z): 192.3 (m + H) +.
实施例90：3-对甲氧基苯基哌啶(1-2)的合成Example 90: Synthesis of 3-p-methoxyphenylpiperidine (1-2)
Figure PCTCN2019076351-appb-000101
Figure PCTCN2019076351-appb-000101
将化合物(4-3)和化合物(5-3)的混合物(7.5g,39.6mmol)、钯碳(0.38g,5％)、无水甲醇(40mL)加入到高压釜中，并通入氢气，真空置换三次，加热到40℃，反应6h，TLC检测原料反应完全，停止反应，将钯碳过滤，将溶剂旋干，粗品用硅胶柱层析，得到产物3-对甲氧基苯基哌啶(1-2)7.3g，收率96.2％，MS-ESI(m/z):192.3(M+H) +。 A mixture of the compound (4-3) and the compound (5-3) (7.5 g, 39.6 mmol), palladium carbon (0.38 g, 5%), anhydrous methanol (40 mL) was placed in an autoclave, and hydrogen was introduced. The mixture was replaced by vacuum three times, heated to 40 ° C, and reacted for 6 h. The reaction of the starting material was completed by TLC, the reaction was stopped, the palladium carbon was filtered, and the solvent was evaporated to dryness. piperidine (1-2) 7.3g, yield 96.2%, MS-ESI (m / z): 192.3 (m + H) +.
实施例91：3-对甲氧基苯基哌啶(1-2)的合成Example 91: Synthesis of 3-p-methoxyphenylpiperidine (1-2)
Figure PCTCN2019076351-appb-000102
Figure PCTCN2019076351-appb-000102
将化合物(4-4)和化合物(5-4)的混合物(10.0g,29.5mmol)、钯碳(1.0g,10％)、无水甲醇(60mL)、冰乙酸(3.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应10h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后，加入水(50mL)，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，粗品用硅胶柱层析，得到产物3-对甲氧基苯基哌啶(1-2)5.2g，收率92.4％，MS-ESI(m/z):192.3(M+H) +。 Mixture of compound (4-4) and compound (5-4) (10.0 g, 29.5 mmol), palladium on carbon (1.0 g, 10%), anhydrous methanol (60 mL), glacial acetic acid (3.0 mL) In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 60 ° C, and reacted for 10 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, and the solvent was spun dry, water (50 mL) was added, and ethyl acetate was used. The organic layer was collected (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the crude product was applied to silica gel column chromatography to give the product 3-p-methoxyphenylpiperidine (1-2) 5.2 g, yield 92.4 %, MS-ESI (m/z): 192.3 (M+H) + .
实施例92：N-叔丁基-3-对甲氧基苯基哌啶(6-3)的合成Example 92: Synthesis of N-tert-butyl-3-p-methoxyphenylpiperidine (6-3)
Figure PCTCN2019076351-appb-000103
Figure PCTCN2019076351-appb-000103
将化合物(4-5)和化合物(5-5)的混合物(7.9g,32.2mmol)、钯碳(0.40g,5％)、无水甲醇(40mL)加入到高压釜中，并通入氢气，真空置换三次，加 热到40℃，反应6h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干，粗品用硅胶柱层析，得到产物N-叔丁基-3-对甲氧基苯基哌啶(6-3)7.9g，收率99.2％，MS-ESI(m/z):248.4(M+H) +。 A mixture of the compound (4-5) and the compound (5-5) (7.9 g, 32.2 mmol), palladium carbon (0.40 g, 5%), anhydrous methanol (40 mL) was added to the autoclave, and hydrogen was introduced. The mixture was replaced by vacuum three times, heated to 40 ° C, and reacted for 6 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was evaporated to dryness, and the crude product was subjected to silica gel column chromatography to obtain the product N-tert-butyl-3-p-methyl. methoxyphenyl piperidine (6-3) 7.9g, yield 99.2%, MS-ESI (m / z): 248.4 (m + H) +.
实施例93：3-对甲氧基苯基哌啶(1-2)的合成Example 93: Synthesis of 3-p-methoxyphenylpiperidine (1-2)
Figure PCTCN2019076351-appb-000104
Figure PCTCN2019076351-appb-000104
将N-叔丁基-3-对甲氧基苯基哌啶(6-3)(7.6g，30.7mmol)加入100mL玻璃烧瓶中，再加入浓盐酸(40mL)。搅拌下，加热回流24小时。检测原料已反应完，停止反应。向反应液中加入NaOH溶液，调节pH值至8-10，乙酸乙酯萃取(50mLX3)，合并有机层，加入无水硫酸钠干燥，过滤，旋干溶剂，粗品用硅胶柱层析，得到产物3-对甲氧基苯基哌啶(1-2)4.2g，收率71.5％，MS-ESI(m/z)：192.3(M+H) +。 N-tert-butyl-3-p-methoxyphenylpiperidine (6-3) (7.6 g, 30.7 mmol) was added to a 100 mL glass flask, and then concentrated hydrochloric acid (40 mL). The mixture was heated under reflux for 24 hours with stirring. After the detection of the raw materials has been completed, the reaction is stopped. NaOH solution was added to the reaction solution, the pH was adjusted to 8-10, ethyl acetate was extracted (50 mL×3), the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. 3-p-methoxyphenyl piperidine (1-2) 4.2g, yield 71.5%, MS-ESI (m / z): 192.3 (m + H) +.
实施例94：3-对乙氧基苯基哌啶(1-3)的合成Example 94: Synthesis of 3-p-ethoxyphenyl piperidine (1-3)
Figure PCTCN2019076351-appb-000105
Figure PCTCN2019076351-appb-000105
将化合物(4-6)和化合物(5-6)的混合物(8.6g,29.3mmol)、钯碳(1.7g,20％)、无水甲醇(40mL)、冰乙酸(2.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应16h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，将溶剂旋干，粗品用硅胶柱层析，得到产物3-对乙氧基苯基哌啶(1-3)5.3g，收率88.1％，MS-ESI(m/z):206.3(M+H) +。 A mixture of compound (4-6) and compound (5-6) (8.6 g, 29.3 mmol), palladium on carbon (1.7 g, 20%), anhydrous methanol (40 mL), glacial acetic acid (2.0 mL) was added to high pressure In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 60 ° C, and reacted for 16 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was sparged, water (50 mL) was added, and extracted with ethyl acetate. (50 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness. yield 88.1%, MS-ESI (m / z): 206.3 (m + H) +.
实施例95：3-对乙氧基苯基哌啶(1-3)的合成Example 95: Synthesis of 3-p-ethoxyphenyl piperidine (1-3)
Figure PCTCN2019076351-appb-000106
Figure PCTCN2019076351-appb-000106
将化合物(4-7)和化合物(5-7)的混合物(10.0g,28.3mmol)、钯碳(1.0 g,10％)、无水甲醇(60mL)、冰乙酸(3.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应10h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后，加入水(50mL)，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对乙氧基苯基哌啶(1-3)5.4g，收率93.1％，MS-ESI(m/z):206.3(M+H) +。 Mixture of compound (4-7) and compound (5-7) (10.0 g, 28.3 mmol), palladium on carbon (1.0 g, 10%), anhydrous methanol (60 mL), glacial acetic acid (3.0 mL) In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 60 ° C, and reacted for 10 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, and the solvent was spun dry, water (50 mL) was added, and ethyl acetate was used. The mixture was extracted (50 mL×3), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj yield 93.1%, MS-ESI (m / z): 206.3 (m + H) +.
实施例96：3-对羟基苯基哌啶(1-4)的合成Example 96: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000107
Figure PCTCN2019076351-appb-000107
将化合物(4-8)和化合物(5-8)的混合物(6.9g,26.0mmol)、钯碳(1.4g,20％)、无水甲醇(40mL)、冰乙酸(2.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应16h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，调节pH值至5-6，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)4.1g，收率88.9％，MS-ESI(m/z):178.3(M+H) +。 Mixture of compound (4-8) and compound (5-8) (6.9 g, 26.0 mmol), palladium on carbon (1.4 g, 20%), anhydrous methanol (40 mL), glacial acetic acid (2.0 mL) In the kettle, hydrogen gas was introduced, replaced three times in vacuum, heated to 60 ° C, and reacted for 16 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was spun dry, and water (50 mL) was added to adjust the pH to 5- And the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was evaporated, dried over anhydrous sodium sulfate 4) 4.1 g, yield 88.9%, MS-ESI (m/z): 178.3 (M+H) + .
实施例97：3-对羟基苯基哌啶(1-4)的合成Example 97: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000108
Figure PCTCN2019076351-appb-000108
将化合物(4-9)和化合物(5-9)的混合物(9.5g,29.2mmol)、钯碳(1.0g,10％)、无水甲醇(60mL)、冰乙酸(3.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应10h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后，加入水(50mL)，调节pH值至5-6，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)4.9g，收率94.7％，MS-ESI(m/z):178.3(M+H) +。 Mixture of compound (4-9) and compound (5-9) (9.5 g, 29.2 mmol), palladium on carbon (1.0 g, 10%), anhydrous methanol (60 mL), glacial acetic acid (3.0 mL) In the kettle, hydrogen gas was introduced, replaced three times in vacuum, heated to 60 ° C, and reacted for 10 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was spun dry, and water (50 mL) was added to adjust the pH to 5. -6, and extraction with ethyl acetate (50 mL × 3), the organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -4) 4.9 g, yield 94.7%, MS-ESI (m/z): 178.3 (M+H) + .
实施例98：3-对羟基苯基哌啶(1-4)的合成Example 98: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000109
Figure PCTCN2019076351-appb-000109
将化合物(4-10)和化合物(5-10)的混合物(6.8g,38.8mmol)、钯碳(0.3g,5％)、无水甲醇(40mL)加入到高压釜中，并通入氢气，真空置换三次，加热到40℃，反应6h，TLC检测原料反应完全，停止反应，将钯碳过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)6.8g，收率98.9％，MS-ESI(m/z):178.3(M+H) +。 A mixture of the compound (4-10) and the compound (5-10) (6.8 g, 38.8 mmol), palladium carbon (0.3 g, 5%), anhydrous methanol (40 mL) was added to the autoclave, and hydrogen was introduced. The mixture was replaced by vacuum three times, heated to 40 ° C, and reacted for 6 h. The reaction of the starting material was completed by TLC, the reaction was stopped, the palladium carbon was filtered, and the residue was applied to silica gel column chromatography to give the product 3-p-hydroxyphenylpiperidine (1. 4) 6.8 g, yield 98.9%, MS-ESI (m/z): 178.3 (M+H) + .
实施例99：3-对羟基苯基哌啶(1-4)的合成Example 99: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000110
Figure PCTCN2019076351-appb-000110
将化合物(4-11)和化合物(5-11)的混合物(10.8g,30.4mmol)、钯碳(2.2g,20％)、无水甲醇(60mL)、冰乙酸(3.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应16h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，调节pH值至5-6，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)4.6g，收率85.6％，MS-ESI(m/z):178.3(M+H) +。 A mixture of compound (4-11) and compound (5-11) (10.8 g, 30.4 mmol), palladium on carbon (2.2 g, 20%), anhydrous methanol (60 mL), glacial acetic acid (3.0 mL) was added to high pressure In the kettle, hydrogen gas was introduced, replaced three times in vacuum, heated to 60 ° C, and reacted for 16 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was spun dry, and water (50 mL) was added to adjust the pH to 5- And the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was evaporated, dried over anhydrous sodium sulfate 4) 4.6 g, yield 85.6%, MS-ESI (m/z): 178.3 (M+H) + .
实施例100：3-对羟基苯基哌啶(1-4)的合成Example 100: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000111
Figure PCTCN2019076351-appb-000111
将化合物(4-12)和化合物(5-12)的混合物(12.6g,30.3mmol)、钯碳(1.3g,10％)、无水甲醇(60mL)、冰乙酸(3.0mL)加入到高压釜中，并通入氢气，真空置换三次，加热到60℃，反应10h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，调节pH值至5-6，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)5.1g，收率94.9％，MS-ESI(m/z):178.3(M+H) +。 Mixture of compound (4-12) and compound (5-12) (12.6 g, 30.3 mmol), palladium on carbon (1.3 g, 10%), anhydrous methanol (60 mL), glacial acetic acid (3.0 mL) In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 60 ° C, and reacted for 10 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was spun dry, and water (50 mL) was added to adjust the pH to 5- And the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was evaporated, dried over anhydrous sodium sulfate 4) 5.1 g, yield 94.9%, MS-ESI (m/z): 178.3 (M+H) + .
实施例101：3-对羟基苯基哌啶(1-4)的合成Example 101: Synthesis of 3-p-hydroxyphenyl piperidine (1-4)
Figure PCTCN2019076351-appb-000112
Figure PCTCN2019076351-appb-000112
将化合物(4-13)和化合物(5-13)的混合物(8.2g,30.9mmol)、钯碳(0.8g,10％)、无水甲醇(40mL)、冰乙酸(1.6mL)加入到高压釜中，并通入氢气，真空置换三次，加热到40℃，反应10h，TLC检测原料反应完全，停止反应，将钯碳过滤，溶剂旋干后加入水(50mL)，调节pH值至5-6，并用乙酸乙酯进行萃取(50mL×3)，收集有机层，用无水硫酸钠干燥，过滤，旋干，粗品用硅胶柱层析，得到产物3-对羟基苯基哌啶(1-4)5.1g，收率93.2％，MS-ESI(m/z):178.3(M+H) +。 A mixture of compound (4-13) and compound (5-13) (8.2 g, 30.9 mmol), palladium on carbon (0.8 g, 10%), anhydrous methanol (40 mL), glacial acetic acid (1.6 mL) was added to high pressure In the kettle, hydrogen gas was introduced, three times in a vacuum, heated to 40 ° C, and reacted for 10 h. The reaction of the starting material was completely detected by TLC, the reaction was stopped, the palladium carbon was filtered, the solvent was spun dry, and water (50 mL) was added to adjust the pH to 5- And the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was evaporated, dried over anhydrous sodium sulfate 4) 5.1 g, yield 93.2%, MS-ESI (m/z): 178.3 (M+H) + .
实施例102：(S)-3-对甲氧基苯基哌啶((S)-1-2)的制备Example 102: Preparation of (S)-3-p-methoxyphenylpiperidine ((S)-1-2)
Figure PCTCN2019076351-appb-000113
Figure PCTCN2019076351-appb-000113
将3-对甲氧基苯基哌啶(1-2,20.2g,105.6mmol)溶于异丙醇(30mL)，将溶有L-酒石酸(15.91g,106.0mmol)的异丙醇(40mL)溶液滴加到外消旋3-对甲氧基苯基哌啶的异丙醇溶液中，搅拌2h，过滤，得到酒石酸盐；然后，向该酒石酸盐加入甲醇(2L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-20℃析晶7天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品用硅胶柱层析，得到产物5.8g，即(S)-3-对甲氧基苯基哌啶，收率28.8％，MS-ESI(m/z):192.3(M+H) +；ee＝94.86％。 3-p-methoxyphenylpiperidine (1-2, 20.2 g, 105.6 mmol) was dissolved in isopropanol (30 mL) and isopropyl alcohol (40 mL) was dissolved in L-tartaric acid (15.91 g, 106.0 mmol). The solution was added dropwise to a solution of racemic 3-p-methoxyphenylpiperidine in isopropanol, stirred for 2 h, filtered to give the tartrate; then, methanol (2 L) was added to the tartrate and heated to dissolve completely. After that, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -20 ° C for 7 days, and filtered to give a white solid. EtOAc (EtOAc m. Drying over anhydrous sodium sulfate, filtration, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ): 192.3 (M+H) + ; ee = 94.86%.
实施例103：(S)-3-对乙氧基苯基哌啶((S)-1-3)的制备Example 103: Preparation of (S)-3-p-ethoxyphenyl piperidine ((S)-1-3)
Figure PCTCN2019076351-appb-000114
Figure PCTCN2019076351-appb-000114
将3-对乙氧基苯基哌啶(1-3,22.5g,109.6mmol)溶于异丙醇(30mL)，将溶有L-酒石酸(17.3g,115.0mmol)的异丙醇(40mL)溶液滴加到外消旋3-对乙氧基苯基哌啶的异丙醇溶液中，搅拌2h，过滤，得到酒石酸盐；然后，向该酒石酸盐加入甲醇(2L)，加热至完全溶解后，停止搅拌；缓慢降温到室温， -20℃析晶7天，过滤，得到白色固体粗品，加入1N氢氧化钠水溶液(50mL)，用乙酸乙酯萃取(25mL×2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品用硅胶柱层析，得到产物5.6g，即(S)-3-对乙氧基苯基哌啶，收率24.9％，MS-ESI(m/z):206.3(M+H) +；ee＝96.73％。 3-p-Ethoxyphenylpiperidine (1-3, 22.5 g, 109.6 mmol) was dissolved in isopropanol (30 mL), and isopropyl alcohol (40 mL) was dissolved in L-tartaric acid (17.3 g, 115.0 mmol). The solution was added dropwise to a solution of racemic 3-p-ethoxyphenylpiperidine in isopropanol, stirred for 2 h, filtered to give the tartrate; then, methanol (2 L) was added to the tartrate and heated to dissolve completely. After that, the stirring was stopped; the temperature was gradually lowered to room temperature, and the mixture was crystallized at -20 ° C for 7 days, and filtered to give a white solid (yield: EtOAc (EtOAc) Drying over anhydrous sodium sulfate, filtration, EtOAcqqqqqqqqq ): 206.3 (M+H) + ; ee = 96.73%.
实施例104：(S)-3-对羟基苯基哌啶((S)-1-4)的制备Example 104: Preparation of (S)-3-p-hydroxyphenylpiperidine ((S)-1-4)
Figure PCTCN2019076351-appb-000115
Figure PCTCN2019076351-appb-000115
将3-对羟基苯基哌啶(1-4,26.8g,151.2mmol)溶于异丙醇(40mL)，将溶有L-酒石酸(23.8g,158.8mmol)的异丙醇(50mL)溶液滴加到外消旋3-对羟基苯基哌啶的异丙醇溶液中，搅拌2h，过滤，得到酒石酸盐；然后，向该酒石酸盐加入甲醇(2.5L)，加热至完全溶解后，停止搅拌；缓慢降温到室温，-20℃析晶7天，过滤，得到白色固体粗品，加入氢氧化钠水溶液，调节pH值至6-7，用乙酸乙酯萃取(25mL,4)，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品用硅胶柱层析，得到的粗品再用硅胶纯化，得到产物9.0g，即(S)-3-对羟基苯基哌啶，收率33.6％，ESI(m/z):178.3(M+H) +；ee＝96.52％。 3-p-Hydroxyphenylpiperidine (1-4, 26.8 g, 151.2 mmol) was dissolved in isopropanol (40 mL) and a solution of L-tartaric acid (23.8 g, 158.8 mmol) in isopropanol (50 mL) Add dropwise to a solution of racemic 3-p-hydroxyphenylpiperidine in isopropanol, stir for 2 h, and filter to obtain tartrate; then, add methanol (2.5 L) to the tartrate, heat to complete dissolution, stop Stirring; slowly cooling to room temperature, crystallization at -20 ° C for 7 days, filtration, to obtain a crude white solid, add aqueous sodium hydroxide, adjust the pH to 6-7, extract with ethyl acetate (25mL, 4), the organic phase Drying with anhydrous sodium sulfate, filtration, EtOAc (EtOAc) ESI (m/z): 178.3 (M+H) + ; ee = 96.52%.
实施例105：(S)-3-对甲氧基苯基-N-乙酰基-哌啶((S)-8-3)的制备Example 105: Preparation of (S)-3-p-methoxyphenyl-N-acetyl-piperidine ((S)-8-3)
Figure PCTCN2019076351-appb-000116
Figure PCTCN2019076351-appb-000116
将(S)-3-对甲氧基苯基哌啶((S)-1-2，5.3g,27.7mmol)溶于二氯甲烷(30mL)中，再加入三乙胺(5.6g，55.4mmol)，冰水浴下，慢慢滴加乙酸酐(3.4g,33.3mmol)。滴加完毕后，慢慢升至室温，继续搅拌5小时。将反应液用水洗至中性，再用饱和食盐水(10mL)洗涤，无水硫酸钠干燥后，过滤，旋干溶剂，粗品用硅胶柱层析，得到(S)-3-对甲氧基苯基-N-乙酰基-哌啶((S)-8-3)6.4g，收率99.1％，ESI(m/z):234.3(M+H) +。 (S)-3-p-methoxyphenylpiperidine ((S)-1-2, 5.3 g, 27.7 mmol) was dissolved in dichloromethane (30 mL) then triethylamine (5.6 g, 55.4) Methyl acetate (3.4 g, 33.3 mmol) was slowly added dropwise under ice-water bath. After the dropwise addition was completed, the temperature was gradually raised to room temperature, and stirring was continued for 5 hours. The reaction mixture was washed with EtOAc (3 mL). -N- phenyl-acetyl - piperidine ((S) -8-3) 6.4g, yield 99.1%, ESI (m / z ): 234.3 (m + H) +.
实施例106：(S)-3-对乙氧基苯基-N-乙酰基-哌啶((S)-8-4)的制备Example 106: Preparation of (S)-3-p-ethoxyphenyl-N-acetyl-piperidine ((S)-8-4)
Figure PCTCN2019076351-appb-000117
Figure PCTCN2019076351-appb-000117
将(S)-3-对乙氧基苯基哌啶((S)-1-3，5.2g,25.3mmol)溶于二氯甲烷(30mL)中，再加入三乙胺(5.1g，50.7mmol)，冰水浴下，慢慢滴加乙酸酐(3.1g,30.4mmol)。滴加完毕后，慢慢升至室温，继续搅拌5小时。将反应液用水洗至中性，再用饱和食盐水(10mL)洗涤，无水硫酸钠干燥后，过滤，旋干溶剂，粗品用硅胶柱层析，得到(S)-3-对乙氧基苯基-N-乙酰基-哌啶((S)-8-4)6.1g，收率97.5％，ESI(m/z):248.3(M+H) +。 (S)-3-p-Ethoxyphenylpiperidine ((S)-1-3, 5.2 g, 25.3 mmol) was dissolved in dichloromethane (30 mL), then triethylamine (5.1 g, 50.7) (mmol), acetic anhydride (3.1 g, 30.4 mmol) was slowly added dropwise under ice-water bath. After the dropwise addition was completed, the temperature was gradually raised to room temperature, and stirring was continued for 5 hours. The reaction mixture was washed with EtOAc (EtOAc) (EtOAc) -N- phenyl-acetyl - piperidine ((S) -8-4) 6.1g, yield 97.5%, ESI (m / z ): 248.3 (m + H) +.
实施例107：(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1)的制备Example 107: Preparation of (S)-3-p-hydroxyphenyl-N-acetyl-piperidine ((S)-9'-1)
Figure PCTCN2019076351-appb-000118
Figure PCTCN2019076351-appb-000118
将(S)-3-对羟基苯基哌啶((S)-1-4，4.7g,26.5mmol)溶于二氯甲烷(30mL)中，再加入三乙胺(8.5g，79.6mmol)，冰水浴下，慢慢滴加乙酸酐(6.8g,66.3mmol)。滴加完毕后，慢慢升至室温，继续搅拌5小时。先将反应液用水洗至中性，旋干溶剂后，所得粗品用甲醇(20mL)和水(20mL)溶解，再向溶液中加入NaOH溶液(2.0mol/L,20mL)，搅拌1小时后，减压蒸干有机溶剂，再向剩余水相中加入盐酸，调节pH值至3-5，乙酸乙酯(20mL*2)萃取，合并有机层，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，蒸干溶剂，粗品用硅胶柱层析，得到(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1)5.7g，收率98.0％，ESI(m/z):220.3(M+H) +。 (S)-3-p-Hydroxyphenylpiperidine ((S)-1-4, 4.7 g, 26.5 mmol) was dissolved in dichloromethane (30 mL) then triethylamine (8.5 g, 79.6 mmol) Under an ice water bath, acetic anhydride (6.8 g, 66.3 mmol) was slowly added dropwise. After the dropwise addition was completed, the temperature was gradually raised to room temperature, and stirring was continued for 5 hours. The reaction solution was washed with water until neutral. After the solvent was evaporated, the obtained crude product was dissolved in methanol (20 mL) and water (20 mL), and then NaOH solution (2.0 mol/L, 20 mL) was added to the solution, and after stirring for 1 hour, The organic solvent was evaporated to dryness under reduced pressure, and then aqueous hydrochloric acid was added to the residue, and the mixture was adjusted to pH 3-5, ethyl acetate (20mL*2) was extracted, and the organic layer was combined and washed with brine (20mL) The organic layer was dried, filtered, and evaporated to dryness. %, ESI (m/z): 220.3 (M+H) + .
实施例108：(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1)的制备Example 108: Preparation of (S)-3-p-hydroxyphenyl-N-acetyl-piperidine ((S)-9'-1)
Figure PCTCN2019076351-appb-000119
Figure PCTCN2019076351-appb-000119
将(S)-3-对甲氧基苯基-N-乙酰基-哌啶((S)-8-3，5.3g，22.7mmol)溶于干燥的二氯甲烷(20mL)中，冰水浴下，冷却反应液至5℃以下，慢慢滴加BCl 3(5.3g，45.4mmol)溶于干燥二氯甲烷(10mL)的溶液。滴加完毕后，室温继续搅拌3小时，检测原料消失。向反应液中加水猝灭，并用饱和食盐水(20mLX2)洗涤，无水硫酸钠干燥，过滤，溶剂减压蒸干，粗品用硅胶柱层析，得产品3.8g，收率75.9％，ESI(m/z):220.3(M+H) +。 (S)-3-p-methoxyphenyl-N-acetyl-piperidine ((S)-8-3, 5.3 g, 22.7 mmol) was dissolved in dry dichloromethane (20 mL), ice water bath Next, the reaction liquid was cooled to below 5 ° C, and a solution of BCl 3 (5.3 g, 45.4 mmol) dissolved in dry dichloromethane (10 mL) was slowly added dropwise. After the completion of the dropwise addition, stirring was continued for 3 hours at room temperature, and the disappearance of the starting material was detected. The reaction mixture was quenched with water and EtOAc (EtOAc)EtOAc. m/z): 220.3 (M+H) + .
实施例109：(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1)的制备Example 109: Preparation of (S)-3-p-hydroxyphenyl-N-acetyl-piperidine ((S)-9'-1)
Figure PCTCN2019076351-appb-000120
Figure PCTCN2019076351-appb-000120
将(S)-3-对乙氧基苯基-N-乙酰基-哌啶((S)-8-4，5.1g，20.6mmol)溶于干燥的二氯甲烷(20mL)中，冰水浴下，冷却反应液至5℃以下，慢慢滴加BCl 3(4.8g，41.2mmol)溶于干燥二氯甲烷(10mL)的溶液。滴加完毕后，室温继续搅拌3小时，检测原料消失。向反应液中加水猝灭，并用饱和食盐水(20mLX2)洗涤，无水硫酸钠干燥，过滤，溶剂减压蒸干，粗品用硅胶柱层析，得产品3.4g，收率75.2％，ESI(m/z):220.3(M+H) +。 (S)-3-p-ethoxyphenyl-N-acetyl-piperidine ((S)-8-4, 5.1 g, 20.6 mmol) was dissolved in dry dichloromethane (20 mL), ice water bath Next, the reaction solution was cooled to below 5 ° C, and a solution of BCl 3 (4.8 g, 41.2 mmol) in dry dichloromethane (10 mL) was slowly added dropwise. After the completion of the dropwise addition, stirring was continued for 3 hours at room temperature, and the disappearance of the starting material was detected. The reaction mixture was quenched with EtOAc (EtOAc m. m/z): 220.3 (M+H) + .
实施例110：(S)-3-对羟基苯基-N-叔丁氧羰基-哌啶((S)-9'-2)的制备Example 110: Preparation of (S)-3-p-hydroxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-9'-2)
Figure PCTCN2019076351-appb-000121
Figure PCTCN2019076351-appb-000121
将(S)-3-对羟基苯基哌啶((S)-1-4，4.9g,27.6mmol)溶于二氯甲烷(50mL)中，再加入氢氧化钠溶液(2.0mmol/L，30mL)，搅拌下，慢慢滴加Boc酸酐(7.6g,33.2mmol)。滴加完毕后，慢慢升至室温，继续搅拌1小时，检测反应结束。先将反应液分液，除去水层，用水(20mLX3)洗至中性，再用饱和氯化铵溶液(20mL)洗涤，无水硫酸钠干燥，过滤，旋干溶剂，粗品用硅胶柱层析，得到(S)-3-对羟基苯基-N-叔丁氧羰基-哌啶((S)-9'-2)7.6g，收率99.2％，ESI(m/z):278.4(M+H) +。 (S)-3-p-Hydroxyphenylpiperidine ((S)-1-4, 4.9 g, 27.6 mmol) was dissolved in dichloromethane (50 mL), then sodium hydroxide solution (2.0 mmol/L, 30 mL) Boc anhydride (7.6 g, 33.2 mmol) was slowly added dropwise with stirring. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 1 hour, and the reaction was terminated. The reaction solution was separated, and the aqueous layer was separated, washed with water (20 mL×3), and then washed with a saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate. 7.6 g of (S)-3-p-hydroxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-9'-2), yield 99.2%, ESI (m/z): 278.4 (M) +H) + .
实施例111：(S)-3-对甲磺酰氧基苯基-N-乙酰基-哌啶((S)-10'-1)的制备Example 111: Preparation of (S)-3-p-methanesulfonyloxyphenyl-N-acetyl-piperidine ((S)-10'-1)
Figure PCTCN2019076351-appb-000122
Figure PCTCN2019076351-appb-000122
将(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1，5.9g，26.9mmol)溶于干燥的二氯甲烷(30mL)中，再加入三乙胺(5.45g，53.8mmol)，冰水浴中冷却至5℃以下，慢慢滴加甲磺酰氯(3.7g，32.2mmol)。滴加完毕后，慢慢升至室温，继续搅拌3小时，检测反应完全。将反应液水(10mLX3)洗至中性，再用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，溶剂旋干，粗品用硅胶柱层析， 得产品(S)-3-对甲磺酰氧基苯基-N-乙酰基-哌啶((S)-10'-1，7.4g)，收率92.5％，ESI(m/z):298.4(M+H) +。 (S)-3-p-Hydroxyphenyl-N-acetyl-piperidine ((S)-9'-1, 5.9 g, 26.9 mmol) was dissolved in dry dichloromethane (30 mL), then three Ethylamine (5.45 g, 53.8 mmol) was cooled to 5 ° C or less in an ice water bath, and methanesulfonyl chloride (3.7 g, 32.2 mmol) was slowly added dropwise. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 3 hours, and the reaction was confirmed to be complete. The reaction liquid (10 mL×3) was washed to neutral, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated. methanesulfonyloxy -N- acetyl-phenyl - piperidine ((S) -10'-1,7.4g) , a yield of 92.5%, ESI (m / z ): 298.4 (m + H) +.
实施例112：(S)-4-(1-乙酰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-2)的制备Example 112: Preparation of (S)-4-(1-acetylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-2)
Figure PCTCN2019076351-appb-000123
Figure PCTCN2019076351-appb-000123
将(S)-3-对羟基苯基-N-乙酰基-哌啶((S)-9'-1，6.3g，28.7mmol)溶于干燥的二氯甲烷(30mL)中，再加入三乙胺(5.82g，57.46mmol)，冰水浴中冷却至5℃以下，慢慢加入对甲苯磺酰氯(6.57g，34.5mmol)。滴加完毕后，慢慢升至室温，继续搅拌3小时，检测反应完全。将反应液水(10mLX3)洗至中性，再用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，溶剂旋干，粗品用硅胶柱层析，得产品(S)-4-(1-乙酰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-2，10.1g)，收率94.2％，ESI(m/z):374.5(M+H) +。 (S)-3-p-Hydroxyphenyl-N-acetyl-piperidine ((S)-9'-1, 6.3 g, 28.7 mmol) was dissolved in dry dichloromethane (30 mL), then three Ethylamine (5.82 g, 57.46 mmol) was cooled to below 5 ° C in an ice water bath, and p-toluenesulfonyl chloride (6.57 g, 34.5 mmol) was slowly added. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 3 hours, and the reaction was confirmed to be complete. The reaction liquid (10 mL×3) was washed to neutral, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 1-acetylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-2, 10.1 g), yield 94.2%, ESI (m/z): 374.5 (M +H) + .
实施例113：(S)-3-对甲磺酰氧基苯基-N-叔丁氧羰基-哌啶((S)-10'-3)的制备Example 113: Preparation of (S)-3-p-methanesulfonyloxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-10'-3)
Figure PCTCN2019076351-appb-000124
Figure PCTCN2019076351-appb-000124
将(S)-3-对羟基苯基-N-叔丁氧羰基-哌啶((S)-9'-2，6.1g，22.0mmol)溶于干燥的二氯甲烷(30mL)中，再加入三乙胺(4.45g，44.0mmol)，冰水浴中冷却至5℃以下，慢慢滴加甲磺酰氯(3.02g，26.39mmol)。滴加完毕后，慢慢升至室温，继续搅拌3小时，检测反应完全。将反应液水(10mLX3)洗至中性，再用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，溶剂旋干，粗品用硅胶柱层析，得产品(S)-3-对甲磺酰氧基苯基-N-叔丁氧羰基-哌啶((S)-10'-3，7.5g)，收率95.9％，ESI(m/z):356.4(M+H) +。 (S)-3-p-Hydroxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-9'-2, 6.1 g, 22.0 mmol) was dissolved in dry dichloromethane (30 mL) Triethylamine (4.45 g, 44.0 mmol) was added, and the mixture was cooled to 5 ° C or less in an ice water bath, and methanesulfonyl chloride (3.02 g, 26.39 mmol) was slowly added dropwise. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 3 hours, and the reaction was confirmed to be complete. The reaction solution was washed with water (10 mL×3), and then washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Methanesulfonyloxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-10'-3, 7.5 g), yield 95.9%, ESI (m/z): 356.4 (M+H) + .
实施例114：(S)-4-(1-叔丁氧羰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-4)的制备Example 114: Preparation of (S)-4-(1-tert-butoxycarbonylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-4)
Figure PCTCN2019076351-appb-000125
Figure PCTCN2019076351-appb-000125
将(S)-3-对羟基苯基-N-叔丁氧羰基-哌啶((S)-9'-2，6.6g，23.8mmol)溶于干燥的二氯甲烷(30mL)中，再加入三乙胺(4.82g，47.59mmol)，冰水浴中冷却至5℃以下，慢慢加入对甲苯磺酰氯(5.44g，28.56mmol)。滴加完毕后，慢慢升至室温，继续搅拌3小时，检测反应完全。将反应液水(10mLX3)洗至中性，再用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，溶剂旋干，粗品用硅胶柱层析，得产品(S)-4-(1-叔丁氧羰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-4，9.8g)，收率95.4％，ESI(m/z):432.6(M+H) +。 (S)-3-p-Hydroxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-9'-2, 6.6 g, 23.8 mmol) was dissolved in dry dichloromethane (30 mL). Triethylamine (4.82 g, 47.59 mmol) was added, and the mixture was cooled to 5 ° C or less in an ice water bath, and p-toluenesulfonyl chloride (5.44 g, 28.56 mmol) was slowly added. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 3 hours, and the reaction was confirmed to be complete. The reaction liquid (10 mL×3) was washed to neutral, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 1-tert-Butoxycarbonylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-4, 9.8 g), yield 95.4%, ESI (m/z): 432.6 (M+H) + .
实施例115：(S)-3-对溴苯基哌啶((S)-10)的制备Example 115: Preparation of (S)-3-p-bromophenylpiperidine ((S)-10)
Figure PCTCN2019076351-appb-000126
Figure PCTCN2019076351-appb-000126
将三苯基膦(9.06g，34.53mmol)溶于乙腈(10mL)中，冰水浴冷却至0℃，剧烈搅拌下，慢慢滴加液溴(5.52g，34.53mmol)。滴加完毕后，反应液慢慢升至室温搅拌。将(S)-3-对羟基苯基哌啶((S)-1-4,5.1g，28.77mmol)加入反应液中后，加热至70℃反应30分钟，将溶剂蒸干，残余物继续加热到250℃，反应1小时。冷却至室温后，残余物用适量二氯甲烷溶解，并经硅胶柱层析，得到产物(S)-3-对溴苯基哌啶((S)-10，5.20g，收率75.2％)，ESI(m/z):242.1，240.1(M+H) +。 Triphenylphosphine (9.06 g, 34.53 mmol) was dissolved in acetonitrile (10 mL), cooled to 0 ° C in ice-water bath, and broth (5.52 g, 34. After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and stirred. (S)-3-p-hydroxyphenylpiperidine ((S)-1-4, 5.1 g, 28.77 mmol) was added to the reaction solution, and the mixture was heated to 70 ° C for 30 minutes, and the solvent was evaporated to dryness. Heat to 250 ° C and react for 1 hour. After cooling to room temperature, the residue was dissolved with methylene chloride (m.hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh , ESI (m/z): 242.1, 240.1 (M+H) + .
实施例116：(S)-3-对溴苯基-N-乙酰基-哌啶(9-1)的制备Example 116: Preparation of (S)-3-p-bromophenyl-N-acetyl-piperidine (9-1)
Figure PCTCN2019076351-appb-000127
Figure PCTCN2019076351-appb-000127
将(S)-3-对溴苯基哌啶((S)-10，5.0g，20.8mmol)溶于二氯甲烷(30mL)中，再加入三乙胺(4.2g，41.64mmol)，冰水浴下，慢慢滴加乙酸酐(2.55g,25.0mmol)。滴加完毕后，慢慢升至室温，继续搅拌5小时。将反应液用水洗至中性，再用饱和食盐水(10mL)洗涤，无水硫酸钠干燥后，过滤，旋干溶剂，粗品用硅胶柱层析，得到(S)-3-对溴苯基-N-乙酰基-哌啶(9-1)产品5.7g，收率97.0％，ESI(m/z):284.2，282.2(M+H) +。 (S)-3-p-Bromophenylpiperidine ((S)-10, 5.0 g, 20.8 mmol) was dissolved in dichloromethane (30 mL), then triethylamine (4.2 g, 41. Under a water bath, acetic anhydride (2.55 g, 25.0 mmol) was slowly added dropwise. After the dropwise addition was completed, the temperature was gradually raised to room temperature, and stirring was continued for 5 hours. The reaction mixture was washed with EtOAc (3 mL). -N-acetyl-piperidine (9-1) product 5.7 g, yield 97.0%, ESI (m/z): 284.2, 282.2 (M+H) + .
实施例117：(S)-3-对溴苯基-N-叔丁氧羰基-哌啶(9-3)的制备Example 117: Preparation of (S)-3-p-bromophenyl-N-tert-butoxycarbonyl-piperidine (9-3)
Figure PCTCN2019076351-appb-000128
Figure PCTCN2019076351-appb-000128
将(S)-3-对溴苯基哌啶((S)-10，5.5g,22.9mmol)溶于二氯甲烷(50mL)中，再加入氢氧化钠溶液(2.0mmol/L，30mL)，搅拌下，慢慢滴加Boc酸酐(6.27g,27.5mmol)。滴加完毕后，慢慢升至室温，继续搅拌1小时，检测反应结束。先将反应液分液，除去水层，用水(20mLX3)洗至中性，无水硫酸钠干燥，过滤，旋干溶剂后，粗品用硅胶柱层析，得到(S)-3-对溴苯基-N-叔丁氧羰基-哌啶(9-3)产品7.2克，收率92.6％，ESI(m/z):342.3，340.3(M+H) +。 (S)-3-p-Bromophenylpiperidine ((S)-10, 5.5 g, 22.9 mmol) was dissolved in dichloromethane (50 mL), then sodium hydroxide solution (2.0 mmol/L, 30 mL) Boc anhydride (6.27 g, 27.5 mmol) was slowly added dropwise with stirring. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and stirring was continued for 1 hour, and the reaction was terminated. The reaction solution was separated, and the aqueous layer was separated, washed with water (20 mL×3) to dryness, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. 7.2 g, ESI (m/z): 342.3, 340.3 (M+H) + s .
实施例118：(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24')的合成Example 118: Synthesis of (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24')
Figure PCTCN2019076351-appb-000129
Figure PCTCN2019076351-appb-000129
将(S)-3-对甲磺酰氧基苯基-N-乙酰基-哌啶((S)-10'-1，3.9g，13.1mmol)溶于DMA(20mL)中，再将碳酸钾(5.44g,39.3mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,3.13g,14.43mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.19g，1.31mmol)和CuBr(0.09g，0.66mmol)加入反应瓶中，继续吹氮气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液将至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24'，4.5g，收率81.9％)，ESI(m/z):419.6(M+H) +。 (S)-3-p-Methanesulfonyloxyphenyl-N-acetyl-piperidine ((S)-10'-1, 3.9 g, 13.1 mmol) was dissolved in DMA (20 mL), then carbonic acid Potassium (5.44 g, 39.3 mmol) and N-tert-butyl-1H-carbazole-7-carboxamide (22, 3.13 g, 14.43 mmol) were added to the reaction flask. Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.19 g, 1.31 mmol) and CuBr (0.09 g, 0.66 mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was allowed to reach room temperature, and the reaction mixture was filtered over Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-carboxamide ( 24 ', 4.5g, yield 81.9%), ESI (m / z): 419.6 (m + H) +.
实施例119：(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24')的合成Example 119: Synthesis of (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24')
Figure PCTCN2019076351-appb-000130
Figure PCTCN2019076351-appb-000130
将(S)-4-(1-乙酰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-2，5.9g，15.8mmol)溶于DMA(25mL)中，再将碳酸钾(6.55g,47.39mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,3.78g,17.38mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.22g，1.58mmol)和CuBr(0.11g，0.79mmol)加入反应瓶中，继续吹氮气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液将至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24'，4.88g，收率73.8％)，ESI(m/z):419.6(M+H) +。 (S)-4-(1-Acetylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-2, 5.9 g, 15.8 mmol) was dissolved in DMA (25 mL) Further, potassium carbonate (6.55 g, 47.39 mmol) and N-tert-butyl-1H-carbazole-7-carboxamide (22, 3.78 g, 17.38 mmol) were added to a reaction flask. Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.22g, 1.58mmol) and CuBr (0.11g, 0.79mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was allowed to reach room temperature, and the reaction mixture was filtered over Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-carboxamide ( 24 ', 4.88g, yield 73.8%), ESI (m / z): 419.6 (m + H) +.
实施例120：(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24)的合成Example 120: (S)-2-(4-(1-tert-Butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24) synthesis
Figure PCTCN2019076351-appb-000131
Figure PCTCN2019076351-appb-000131
将(S)-3-对甲磺酰氧基苯基-N-叔丁氧羰基-哌啶((S)-10'-3，6.4g，18.0mmol)溶于DMA(25mL)中，再将碳酸钾(7.47g,54.02mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,4.30g,19.81mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.26g，1.80mmol)和CuBr(0.13g，0.90mmol)加入反应瓶中，继续吹氮 气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液将至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24，7.19g，收率83.8％)，ESI(m/z):477.6(M+H) +。 (S)-3-p-Methanesulfonyloxyphenyl-N-tert-butoxycarbonyl-piperidine ((S)-10'-3, 6.4 g, 18.0 mmol) was dissolved in DMA (25 mL). Potassium carbonate (7.47 g, 54.02 mmol) and N-tert-butyl-1H-carbazole-7-carboxamide (22, 4.30 g, 19.81 mmol) were placed in a reaction flask. Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.26 g, 1.80 mmol) and CuBr (0.13 g, 0.90 mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was allowed to reach room temperature, and the reaction mixture was filtered over Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-tert-butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-- amide (24,7.19g, yield 83.8%), ESI (m / z): 477.6 (m + H) +.
实施例121：(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24)的合成Example 121: (S)-2-(4-(1-tert-Butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24) synthesis
Figure PCTCN2019076351-appb-000132
Figure PCTCN2019076351-appb-000132
将(S)-4-(1-叔丁氧羰基哌啶-3-基)-1-对甲苯磺酰氧基苯((S)-10'-4，5.8g，13.44mmol)溶于DMA(25mL)中，再将碳酸钾(5.57g,40.32mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,3.21g,14.78mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.19g，1.34mmol)和CuBr(0.10g，0.67mmol)加入反应瓶中，继续吹氮气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液降至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24，4.92g，收率76.8％)，ESI(m/z):477.6(M+H) +。 (S)-4-(1-tert-Butoxycarbonylpiperidin-3-yl)-1-p-toluenesulfonyloxybenzene ((S)-10'-4, 5.8 g, 13.44 mmol) was dissolved in DMA Potassium carbonate (5.57 g, 40.32 mmol) and N-tert-butyl-1H-carbazole-7-carboxamide (22, 3.21 g, 14.78 mmol) were added to a reaction flask (25 mL). Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.19 g, 1.34 mmol) and CuBr (0.10 g, 0.67 mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was cooled to room temperature, and the reaction solution was filtered through Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-tert-butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-- amide (24,4.92g, yield 76.8%), ESI (m / z): 477.6 (m + H) +.
实施例122：(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24')的合成Example 122: Synthesis of (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24')
Figure PCTCN2019076351-appb-000133
Figure PCTCN2019076351-appb-000133
将(S)-3-对溴苯基-N-乙酰基-哌啶(9-1，5.7g，20.2mmol)溶于DMA(25mL)中，再将碳酸钾(8.38g,60.6mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,4.83g,22.22mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.29g，2.02mmol)和CuBr(0.14g，1.01mmol)加入反应瓶中，继续吹氮气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液将至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24'，7.49g，收率88.6％)，ESI(m/z):419.6(M+H) +。 (S)-3-P-Phenylphenyl-N-acetyl-piperidine (9-1, 5.7 g, 20.2 mmol) was dissolved in DMA (25 mL), then potassium carbonate (8.38 g, 60.6 mmol) and N-tert-butyl-1H-carbazole-7-carboxamide (22, 4.83 g, 22.22 mmol) was added to a reaction flask. Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.29 g, 2.02 mmol) and CuBr (0.14 g, 1.01 mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was allowed to reach room temperature, and the reaction mixture was filtered over Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-carboxamide ( 24 ', 7.49g, yield 88.6%), ESI (m / z): 419.6 (m + H) +.
实施例123：(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24)的合成Example 123: (S)-2-(4-(1-tert-Butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24) synthesis
Figure PCTCN2019076351-appb-000134
Figure PCTCN2019076351-appb-000134
将(S)-3-对溴苯基-N-叔丁氧羰基-哌啶(9-3，6.4g，18.81mmol)溶于DMA(25mL)中，再将碳酸钾(7.80g,56.43mmol)和N-叔丁基-1H-吲唑-7-甲酰胺(22,4.50g,20.69mmol)加入反应瓶中。搅拌下，将氮气管插入反应液面下吹气，脱氧1小时。再将(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(0.27g，1.88mmol)和CuBr(0.13g，0.94mmol)加入反应瓶中，继续吹氮气脱氧30分钟。氮气保护下，反应液加热至110℃反应24小时。停止反应，将反应液将至室温，反应液用硅藻土过滤，适量DMA洗涤。向滤液中加入水(50mL)，再用二氯甲烷(50mLX2)萃取，合并有机层，水洗(20mLX3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液旋干得粗品。所得粗品用硅胶柱纯化，得产 品(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24，8.01g，收率89.4％)，ESI(m/z):477.6(M+H) +。 (S)-3-P-Phenylphenyl-N-tert-butoxycarbonyl-piperidine (9-3, 6.4 g, 18.81 mmol) was dissolved in DMA (25 mL) and then potassium carbonate (7.80 g, 56.43 mmol And N-tert-butyl-1H-carbazole-7-carboxamide (22, 4.50 g, 20.69 mmol) was added to the reaction flask. Under stirring, a nitrogen tube was inserted into the surface of the reaction liquid to be blown, and deoxidized for 1 hour. (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.27 g, 1.88 mmol) and CuBr (0.13 g, 0.94 mmol) were added to the reaction flask. Continue to blow nitrogen for 30 minutes. The reaction solution was heated to 110 ° C for 24 hours under nitrogen atmosphere. The reaction was stopped, the reaction solution was allowed to reach room temperature, and the reaction mixture was filtered over Celite, and washed with EtOAc. Water (50 mL) was added to the filtrate, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude product was purified by silica gel column to give (S)-2-(4-(1-tert-butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-carbazole-7-- amide (24,8.01g, yield 89.4%), ESI (m / z): 477.6 (m + H) +.
实施例124：(S)-2-(4-(哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(11)的合成Example 124: Synthesis of (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (11)
Figure PCTCN2019076351-appb-000135
Figure PCTCN2019076351-appb-000135
将(S)-2-(4-(1-乙酰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24'，12.60g，30.1mmol)加入邻二甲苯(15mL)中，再向浑浊反应液中加入甲磺酸(39mL，602mmol)。反应液加热至40℃反应3小时，检测原料已反应完全。向反应液中加入水(150mL)，甲苯萃取(40mLX2)，合并有机层，用水(20mLX2)洗，再用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(11)8.88g，收率92.1％，ESI(m/z):321.4(M+H) +。 (S)-2-(4-(1-Acetylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24', 12.60 g, 30.1 mmol Add o-xylene (15 mL) and add methanesulfonic acid (39 mL, 602 mmol) to the turbid reaction. The reaction solution was heated to 40 ° C for 3 hours, and the starting material was detected to be completely reacted. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . The obtained crude product was purified by silica gel column(yield: </RTI> (S)-2-(4-(piperidin-3-yl)phenyl)-2H-carbazole-7-carboxamide (11) 8.88 g, yield 92.1%, ESI (m/z): 321.4 (M+H) + .
实施例125：(S)-2-(4-(哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(11)的合成Example 125: Synthesis of (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (11)
Figure PCTCN2019076351-appb-000136
Figure PCTCN2019076351-appb-000136
将(S)-2-(4-(1-叔丁氧羰基哌啶-3-基)苯基)-N-叔丁基-2H-吲唑-7-甲酰胺(24，16.7g，35.04mmol)加入邻二甲苯(20mL)中，再向浑浊反应液中加入甲磺酸(45mL，700mmol)。反应液加热至40℃反应3小时，检测原料已反应完全。向反应液中加入水(150mL)，甲苯萃取(40mLX2)，合并有机层，用水(20mLX2)洗，再用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，得粗品。所得粗品用硅胶柱纯化，得产品(S)-2-(4-(哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(11)10.00g，收率89.1％，ESI(m/z):321.4(M+H) +。 (S)-2-(4-(1-tert-Butoxycarbonylpiperidin-3-yl)phenyl)-N-tert-butyl-2H-indazole-7-carboxamide (24, 16.7 g, 35.04 Methyl) was added to o-xylene (20 mL), and methanesulfonic acid (45 mL, 700 mmol) was added to the turbid reaction mixture. The reaction solution was heated to 40 ° C for 3 hours, and the starting material was detected to be completely reacted. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . The obtained crude product was purified by silica gel column to yield (1)-(2-(4-(piperidin-3-yl)phenyl)-2H-carbazole-7-carboxamide (11) 10.00 g, yield: ESI (m/z): 321.4 (M+H) + .
以上对本发明的具体实施例进行了详细描述，但其只是作为范例，本发明并 不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。The specific embodiments of the present invention have been described in detail above, but are merely exemplary, and the invention is not limited to the specific embodiments described above. Any equivalent modifications and substitutions to the invention are also within the scope of the invention. Accordingly, equivalents and modifications may be made without departing from the spirit and scope of the invention.

Claims (19)

  1. 一种(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法，其特征在于，包括如下合成路线：A method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route:
    Figure PCTCN2019076351-appb-100001
    Figure PCTCN2019076351-appb-100001
    其中，步骤(a)为：N保护的3-哌啶酮(2)与对位R 2取代的苯基卤化镁发生格氏反应，生成3-羟基-3-苯基哌啶(3)； Wherein step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
    其中，步骤(b)为：3-羟基-3-苯基哌啶(3)发生醇羟基消去反应，生成化合物(4)和化合物(5)的混合物；Wherein step (b) is: 3-hydroxy-3-phenylpiperidine (3) undergoes alcoholic hydroxyl elimination reaction to form a mixture of compound (4) and compound (5);
    其中，步骤(c)为：在过渡金属催化剂催化下，化合物(4)和化合物(5)的混合物与氢源发生加氢还原反应，生成N保护的3-苯基哌啶(6)；Wherein step (c) is: under the catalysis of a transition metal catalyst, a mixture of compound (4) and compound (5) and a hydrogen source are hydrogenated to form N-protected 3-phenylpiperidine (6);
    其中，步骤(d)为：N保护的3-苯基哌啶(6)脱除保护基R 1，生成外消旋的3-苯基哌啶(1)； Wherein step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
    其中，步骤(e)为：化学拆分溶剂中，使用酸性拆分剂对外消旋的3-苯基哌啶(1)进行拆分，得到(R)-3-苯基哌啶((R)-1)或/和(S)-3-苯基哌啶((S)-1)。Wherein step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
  2. 根据权利要求1所述的合成方法，其特征在于，R 1选自以下任一种：三苯甲基，苄基，对甲氧基苄基，2,4-二甲氧基苄基，叔丁基，三甲基硅基，三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基。 The method according to claim 1, wherein R 1 is selected from the group consisting of trityl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, uncle Butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
  3. 根据权利要求1所述的合成方法，其特征在于，R 2选自以下任一种：H，甲氧基，乙氧基，异丙氧基，正丙氧基，烯丙基氧基，正丁基氧基，异丁基氧基，叔丁氧基，甲氧基甲氧基，乙氧基甲氧基，甲氧基乙氧基，2-四氢吡喃氧基，三甲基硅基乙氧基甲氧基，叔丁基二甲基硅基乙氧基甲氧基，三甲基硅氧基，三乙基硅氧基，三异丙基硅氧基，叔丁基二甲基硅氧基，叔丁基二苯基硅氧基，苄氧基，对甲氧基苄氧基，2,4-二甲氧基苄氧基。 The method according to claim 1, wherein R 2 is selected from the group consisting of H, methoxy, ethoxy, isopropoxy, n-propoxy, allyloxy, and Butyloxy, isobutyloxy, tert-butoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilyl Ethyloxymethoxy, tert-butyldimethylsilylethoxymethoxy, trimethylsiloxy, triethylsilyloxy, triisopropylsilyloxy, tert-butyldimethyl Silyloxy, tert-butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy, 2,4-dimethoxybenzyloxy.
  4. 根据权利要求1所述的合成方法，其特征在于，在所述步骤(c)中，所述过渡金属催化剂选自以下任一种：雷尼镍，钯碳，二氧化钯，铂黑，二氧化铂。The synthesis method according to claim 1, wherein in the step (c), the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, and Platinum oxide.
  5. 根据权利要求1所述的合成方法，其特征在于，在所述步骤(e)中，所述化学拆分溶剂选自以下任一种或多种的组合：甲醇，乙醇，异丙醇，正丙醇，正丁醇，四氢呋喃，乙酸乙酯，二氯甲烷。The synthesis method according to claim 1, wherein in the step (e), the chemical resolution solvent is selected from any one or a combination of the following: methanol, ethanol, isopropanol, positive Propanol, n-butanol, tetrahydrofuran, ethyl acetate, dichloromethane.
  6. 根据权利要求1所述的合成方法，其特征在于，在所述步骤(e)中，所述酸性拆分剂选自以下任一种：酒石酸，二苯甲酰基酒石酸，二对甲基苯甲酰酒石酸，苹果酸，樟脑磺酸，樟脑酸，扁桃酸，奎宁酸。The synthesis method according to claim 1, wherein in the step (e), the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoic acid. Acid tartaric acid, malic acid, camphorsulfonic acid, camphoric acid, mandelic acid, quinic acid.
  7. 一种(R)-3-苯基哌啶或/和(S)-3-苯基哌啶的合成方法，其特征在于，包括如下合成路线：A method for synthesizing (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine, which comprises the following synthetic route:
    Figure PCTCN2019076351-appb-100002
    Figure PCTCN2019076351-appb-100002
    其中，步骤(a)为：N保护的3-哌啶酮(2)与对位R 2取代的苯基卤化镁发生格氏反应，生成3-羟基-3-苯基哌啶(3)； Wherein step (a) is: N-protected 3-piperidone (2) and a para-R 2 substituted phenyl magnesium halide to generate a Grignard reaction to form 3-hydroxy-3-phenyl piperidine (3);
    其中，步骤(f)为：3-羟基-3-苯基哌啶(3)与(C nH 2n+1) 3SiH反应，直接生成N保护的3-苯基哌啶(6)；其中，n为1～4的整数； Wherein step (f) is: 3-hydroxy-3-phenylpiperidine (3) is reacted with (C n H 2n+1 ) 3 SiH to directly form N-protected 3-phenylpiperidine (6); , n is an integer from 1 to 4;
    其中，步骤(d)为：N保护的3-苯基哌啶(6)脱除保护基R 1，生成外消旋的3-苯基哌啶(1)； Wherein step (d) is: N-protected 3-phenylpiperidine (6) to remove the protecting group R 1 to form racemic 3-phenylpiperidine (1);
    其中，步骤(e)为：化学拆分溶剂中，使用酸性拆分剂对外消旋的3-苯基哌啶(1)进行拆分，得到(R)-3-苯基哌啶((R)-1)或/和(S)-3-苯基哌啶((S)-1)。Wherein step (e) is: chemically separating the solvent, and using a acidic resolving agent to resolve the racemic 3-phenylpiperidine (1) to obtain (R)-3-phenylpiperidine ((R) )-1) or / and (S)-3-phenylpiperidine ((S)-1).
  8. 根据权利要求7所述的合成方法，其特征在于，在所述步骤(f)中，所述(C nH 2n+1) 3SiH选自以下任一种：三乙基硅烷，三正丙基硅烷，三异丙基硅烷。 The synthesis method according to claim 7, wherein in the step (f), the (C n H 2n+1 ) 3 SiH is selected from any one of the following: triethylsilane, tri-n-propyl Silane, triisopropylsilane.
  9. 根据权利要求7所述的合成方法，其特征在于，在所述步骤(f)中，所述化学拆分溶剂选自以下任一种或多种的组合：甲醇，乙醇，异丙醇，正丙醇，正丁醇，四氢呋喃，乙酸乙酯，二氯甲烷。The synthesis method according to claim 7, wherein in the step (f), the chemical resolution solvent is selected from any one or a combination of the following: methanol, ethanol, isopropanol, positive Propanol, n-butanol, tetrahydrofuran, ethyl acetate, dichloromethane.
  10. 根据权利要求7所述的合成方法，其特征在于，在所述步骤(f)中，所述酸性拆分剂选自以下任一种：酒石酸，二苯甲酰基酒石酸，二对甲基苯甲酰酒石酸，苹果酸，樟脑磺酸，樟脑酸，扁桃酸，奎宁酸。The synthesis method according to claim 7, wherein in the step (f), the acidic resolving agent is selected from any one of the following: tartaric acid, dibenzoyl tartaric acid, di-p-methylbenzoic acid. Acid tartaric acid, malic acid, camphorsulfonic acid, camphoric acid, mandelic acid, quinic acid.
  11. 一种尼拉帕尼的手性中间体α的合成方法，其特征在于，包括以下步骤：A method for synthesizing a chiral intermediate α of nilapani, which comprises the following steps:
    S1：根据权利要求1或权利要求7所述的合成方法制备(S)-3-苯基哌啶((S)-1)，其中，R 2为H； S1: Preparation of (S)-3-phenylpiperidine ((S)-1) according to the synthesis method according to claim 1 or claim 7, wherein R 2 is H;
    S2：将(S)-3-苯基哌啶((S)-1)与硝化剂发生硝化反应，生成(S)-3-对硝基苯基哌啶；S2: nitration of (S)-3-phenylpiperidine ((S)-1) with a nitrating agent to form (S)-3-p-nitrophenylpiperidine;
    S3：将(S)-3-对硝基苯基哌啶与还原体系进行硝基还原反应，生成(S)-3-对胺基苯基哌啶，即尼拉帕尼的手性中间体α。S3: nitro reduction of (S)-3-p-nitrophenyl piperidine with a reduction system to form (S)-3-p-aminophenyl piperidine, a chiral intermediate of nilapani α.
  12. 根据权利要求11所述的尼拉帕尼的手性中间体α的合成方法，其特征在于，所述硝化剂选自以下任一种：硝酸，硝酸钾，硝酸钠，硝酸铵，硝酰氯，硝酸丁酯，硝酸甲酯，NO 2BF 4，NO 2PF 6。 The method for synthesizing a chiral intermediate α of nilapani according to claim 11, wherein the nitrating agent is selected from the group consisting of nitric acid, potassium nitrate, sodium nitrate, ammonium nitrate, and nitroxyl chloride. Butyl nitrate, methyl nitrate, NO 2 BF 4 , NO 2 PF 6 .
  13. 根据权利要求11所述的尼拉帕尼的手性中间体α的合成方法，其特征在于，所述还原体系选自以下任一种：三氯化铁/水合肼，Fe/HCl，Zn/HCl，LiAlH 4，过渡金属催化剂/氢气，连二亚硫酸钠；其中，所述过渡金属催化剂选自以下任一种：雷尼镍，钯碳，二氧化钯，铂黑，二氧化铂。 The method for synthesizing a chiral intermediate α of nilapani according to claim 11, wherein the reducing system is selected from any one of the following: ferric chloride/hydrated hydrazine, Fe/HCl, Zn/ HCl, LiAlH 4 , transition metal catalyst / hydrogen, sodium dithionite; wherein the transition metal catalyst is selected from any one of the following: Raney nickel, palladium carbon, palladium dioxide, platinum black, platinum dioxide.
  14. 一种尼拉帕尼的手性中间体β的合成方法，其特征在于，包括以下步骤：A method for synthesizing chiral intermediate β of nilapani, characterized in that it comprises the following steps:
    P1：根据权利要求1或权利要求7所述的合成方法制备(S)-3-苯基哌啶((S)-1)，其中，R 2为H； P1: Preparation of (S)-3-phenylpiperidine ((S)-1) according to the synthesis method according to claim 1 or claim 7, wherein R 2 is H;
    P2：将(S)-3-苯基哌啶((S)-1)与N保护试剂发生反应，生成N-保护的(S)-3-苯基哌啶；P2: reacting (S)-3-phenylpiperidine ((S)-1) with an N protecting reagent to form N-protected (S)-3-phenylpiperidine;
    P3：将N-保护的(S)-3-苯基哌啶与溴代试剂发生溴代反应，生成N-保护的(S)-3-对溴苯基哌啶；P3: bromination of N-protected (S)-3-phenylpiperidine with a bromination reagent to form N-protected (S)-3-p-bromophenylpiperidine;
    P4：将N-保护的(S)-3-对溴苯基哌啶进行脱保护反应，生成(S)-3-对溴苯基哌啶，即尼拉帕尼的手性中间体β。P4: Deprotection of N-protected (S)-3-p-bromophenylpiperidine to give (S)-3-p-bromophenylpiperidine, the chiral intermediate β of nilapani.
  15. 根据权利要求14所述的尼拉帕尼的手性中间体β的合成方法，其特征在于，所述N保护试剂选自以下任一种：乙酰氯，丙酰氯，丁酰氯，苯磺酰氯，BOC酸酐。The method for synthesizing a chiral intermediate β of nilapani according to claim 14, wherein the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
  16. 根据权利要求14所述的尼拉帕尼的手性中间体β的合成方法，其特征在于，所述溴代试剂选自以下任一种：NBS，Br 2，HBr，过溴化吡啶氢溴酸盐，二溴海因，2,4,4,6-四溴-2,5-环己二烯酮。 The method for synthesizing a chiral intermediate β of nilapani according to claim 14, wherein the brominated reagent is selected from the group consisting of NBS, Br 2 , HBr, and pyridine hydrobromine perbromination. Acid salt, dibromohydantoin, 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
  17. 一种尼拉帕尼的手性中间体γ的合成方法，其特征在于，包括以下步骤：A method for synthesizing chiral intermediate γ of nilapani, which comprises the following steps:
    P'1：根据权利要求1或权利要求7所述的合成方法制备(S)-3-苯基哌啶((S)-1)，其中，R 2选自以下任一种：甲氧基，乙氧基，异丙氧基，正丙氧基，烯丙基氧基，正丁基氧基，异丁基氧基，叔丁氧基，甲氧基甲氧基，乙氧基甲氧基，甲氧基乙氧基，2-四氢吡喃氧基，三甲基硅基乙氧基甲氧基，叔丁基二甲基硅基乙氧基甲氧基，三甲基硅氧基，三乙基硅氧基，三异丙基硅氧基，叔丁基二甲基硅氧基，叔丁基二苯基硅氧基，苄氧基，对甲氧基苄氧基，2,4-二甲氧基苄氧基； P'1: (S)-3-phenylpiperidine ((S)-1), wherein R 2 is selected from any one of the following: a methoxy group according to the synthesis method according to claim 1 or claim 7. , ethoxy, isopropoxy, n-propoxy, allyloxy, n-butyloxy, isobutyloxy, tert-butoxy, methoxymethoxy, ethoxymethoxy , methoxyethoxy, 2-tetrahydropyranyloxy, trimethylsilylethoxymethoxy, tert-butyldimethylsilylethoxymethoxy, trimethylsiloxy , triethylsilyloxy, triisopropylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, benzyloxy, p-methoxybenzyloxy, 2 , 4-dimethoxybenzyloxy;
    P'2：将(S)-3-苯基哌啶((S)-1)与N保护试剂发生反应，生成N-保护的(S)-3-苯基哌啶；P'2: reacting (S)-3-phenylpiperidine ((S)-1) with an N protecting reagent to form N-protected (S)-3-phenylpiperidine;
    P'3：将N-保护的(S)-3-苯基哌啶脱除羟基保护基，生成N-保护的(S)-3-(4- 羟基苯基)-哌啶；P'3: deprotecting the N-protected (S)-3-phenylpiperidine to form a N-protected (S)-3-(4-hydroxyphenyl)-piperidine;
    P'4：将N-保护的(S)-3-(4-羟基苯基)-哌啶与活性磺酰氯或活性磺酸酐反应，生成活性酯，即尼拉帕尼的手性中间体γ。P'4: The N-protected (S)-3-(4-hydroxyphenyl)-piperidine is reacted with an active sulfonyl chloride or an active sulfonic anhydride to form an active ester, ie a chiral intermediate γ of nilapani. .
  18. 根据权利要求17所述的尼拉帕尼的手性中间体γ的合成方法，其特征在于，所述N保护试剂选自以下任一种：乙酰氯，丙酰氯，丁酰氯，苯磺酰氯，BOC酸酐。The method for synthesizing chiral intermediate γ of nilapani according to claim 17, wherein the N protecting reagent is selected from any one of the following: acetyl chloride, propionyl chloride, butyryl chloride, benzenesulfonyl chloride, BOC anhydride.
  19. 根据权利要求17所述的尼拉帕尼的手性中间体γ的合成方法，其特征在于，所述活性磺酰氯选自以下任一种：甲磺酰氯，对甲苯磺酰氯，苯磺酰氯；所述活性磺酸酐为三氟甲磺酸酐。The method for synthesizing chiral intermediate γ of nilapani according to claim 17, wherein the active sulfonyl chloride is selected from any one of the following: methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride; The reactive sulfonic anhydride is trifluoromethanesulfonic anhydride.
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