CN109134351A - S-3-(4- aminophenyl) piperidines synthetic method - Google Patents

S-3-(4- aminophenyl) piperidines synthetic method Download PDF

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CN109134351A
CN109134351A CN201811104844.5A CN201811104844A CN109134351A CN 109134351 A CN109134351 A CN 109134351A CN 201811104844 A CN201811104844 A CN 201811104844A CN 109134351 A CN109134351 A CN 109134351A
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pyridine
piperidines
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reaction
aminophenyl
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CN109134351B (en
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申永存
戴礼林
黄国凯
罗梦玲
邹颖
李天成
陈瑶
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Wuhan University of Technology WUT
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    • 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

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of synthetic methods of S-3- (4- aminophenyl) piperidines.The synthetic method of S-3- (4- aminophenyl) piperidines, with 3- pyridine boronic acid (I) for raw material, it is coupled to obtain 3- (4- nitrobenzophenone) pyridine (III) through Suzuki with 4- bromo nitrobenzene (II), III reduction obtains 3- (4- aminophenyl) pyridine (IV), IV obtains 3- (4- acetylamino phenyl) pyridine (IV) with aceticanhydride acylation, IV obtains 3- (4- acetylamino phenyl) piperidines (V) through reduction, V is split to obtain S-3- (4- aminophenyl) piperidines camsilate (VI) with L- camphorsulfonic acid, S-3- (4- aminophenyl) piperidines camsilate is through parsing, hydrolysis obtains S-3- (4- aminophenyl) piperidines (VII).Synthetic method of the present invention is simple, and for the enantioselectivity of product up to 99% or more, mild condition is easy to operate, and production cost is low, can be used for industrialized production.

Description

The synthetic method of S-3- (4- aminophenyl) piperidines
Technical field
The invention belongs to technical field of organic chemistry and field of pharmaceutical chemistry technology, and in particular to a kind of S-3- (4- amino Phenyl) piperidines synthetic method.
Background technique
S-3- (4- aminophenyl) piperidines is synthesis Ni Lapani (niraparib) important intermediate.Ni Lapani (niraparib) be boston, U.S.A biotech company Tesaro research advanced ovarian cancer effective therapeutic agent, it is clinical Research shows that the medicine is a kind of oral selective parp-1 and parp-2 inhibitor, and it is PARP gene target drug, it can be effective Advanced ovarian cancer is treated, is listed in April, 2017.Therefore, the effective preparation method of the intermediate is studied to be of great significance.
The preparation method of S-3- (4- aminophenyl) piperidines, document report (J.Med.chem, 2009,52 (22), 7179- 7185) it using the iodo- 4- nitrobenzene of 1- and 3- pyridine boronic acid as raw material, is obtained through SUZUKI reaction, reduction, fractionation, the mapping of product Selectivity only 82%, although route is short, the optical purity of product is not able to satisfy the requirement of drug production, and to nitro iodine Benzene price is more expensive, and reaction route is as follows:
Document report (Org.Process Res.Dev.2011,15,831-840) is with the bromo- 4- nitrobenzene of 1- and 3- pyridine Boric acid is raw material, reaches product through Suzuki reaction, reduction, protection, chiral post separation；
Document (CN106432058) is raw material through asymmetric Michael reaction using hexamethylene pentenone, then through Beckmann It resets, reduction obtains.These three methods all have the defects that certain.The enantioselectivity of first method only has 82%ee, at This height is unsatisfactory for the requirement of drug production；Second method is not suitable for industrial scale production using chiral post separation；The third Method can generate another isomers when resetting and be difficult to isolate and purify.
So finding one kind production method simple, safe, at low cost has very big necessity and important meaning.
Summary of the invention
That the object of the present invention is to provide a kind of methods is simple, enantioselectivity is high, S-3- at low cost (4- aminophenyl) The synthetic method of piperidines.
To achieve the goals above, the technical scheme is that
The synthetic method of S-3- (4- aminophenyl) piperidines is with 3- pyridine boronic acid (I) for raw material, and to Nitrobromobenzene (II) it is coupled to obtain 3- (4- nitrobenzophenone) pyridine, 3- (4- nitrobenzophenone) pyridine through primary reduction, acylated, secondary through Suzuki Reduction, fractionation, hydrolysis obtain S-3- (4- aminophenyl) piperidines, and method of the invention can be indicated with following reaction equations:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) in a solvent, 3- pyridine boronic acid (I) and 4- bromo nitrobenzene (II) carry out Suzuki coupling instead under catalyst It should obtain 3- (4- nitrobenzophenone) pyridine (III), reaction equation are as follows:
2) by 3- (4- nitrobenzophenone) pyridine (III) in the presence of iron powder and hydrochloric acid in a solvent, reduction reaction obtains 3- (4- aminophenyl) pyridine (IV), reaction equation are as follows:
3) 3- (4- aminophenyl) pyridine (IV) is reacted in a solvent to obtain 3- (4- acetyl amino phenyl through amide with aceticanhydride Base) pyridine (V), reaction equation are as follows:
4) 3- (4- acetylamino phenyl) pyridine (V) is dissolved in solvent, and hydrogen reducing reacts to obtain 3- (4- acetylamino Phenyl) piperidines (VI), reaction equation are as follows:
5) 3- (4- acetylamino phenyl) piperidines (VI) is dissolved in solvent, L- camphorsulfonic acid is added, rising temperature for dissolving gradually drops Temperature has white solid precipitation, then filters, and chiral resolution obtains S-3- (4- acetylamino phenyl) piperidines-L- camsilate, Alkali is added to be precipitated to obtain 3- (4- acetylamino phenyl) piperidines (VII), reaction equation are as follows:
6) S-3- (4- acetylamino phenyl) piperidines (VII) is dissolved in solvent, macromolecule alkali for hydrolysis is added and obtains S-3- (4- Aminophenyl) piperidines, reaction equation are as follows:
According to the above scheme, the molar ratio of 4- bromo nitrobenzene (II) and 3- pyridine boronic acid (I) are 1:1-3, catalysis in step 1) The molar ratio of agent and 3- pyridine boronic acid is 0.01-1:1 alkali and the molar ratio of 3- pyridine boronic acid is 1-4:1, is reacted at 20-100 DEG C 1-10 hours generation 3- (4- nitrobenzophenone) pyridines；Then end of reaction, solvent evaporated obtain sterling through alcohol crystal and are used for down Step reaction.
According to the above scheme, step 1) solvent for use is a kind of in acetonitrile, THF, DMF, acetone, dioxane, toluene and water Or a kind of mixed solvent with water in them, the envelope-bulk to weight ratio of solvent and 3- pyridine boronic acid is 1-30:1, preferably 10-25: 1。
According to the above scheme, step 1) used catalyst are as follows: Pd (PPh3)4、Pd(PPh3)2Cl、Pd(dppf)Cl2DCM, it is excellent It is selected as Pd (dppf) Cl2·DCM。
According to the above scheme, alkali used in step 1) be sodium carbonate, potassium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, most Excellent alkali is potassium carbonate；
According to the above scheme, the reaction optimum temperature of step 1) is 60-100 DEG C, and optimum reacting time is 1-3 hours；
According to the above scheme, the optimum mole ratio of the bromo- 4- nitrobenzene (II) of 1- and 3- pyridine boronic acid (I) are 1:1- in step 1) 1.5, the optimum mole ratio of catalyst and 3- pyridine boronic acid (I) are 0.01-0.2:1, the optimum molar of alkali and 3- pyridine boronic acid (I) Than for 3-4:1.
According to the above scheme, step 2) solvent for use be acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, dioxane, water, or The mixture of their two kinds of solvents, preferably one of acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, dioxane are pressed with water Volume basis is the mixed solvent of 2-5:1；The envelope-bulk to weight ratio of solvent and 3- (4- nitrobenzophenone) pyridine is 3-10:1.
According to the above scheme, in step 2) reduction reaction be 25 DEG C -100 DEG C of reactions 5-24 hours, preferably 50-90 DEG C react 5-10 hours；
According to the above scheme, the molar ratio of 3- (4- nitrobenzophenone) pyridine and iron powder is 1:1.05-4 in step 2)；TLC tracking Reduction reaction is completed, and reaction solution is filtered, mother liquor concentrations to dry, residue addition ethyl acetate extraction, organic layer saturation food Salt water washing, anhydrous sodium sulfate is dry, is concentrated to dryness, residue with Ethyl acetate recrystallizes to obtain 3- (4- aminophenyl) pyridine.
In step 2)；The molar ratio of hydrochloric acid and 3- (4- nitrobenzophenone) pyridine is 0.05-1.5:1, is preferably 0.1- The envelope-bulk to weight ratio of 0.8:1, recrystallization solvent ethyl acetate and 3- (4- aminophenyl) pyridine is 3-5:1, preferably 3-4:1.
According to the above scheme, in step 3) reaction temperature be 25 DEG C -100 DEG C, the reaction time be 5-24 hours, preferably 25 DEG C -40 DEG C reaction 5-12 hours；The molar ratio of 3- (4- aminophenyl) pyridine and aceticanhydride is 1:1-3, preferably 1:1-2；
According to the above scheme, the solvent of step 3) is methylene chloride, chloroform, toluene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), vinegar The w/v of acid, ethyl acetate etc., 3- (4- aminophenyl) pyridine and solvent is 1:2-10, preferably 1:5-8；TLC with Track acylation reaction is completed, and reaction solution is poured into water, and with solvent extraction, merges organic layer, organic layer saturated common salt water washing, Anhydrous sodium sulfate is dry, is concentrated to dryness, residue is directly used in the next step.
According to the above scheme, in step 4), the described hydrogen reducing reaction in the presence of solvent and acidic materials additive, 2-15 kilograms of Hydrogen Vapor Pressure, platinum dioxide catalysis under, in 25 DEG C -100 DEG C of hydrogenations 2-24 hour, reaction no longer suction hydrogen be Reaction end；Reaction solution is arranged into hydrogen by hydrogenation procedure, nitrogen charging, filtration catalytic agent, filtrate condensing crystallizing obtains 3- (4- acetylamino Phenyl) piperidines；；
According to the above scheme, in step 4), acidic materials additive is concentrated hydrochloric acid, the concentrated sulfuric acid, glacial acetic acid, phosphoric acid, methyl sulphur The molar ratio of acid, toluenesulfonic acid etc., additive and substrate is 0.1-3:1；Optimum addn is glacial acetic acid, glacial acetic acid and substrate Optimum mole ratio be 0.3-0.5:1；
According to the above scheme, the envelope-bulk to weight ratio of step 4) solvent for use and substrate is 3-10:1；Solvent for use in step 4) For the mixture of acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, dioxane, water or their two kinds of solvents, optimum solvent is first The optimal volume weight ratio of alcohol, methanol and substrate is 4-8:1；
According to the above scheme, step 4) optimum response pressure is 2-6 kilograms, and optimal reaction temperature is 25-40 DEG C, optimum response Time is 16-24 hours.
According to the above scheme, step 5) are as follows: 3- (4- acetylamino phenyl) piperidines (VI) is dissolved in suitable solvent, L- is added Camphorsulfonic acid, rising temperature for dissolving gradually cool down, and have white solid precipitation, and filtering, solid is S-3- (4- acetylamino phenyl) piperazine Pyridine-L- camsilate, L- camphorsulfonic acid and 3- (4- acetylamino phenyl) pyridine molar ratio are 1-2:1, parse alkali and camphor The molar ratio of sulfonate is 1-2:1；
According to the above scheme, step 5) solvent be acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, isopropanol, dioxane, Water or a kind of mixed solvent with water in them, optimum solvent are the mixed solvent of isopropanol and water, isopropanol and water it is best Volume ratio is 3:1；Solvent and 3- (4- acetylamino phenyl) pyridine molar ratio are 3-10:1.
According to the above scheme, step 5) optimum temperature of solubilization temperature is 60-100 DEG C, and the optimal dissolution time is 0.5-1 hours.
According to the above scheme, the best Precipitation Temperature of step 5) is 10-25 DEG C, and crystallization time is 3-5 hours.
According to the above scheme, the optimum mole ratio of step 5) 3- (4- acetylamino phenyl) piperidines and L- camphorsulfonic acid is 1:1- The optimum weight volume ratio of 1.2,3- (4- acetylamino phenyl) piperidines and solvent is 1:5-8.
According to the above scheme, in step 5) parsing alkali be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, Saleratus, ammonium hydroxide etc.；The optimum mole ratio of S-3- (4- acetylamino phenyl) piperidines-L- camsilate and alkali is 1:1- 1.2, resolution temperature is 20-30 DEG C.
According to the above scheme, step 6) are as follows: hydrolysising reacting temperature is 50-100 DEG C, is reacted 3-12 hours, cooling that solid is precipitated, Solid is S-3- (4- aminophenyl) piperidines, and wherein the molar ratio of alkali and S-3- (4- acetylamino phenyl) piperidines is 1-2:1.
According to the above scheme, hydrolysising solvent is acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, isopropanol, dioxy in step 6) Six rings, water or a kind of mixed solvent with water in them, optimum solvent are the mixed solvent of ethyl alcohol and water, and ethyl alcohol is best with water Volume ratio is 2-3:1；The envelope-bulk to weight ratio of solvent and S-3- (4- acetylamino phenyl) piperidines is 3-8:1.
According to the above scheme, optimal reaction temperature is 50-100 DEG C in step 6), and the reaction time is 8-10 hours.
The present invention successively restores different functional groups by different restoring method, will restore for the first time obtained amino into Row protection, using obtained amino is restored for the second time as the recognition site of chiral molecules, improves the hand of chiral selectors Property recognition capability, has obtained the product of high-optical-purity.
Beneficial effects of the present invention:
Method of the invention for raw material, is coupled to obtain with the bromo- 4- nitrobenzene (II) of 1- and 3- pyridine boronic acid (I) through SUZUKI 3- (4- nitrobenzophenone) pyridine, then primary reduction, acylation, secondary reduction, fractionation, hydrolysis, stepwise reaction obtain S-3- (4- ammonia Base phenyl) piperidines method, method is simple, enantioselectivity is high, at low cost, have industrial utility value.
Specific embodiment
For a better understanding of the present invention, below with reference to the embodiment content that the present invention is furture elucidated, but it is of the invention Content is not limited solely to the following examples.
Embodiment 1:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), THF (30mL), 2.0M sodium carbonate liquor (16.6mL) and Pd (dppf) Cl2DCM, 0.167g (0.2mmol) vacuumizes with nitrogen ventilation three times, is then warming up to 60 DEG C of reactions 3 hours under nitrogen protection, after reaction Stratification, aqueous layer with ethyl acetate (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, filters Liquid is concentrated to dryness, and ethyl alcohol (5mL) is added into residue, temperature rising reflux, cooling that solid is precipitated, and filtering is light yellow admittedly dry Body 1.72g (79%).
1HNMR(400MHz,CDCl3) δ ppm:8.85 (1H, s), 8.67 (1H, d, J=4.7Hz), 8.35 (2H, d, J= 8.5Hz), 7.94 (1H, d, J=8.1Hz), 7.73 (2H, d, J=8.5Hz), 7.46 (1H, dd, J=8.1,4.7Hz)
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 1.56g (0.03mol) water (2mL) and ethyl alcohol (10mL) are put into the three-necked flask of 50mL, and hydrochloric acid is added (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), temperature rising reflux is then added 5 hours, TLC tracked fully reacting, stopped reaction, filtering, and mother liquor concentrations are added ethyl acetate (5mL) and rise to doing in residue Temperature is back to solid dissolution, cooling to be precipitated solid, filtering, solid it is dry off-white powder 1.16g (85%)
1HNMR(400MHz,CDCl3) δ ppm:8.81 (1H, s), 8.55 (1H, d, J=4.9Hz), 7.95 (2H, d, J= 8.7Hz),
6.94 (1H, d, J=8.4Hz), 6.73 (2H, d, J=8.6Hz), 6.46 (1H, dd, J=8.0,4.9Hz), 4.0 (2H,s).
3) preparation of 3- (4- acetylamino phenyl) pyridine
3- (4- aminophenyl) pyridine 1g (0.005mol) aceticanhydride (0.5mL) and two is put into 50 milliliters of three-necked flasks Chloromethanes (5mL) be stirred at room temperature reaction 12 hours, TLC tracking reaction complete, be poured into water, with protection sodium carbonate liquor wash to Alkalinity, stratification, organic layer saturated common salt water washing is dry, is concentrated to get solid 1.22 (98%), is used for without purifying The next step.
1HNMR(400MHz,CDCl3) δ ppm:8.83 (1H, s), 8.57 (1H, d, J=5.1Hz), 7.79 (1H, d, J= 8.5Hz), 7.70 (2H, d, J=7.7Hz), 7.48 (2H, d, J=8.2Hz), 7.40 (1H, dd, J=8.1,4.8Hz), 2.02 (3H,s).
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and hydrochloric acid (0.9mL), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 3 kilograms, room temperature is anti- 24 hours are answered to hydrogen is no longer inhaled, reaction was completed, is vented and takes a breath by hydroprocessing, and reaction solution filters, and acetic acid second is added in filtrate Ester (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 1.97g (90%).
1HNMR(400MHz,CDCl3) δ ppm:8.0 (1H, s), 7.60 (2H, d, J=7.7Hz), 7.48 (2H, d, J= 8.2Hz),2.9-3.15(2H,m),2.73-2.78(3H,m),1.99-1.91(2H,m),1.45-1.55(2H,m),2.02 (3H,s).2.0(1H,m).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), methanol are added into 50 milliliters of single-necked flasks (15mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (4mL), rising temperature for dissolving half an hour, slow cooling have white to 25 DEG C Color solid is precipitated, filtering, and dry white solid 1.94g (42%) is soluble in water by obtained white solid, and potassium carbonate is added Solid, filtering, dry white solid 0.83g (38%, optics content analysis: ee 94.5%) is precipitated in solution, stirring.
The analysis of optics content:
Chiral column: AD-H
Flow velocity: 1mL/min
Mobile phase: n-hexane: isopropanol: DEA=97:3:0.1
Detection wavelength: 254nm
Column temperature: 30 DEG C
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), ethyl alcohol are added into 50 milliliters of single-necked flasks (5mL), water (2mL), sodium hydroxide 0.5g (0.0125mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point disappearance, It is cooled to room temperature precipitation solid, is filtered, dry white solid 1.52g (81.6%)；Mother liquor is extracted with ethyl acetate, and is associated with Machine layer, organic layer saturated common salt water washing is dry, is concentrated to give solid 0.12g (6.4%), white solid 1.64g total twice (88%).
1HNMR(400MHz,CDCl3) δ ppm:6.88 (2H, d, J=7.7Hz), 6.48 (2H, d, J=8.2Hz), 4.0 (2H,s),2.9-3.15(2H,m),2.73-2.78(3H,m),1.99-1.91(3H,m),1.45-1.55(2H,m).
Embodiment 2:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), THF (30mL), 2.0M sodium carbonate liquor (16.6mL) and 0.38gPd (PPh3)4(0.33mmol), vacuumizes use Nitrogen is taken a breath three times, is then warming up to 60 DEG C of reactions 3 hours under nitrogen protection, after reaction stratification, water layer second Acetoacetic ester (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated to dryness, to residual Ethyl alcohol (5mL) is added in object, temperature rising reflux is cooling to be precipitated solid, overanxious, dry light yellow solid 1.57g (72%).
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 1.56g (0.03mol) water (2mL) and methanol (10mL) are put into the three-necked flask of 50mL, and hydrochloric acid is added (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), temperature rising reflux is then added 5 hours, TLC tracked fully reacting, stopped reaction, filtering, and mother liquor concentrations are added ethyl acetate (5mL) and rise to doing in residue Temperature is back to solid dissolution, cooling to be precipitated solid, filtering, solid it is dry off-white powder 1.10g (82%)
3) preparation of 3- (4- acetylamino phenyl) pyridine
3- (4- aminophenyl) pyridine 1g (0.005mol) aceticanhydride (0.5mL) and second are put into 50 milliliters of three-necked flasks Acetoacetic ester (5mL) be stirred at room temperature reaction 12 hours, TLC tracking reaction complete, be poured into water, with protection sodium carbonate liquor wash to Alkalinity, stratification, organic layer saturated common salt water washing is dry, is concentrated to get solid 1.12 (90%), is used for without purifying The next step.
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and phosphoric acid (0.7mL, 85%), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 3 kilograms, Room temperature reaction is to hydrogen is no longer inhaled, and reaction was completed, is vented and takes a breath by hydroprocessing, reaction solution filtering, and acetic acid second is added in filtrate Ester (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 1.93g (88%).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), ethyl alcohol are added into 50 milliliters of single-necked flasks (10mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (4mL), rising temperature for dissolving half an hour, slow cooling have white to 25 DEG C Color solid is precipitated, filtering, and dry white solid 2.08g (45%) is soluble in water by obtained white solid, and potassium carbonate is added Solid, filtering, dry white solid 1.05g (40%, optics content analysis: ee 91.5%) is precipitated in solution, stirring.
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), methanol are added into 50 milliliters of single-necked flasks (5mL), water (2mL), sodium hydroxide 0.5g (0.0125mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point disappearance, It is cooled to room temperature precipitation solid, is filtered, dry white solid 1.46g；Mother liquor is extracted with ethyl acetate, and merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to give solid 0.08g (), there are white solid 1.54g (83%) twice.
Embodiment 3:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), dioxane (30mL), 2.0M sodium carbonate liquor (16.6mL) and Pd (dppf) ClDCM, 0.167g (0.2mmol) vacuumizes with nitrogen ventilation three times, is then warming up to 60 DEG C of reactions 3 hours under nitrogen protection, after reaction Stratification, aqueous layer with ethyl acetate (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, filters Liquid is concentrated to dryness, and ethyl alcohol (5mL) is added into residue, temperature rising reflux, cooling precipitation solid, overanxious, light yellow admittedly dry Body 1.81g (83%).
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 1.56g (0.03mol) water (2mL) and THF (10mL) are put into the three-necked flask of 50mL, and hydrochloric acid is added (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), temperature rising reflux is then added 5 hours, TLC tracked fully reacting, stopped reaction, filtering, and mother liquor concentrations are added ethyl acetate (5mL) and rise to doing in residue Temperature is back to solid dissolution, cooling to be precipitated solid, filtering, solid it is dry off-white powder 1.00g (75%)
3) preparation of 3- (4- acetylamino phenyl) pyridine
Into 50 milliliters of three-necked flasks put into 3- (4- aminophenyl) pyridine 1g (0.005mol) aceticanhydride (0.5mL) and Reaction 12 hours is stirred at room temperature in THF (5mL), and TLC tracking reaction is completed, is poured into water, washed with protection sodium carbonate liquor to alkali Property, stratification, organic layer saturated common salt water washing is dry, is concentrated to get solid 0.93 (75%), is used for down without purifying Step reaction.
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and sulfuric acid (0.56mL), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 3 kilograms, room temperature Reaction is to hydrogen is no longer inhaled, and reaction was completed, is vented and takes a breath by hydroprocessing, reaction solution filtering, and ethyl acetate is added in filtrate (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, organic Layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 1.86g (85%).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), isopropanol are added into 50 milliliters of single-necked flasks (10mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (4mL), rising temperature for dissolving half an hour, slow cooling have white to 25 DEG C Color solid is precipitated, filtering, and obtained white solid is dissolved in the solvent by upper proportion by dry white solid 2.00g (43%) Temperature rising reflux dissolves in (14mL), and slow cooling has white solid generation to 25 DEG C, filters, dry；The solid of recrystallization is molten In water (6mL), solution of potassium carbonate is added, solid is precipitated in stirring, and filtering, (40%, optics contains dry white solid 1.05g Amount analysis: ee 99.1%).
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), ethyl alcohol are added into 50 milliliters of single-necked flasks (5mL), water (2mL), potassium hydroxide 0.7g (0.0125mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point disappearance, It is cooled to room temperature precipitation solid, is filtered, dry white solid 1.46g；Mother liquor is extracted with ethyl acetate, and merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to give solid 0.08g (), there are white solid 1.58g (85%) twice.
Embodiment 4:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), dioxane (30mL), 2.0M sodium acetate solution (16.6mL) and Pd (dppf) Cl2DCM, 0.167g (0.2mmol) vacuumizes with nitrogen ventilation three times, is then warming up to 60 DEG C of reactions 3 hours under nitrogen protection, after reaction Stratification, aqueous layer with ethyl acetate (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, filters Liquid is concentrated to dryness, and ethyl alcohol (5mL) is added into residue, temperature rising reflux, cooling precipitation solid, overanxious, light yellow admittedly dry Body 1.55g (83%).
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 1.56g (0.03mol) water (2mL) and dioxane (10mL) are put into the three-necked flask of 50mL, are added Hydrochloric acid (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), heating is then added It flows back 5 hours, TLC tracks fully reacting, stops reaction, filtering, and ethyl acetate is added to doing in mother liquor concentrations in residue (5mL) temperature rising reflux to solid dissolves, cooling to be precipitated solid, filtering, solid it is dry off-white powder 0.93g (70%)
3) preparation of 3- (4- acetylamino phenyl) pyridine
3- (4- aminophenyl) pyridine 1g (0.006mol) aceticanhydride (0.5mL) and first are put into 50 milliliters of three-necked flasks Reaction 12 hours is stirred at room temperature in benzene (5mL), and TLC tracking reaction is completed, is poured into water, washed with protection sodium carbonate liquor to alkali Property, stratification, organic layer saturated common salt water washing is dry, is concentrated to get solid 0.97 (78%), is used for down without purifying Step reaction.
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and glacial acetic acid (0.6mL), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 3 kilograms, room temperature Reaction is to hydrogen is no longer inhaled, and reaction was completed, is vented and takes a breath by hydroprocessing, reaction solution filtering, and ethyl acetate is added in filtrate (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, organic Layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 2.08g (95%).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), isopropanol are added into 50 milliliters of single-necked flasks (15mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (5mL), rising temperature for dissolving half an hour, slow cooling have white to 25 DEG C Color solid is precipitated, filtering, and obtained white solid is dissolved in the solvent by upper proportion by dry white solid 1.91g (41%) Temperature rising reflux dissolves in (20mL), and slow cooling has white solid generation to 25 DEG C, filters, dry；The solid of recrystallization is molten In water (6mL), solution of potassium carbonate is added, solid is precipitated in stirring, and filtering, (40%, optics contains dry white solid 1.05g Amount analysis: ee 99.7%).
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), ethyl alcohol are added into 50 milliliters of single-necked flasks (5mL), water (2mL), sodium hydroxide 0.7g (0.0175mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point disappearance, It is cooled to room temperature precipitation solid, is filtered, dry white solid 1.66g；Mother liquor is extracted with ethyl acetate, and merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to give solid 0.08g, there are white solid 174g (93.6%) twice.
Embodiment 5:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), dioxane (30mL), 2.0M sodium carbonate liquor (16.6mL) and Pd (PPh3)2Cl2 0.14g(0.2mmol), It vacuumizes with nitrogen ventilation three times, is then warming up to 60 DEG C of reactions 3 hours under nitrogen protection, after reaction stratification, Aqueous layer with ethyl acetate (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated into It is dry, ethyl alcohol (5mL) is added into residue, temperature rising reflux is cooling to be precipitated solid, overanxious, dry light yellow solid 1.42g (65%).
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 2.24g (0.03mol) water (2mL) and ethyl alcohol (10mL) are put into the three-necked flask of 50mL, and hydrochloric acid is added (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), temperature rising reflux is then added 5 hours, TLC tracked fully reacting, stopped reaction, filtering, and mother liquor concentrations are added ethyl acetate (5mL) and rise to doing in residue Temperature is back to solid dissolution, cooling to be precipitated solid, filtering, solid it is dry off-white powder 1.18g (89%)
3) preparation of 3- (4- acetylamino phenyl) pyridine
3- (4- aminophenyl) pyridine 1g (0.006mol) aceticanhydride (0.5mL) and first are put into 50 milliliters of three-necked flasks Reaction 12 hours is stirred at room temperature in base tertbutyl ether (5mL), and TLC tracking reaction is completed, is poured into water, washed with protection sodium carbonate liquor It washs to alkalinity, stratification, organic layer saturated common salt water washing, it is dry, it is concentrated to get solid 0.93g (75%), Wu Xuchun Change and is used for the next step.
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and glacial acetic acid (0.6mL), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 3 kilograms, 40 DEG C To hydrogen is no longer inhaled, reaction was completed within 18 hours for reaction, is vented and takes a breath by hydroprocessing, reaction solution filtering, and acetic acid is added in filtrate Ethyl ester (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, Organic layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 2.10g (96%).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), isopropanol are added into 50 milliliters of single-necked flasks (15mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (5mL), rising temperature for dissolving half an hour, slow cooling have white to 15 DEG C Color solid is precipitated, filtering, and obtained white solid is dissolved in the solvent by upper proportion by dry white solid 2.10g (45%) Temperature rising reflux dissolves in (20mL), and slow cooling has white solid generation to 15 DEG C, filters, dry；The solid of recrystallization is molten In water (6mL), solution of potassium carbonate is added, solid is precipitated in stirring, and filtering, (40%, optics contains dry white solid 1.05g Amount analysis: ee 99.0%).
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), ethyl alcohol are added into 50 milliliters of single-necked flasks (8mL), water (2mL), sodium hydroxide 0.7g (0.0175mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point disappearance, It is cooled to room temperature precipitation solid, is filtered, dry white solid 1.56g；Mother liquor is extracted with ethyl acetate, and merges organic layer, has Machine layer saturated common salt water washing, it is dry, it is concentrated to give solid 0.08g, there are white solid 1.58g (88.2%) twice.
Embodiment 6:
The synthetic method of S-3- (4- aminophenyl) piperidines, is realized by following step:
1) preparation of 3- (4- nitrobenzophenone) pyridine
The bromo- 4- nitrobenzene 2.3g (0.011mol) of 1-, 3- pyridine boronic acid 1.47g are added into 25ml single port bottle (0.012mol), dioxane (30mL), 2.0M sodium carbonate liquor (16.6mL) and Pd (dppf) Cl2DCM0.167g (0.2mmol) vacuumizes with nitrogen ventilation three times, is then warming up to 80 DEG C of reactions 3 hours under nitrogen protection, after reaction Stratification, aqueous layer with ethyl acetate (10mL*3) extraction, merges organic layer, and organic layer is dried, filtered with anhydrous sodium sulfate, filters Liquid is concentrated to dryness, and ethyl alcohol (5mL) is added into residue, temperature rising reflux, cooling precipitation solid, overanxious, light yellow admittedly dry Body 1.86g (85%).
2) preparation of 3- (4- aminophenyl) pyridine
Iron powder 1.12g (0.02mol) water (2mL) and ethyl alcohol (10mL) are put into the three-necked flask of 50mL, and hydrochloric acid is added (0.5mL) is warming up to 50 DEG C of stirring half an hour, and 3- (4- nitrobenzophenone) pyridine 1.6g (0.008mol), temperature rising reflux is then added 5 hours, TLC tracked fully reacting, stopped reaction, filtering, and mother liquor concentrations are added ethyl acetate (5mL) and rise to doing in residue Temperature is back to solid dissolution, cooling to be precipitated solid, filtering, solid it is dry off-white powder 0.86g (65%)
3) preparation of 3- (4- acetylamino phenyl) pyridine
Into 50 milliliters of three-necked flasks put into 3- (4- aminophenyl) pyridine 1g (0.006mol) aceticanhydride (0.8mL) and Reaction 12 hours is stirred at room temperature in DCM (5mL), and TLC tracking reaction is completed, is poured into water, washed with protection sodium carbonate liquor to alkali Property, stratification, organic layer saturated common salt water washing is dry, is concentrated to get solid 1.18g (95%), is used for without purifying The next step.
4) preparation of 3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) pyridine 2.12g (0.01mmol), methanol (10mL), titanium dioxide are added into autoclave Platinum 0.25g and glacial acetic acid (0.6mL), vacuumize, and respectively three times with nitrogen and hydrogen ventilation, are then flushed with hydrogen gas to 4 kilograms, 40 DEG C To hydrogen is no longer inhaled, reaction was completed within 16 hours for reaction, is vented and takes a breath by hydroprocessing, reaction solution filtering, and acetic acid is added in filtrate Ethyl ester (10mL) is added saturated sodium carbonate solution and washs to alkalinity, and aqueous layer with ethyl acetate (5mL*3) extraction merges organic layer, Organic layer saturated common salt water washing, it is dry, it is concentrated to dryness to obtain white solid 2.11g (96.5%).
5) preparation of S-3- (4- acetylamino phenyl) piperidines
3- (4- acetylamino phenyl) piperidines 2.18g (0.01mmol), isopropanol are added into 50 milliliters of single-necked flasks (15mL), L- camphorsulfonic acid 2.46g (0.0105mmol), water (3mL), rising temperature for dissolving half an hour, slow cooling have white to 15 DEG C Color solid is precipitated, filtering, and obtained white solid is dissolved in the solvent by upper proportion by dry white solid 2.19g (47%) Temperature rising reflux dissolves in (20mL), and slow cooling has white solid generation to 15 DEG C, filters, dry；The solid of recrystallization is molten In water (6mL), solution of potassium carbonate is added, solid is precipitated in stirring, and filtering, (42%, optics contains dry white solid 1.105g Amount analysis: ee 97.8%).
6) preparation of S-3- (4- aminophenyl) piperidines
S-3- (4- acetylamino phenyl) piperidines 2.18g (0.01mol), dioxy six are added into 50 milliliters of single-necked flasks Ring (8mL), water (2mL), sodium hydroxide 0.7g (0.0175mol), stirring and dissolving, temperature rising reflux, TLC track to raw material point and disappear It loses, is cooled to room temperature precipitation solid, filter, dry white solid 1.36g；Mother liquor is extracted with ethyl acetate, and merges organic layer, Organic layer saturated common salt water washing, it is dry, it is concentrated to give solid 0.08g, there are white solid 1.58g (80.4%) twice.
The bound value and interval value of each raw material of the present invention can realize the present invention and cited each raw material all It is able to achieve the present invention, embodiment is just not listed one by one herein.
It should be noted that all documents referred in the present invention are incorporated by reference herein, just as each text It offers and is individually recited as with reference to the same.It should also be understood that above-described is specific embodiments of the present invention and the technology used Principle, after having read above content of the invention, those skilled in the art can be used for various modifications and change to the present invention It moves without departing from the spirit and scope of the invention, such equivalent forms are also fallen in the scope of the present invention.

Claims (10)

  1. The synthetic method of 1.S-3- (4- aminophenyl) piperidines, it is characterised in that: with 3- pyridine boronic acid (I) for raw material, and to nitre Bromide benzene (II) is coupled to obtain 3- (4- nitrobenzophenone) pyridine, 3- (4- nitrobenzophenone) pyridine through primary reduction, acyl through Suzuki Change, secondary reduction, fractionation, hydrolysis obtain S-3- (4- aminophenyl) piperidines, are indicated with following reaction equations:
  2. 2. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: under State step realization:
    1) in a solvent, 3- pyridine boronic acid (I) is obtained with 4- bromo nitrobenzene (II) progress Suzuki coupling reaction under catalyst To 3- (4- nitrobenzophenone) pyridine (III), reaction equation are as follows:
    2) by 3- (4- nitrobenzophenone) pyridine (III) in the presence of iron powder and hydrochloric acid in a solvent, reduction reaction obtains 3- (4- ammonia Base phenyl) pyridine (IV), reaction equation are as follows:
    3) 3- (4- aminophenyl) pyridine (IV) is reacted in a solvent to obtain 3- (4- acetylamino phenyl) through amide with aceticanhydride Pyridine (V), reaction equation are as follows:
    4) 3- (4- acetylamino phenyl) pyridine (V) is dissolved in solvent, and hydrogen reducing reacts to obtain 3- (4- acetylamino phenyl) Piperidines (VI), reaction equation are as follows:
    5) 3- (4- acetylamino phenyl) piperidines (VI) being dissolved in solvent, L- camphorsulfonic acid is added, rising temperature for dissolving gradually cools down, There is white solid precipitation, then filter, chiral resolution obtains S-3- (4- acetylamino phenyl) piperidines-L- camsilate, adds Alkali is precipitated to obtain 3- (4- acetylamino phenyl) piperidines (VII),
    Reaction equation are as follows:
    6) S-3- (4- acetylamino phenyl) piperidines (VII) is dissolved in solvent, macromolecule alkali for hydrolysis is added and obtains S-3- (4- amino Phenyl) piperidines, reaction equation are as follows:
  3. 3. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: 4- in step 1) The molar ratio of bromo nitrobenzene (II) and 3- pyridine boronic acid (I) are 1:1-3, and the molar ratio of catalyst and 3- pyridine boronic acid is 0.01- The molar ratio of 1:1 alkali and 3- pyridine boronic acid is 1-4:1, in 20-100 DEG C of reaction 1-10 hours generation 3- (4- nitrobenzophenone) pyrrole Pyridine；
    Step 1) used catalyst are as follows: Pd (PPh3)4、Pd(PPh3)2Cl、Pd(dppf)Cl2·DCM；
    Alkali used in step 1) is sodium carbonate, potassium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, and optimal alkali is potassium carbonate.
  4. 4. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: in step 2) also Original reaction for 25 DEG C -100 DEG C of reactions 5-24 hours, preferably 50-90 DEG C reaction 5-10 hours；3- (4- nitrobenzene in step 2) Base) molar ratio of pyridine and iron powder is 1:1.05-4, TLC tracks reduction reaction and completes, reaction solution filtered, mother liquor concentrations are extremely Dry, ethyl acetate extraction is added in residue, and organic layer saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated to dryness, and remains Object obtains 3- (4- aminophenyl) pyridine with re-crystallizing in ethyl acetate.
  5. 5. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: anti-in step 3) Answer temperature be 25 DEG C -100 DEG C, the reaction time be 5-24 hours, preferably 25 DEG C -40 DEG C of reactions 5-12 hours；3- (4- aminobenzene Base) molar ratio of pyridine and aceticanhydride is 1:1-3, preferably 1:1-2.
  6. 6. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: in step 4), The hydrogen reducing reaction is in the presence of solvent and acidic materials additive, 2-15 kilograms of Hydrogen Vapor Pressure, platinum dioxide is urged Under change, in 25 DEG C -100 DEG C of hydrogenations 2-24 hours, reaction no longer inhale hydrogen be reaction end；Reaction solution is pressed into hydrogenation procedure Row's hydrogen, nitrogen charging, filtration catalytic agent, filtrate condensing crystallizing obtain 3- (4- acetylamino phenyl) piperidines；
    Acidic materials additive is concentrated hydrochloric acid, the concentrated sulfuric acid, glacial acetic acid, phosphoric acid, methane sulfonic acid, toluenesulfonic acid etc., additive with The molar ratio of substrate is 0.1-3:1；Optimum addn is glacial acetic acid, and the optimum mole ratio of glacial acetic acid and substrate is 0.3-0.5:1.
  7. 7. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: step 5) are as follows: 3- (4- acetylamino phenyl) piperidines (VI) is dissolved in suitable solvent, L- camphorsulfonic acid is added, rising temperature for dissolving gradually cools down, There is white solid precipitation, filters, solid is S-3- (4- acetylamino phenyl) piperidines-L- camsilate, L- camphorsulfonic acid It is 1-2:1 with 3- (4- acetylamino phenyl) pyridine molar ratio, the molar ratio for parsing alkali and camsilate is 1-2:1.
  8. 8. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that:
    Parsing alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, ammonium hydroxide etc. in step 5)； The optimum mole ratio of S-3- (4- acetylamino phenyl) piperidines-L- camsilate and alkali is 1:1-1.2, resolution temperature 20- 30℃；
    Step 5) optimum temperature of solubilization temperature is 60-100 DEG C, and the optimal dissolution time is 0.5-1 hours；
    The best Precipitation Temperature of step 5) is 10-25 DEG C, and crystallization time is 3-5 hours.
  9. 9. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that: step 6) are as follows: Hydrolysising reacting temperature is 50-100 DEG C, is reacted 3-12 hours, and cooling that solid is precipitated, solid is S-3- (4- aminophenyl) piperazine Pyridine, wherein the molar ratio of alkali and S-3- (4- acetylamino phenyl) piperidines is 1-2:1.
  10. 10. the synthetic method of S-3- (4- aminophenyl) piperidines according to claim 1, it is characterised in that:
    Step 1) solvent for use is a kind of in acetonitrile, THF, DMF, acetone, dioxane, toluene and water or a kind of and water in them Mixed solvent, the envelope-bulk to weight ratio of solvent and 3- pyridine boronic acid is 1-30:1, preferably 10-25:1；The reaction of step 1) is most Good temperature is 60-100 DEG C, and optimum reacting time is 1-3 hours；The bromo- 4- nitrobenzene (II) of 1- and 3- pyridine boronic acid in step 1) (I) optimum mole ratio is 1:1-1.5, and the optimum mole ratio of catalyst and 3- pyridine boronic acid (I) are 0.01-0.2:1, alkali and 3- The optimum mole ratio of pyridine boronic acid (I) is 3-4:1；Then end of reaction, solvent evaporated obtain sterling through alcohol crystal and are used for down Step reaction；
    Step 2) solvent for use is acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, dioxane, water or their two kinds of solvents One of mixture, preferably acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, dioxane are calculated as 2-5 with water by volume: 1 mixed solvent；The envelope-bulk to weight ratio of solvent and 3- (4- nitrobenzophenone) pyridine is 3-10:1；In step 2)；Hydrochloric acid and 3- (4- Nitrobenzophenone) molar ratio of pyridine is 0.05-1.5:1, it is preferably 0.1-0.8:1, recrystallization solvent ethyl acetate and 3- (4- Aminophenyl) envelope-bulk to weight ratio of pyridine is 3-5:1, preferably 3-4:1；
    The solvent of step 3) is methylene chloride, chloroform, toluene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), acetic acid, ethyl acetate etc., 3- The w/v of (4- aminophenyl) pyridine and solvent is 1:2-10, preferably 1:5-8；TLC tracks acylation reaction and completes, will Reaction solution is poured into water, and with solvent extraction, merges organic layer, organic layer saturated common salt water washing, anhydrous sodium sulfate is dry, dense It is reduced to dry, residue is directly used in the next step；
    The envelope-bulk to weight ratio of step 4) solvent for use and substrate is 3-10:1；In step 4) solvent for use be acetonitrile, THF, DMF, Acetone, methanol, ethyl alcohol, dioxane, water or their two kinds of solvents mixture, optimum solvent is methanol, methanol and substrate Optimal volume weight ratio is 4-8:1；Step 4) optimum response pressure is 2-6 kilograms, and optimal reaction temperature is 25-40 DEG C, most preferably Reaction time is 16-24 hours；
    Step 5) solvent be acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, isopropanol, dioxane, water or they in it is a kind of with The mixed solvent of water, optimum solvent are the mixed solvent of isopropanol and water, and the optimum volume ratio of isopropanol and water is 3:1；Solvent It is 3-10:1 with 3- (4- acetylamino phenyl) pyridine molar ratio；Step 5) 3- (4- acetylamino phenyl) piperidines and L- camphor sulphur The optimum mole ratio of acid is 1:1-1.2；
    In step 6) hydrolysising solvent be acetonitrile, THF, DMF, acetone, methanol, ethyl alcohol, isopropanol, dioxane, water or they in A kind of mixed solvent with water, optimum solvent are the mixed solvent of ethyl alcohol and water, and ethyl alcohol and water optimum volume ratio are 2-3:1；It is molten The envelope-bulk to weight ratio of agent and S-3- (4- acetylamino phenyl) piperidines is 3-8:1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778193A (en) * 2021-03-23 2021-05-11 康化（上海）新药研发有限公司 Synthesis method of (S) -3- (4-chlorphenyl) -piperidine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557674A (en) * 2015-01-13 2015-04-29 江苏中邦制药有限公司 Preparation method of (S)-N-Boc-3-hydroxypiperidine
CN104876869A (en) * 2011-12-22 2015-09-02 四川科伦药物研究院有限公司 Resolution method for chiral Fenoldopam
CN106432058A (en) * 2016-09-17 2017-02-22 青岛云天生物技术有限公司 Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline
CN106496187A (en) * 2016-09-14 2017-03-15 陕西科技大学 A kind of synthetic method for preparing PARP inhibitor Niraparib
CN106749181A (en) * 2016-12-21 2017-05-31 南京艾德凯腾生物医药有限责任公司 A kind of method for preparing Ni Lapani
CN108203404A (en) * 2018-03-02 2018-06-26 上海博邦医药科技有限公司 (R) synthetic method of -3- Phenylpiperidines or/and the chiral intermediate of (S) -3- Phenylpiperidines and Ni Lapani

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104876869A (en) * 2011-12-22 2015-09-02 四川科伦药物研究院有限公司 Resolution method for chiral Fenoldopam
CN104557674A (en) * 2015-01-13 2015-04-29 江苏中邦制药有限公司 Preparation method of (S)-N-Boc-3-hydroxypiperidine
CN106496187A (en) * 2016-09-14 2017-03-15 陕西科技大学 A kind of synthetic method for preparing PARP inhibitor Niraparib
CN106432058A (en) * 2016-09-17 2017-02-22 青岛云天生物技术有限公司 Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline
CN106749181A (en) * 2016-12-21 2017-05-31 南京艾德凯腾生物医药有限责任公司 A kind of method for preparing Ni Lapani
CN108203404A (en) * 2018-03-02 2018-06-26 上海博邦医药科技有限公司 (R) synthetic method of -3- Phenylpiperidines or/and the chiral intermediate of (S) -3- Phenylpiperidines and Ni Lapani

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DEBRA J. WALLACE，ET AL.: "Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor", 《ORGANIC PROCESS RESEARCH & DELVELOPMENT》 *
许苗军等: "《有机化学实验》", 31 July 2017, 中国农业大学出版社 *
黄培强等: "《有机合成》", 28 February 2005, 高等教育出版社 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778193A (en) * 2021-03-23 2021-05-11 康化（上海）新药研发有限公司 Synthesis method of (S) -3- (4-chlorphenyl) -piperidine
CN112778193B (en) * 2021-03-23 2024-03-12 康化（上海）新药研发有限公司 Synthesis method of (S) -3- (4-chlorophenyl) -piperidine

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