Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate, which comprises the steps of taking (5R) -2-methyl-5-amino-1-benzylpiperidine or salts thereof as raw materials, carrying out substitution reaction, resolution, Ts protection removal and benzyl removal to obtain a target compound (2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09), and carrying out amidation on the compound 09 to obtain PF-06651600.
In a first aspect, the present invention provides a process for the preparation of intermediate compound 09. A process for preparing compound 09, which comprises reacting compound 08 in a reaction solvent under the action of a catalyst and hydrogen to obtain compound 09,
wherein the catalyst is palladium hydroxide/carbon, palladium dichloride (PdCl)2) At least one of; the method has mild reaction conditions and easy operation, and the prepared compound 09 has high purity and high yield, and is suitable for industrial production.
In some embodiments, the mass ratio of compound 08 to catalyst is from 1:0.05 to 1: 0.2; or the mass ratio is 1:0.1-1: 0.5; or the mass ratio is 1:0.2-1: 0.4. The catalyst with the proportion can better catalyze the reaction to prepare the compound 09.
In some embodiments, the reaction solvent is at least one of isopropanol, n-propanol, methanol, ethanol. The reaction condition is mild, the reagent is easy to obtain, and the method is suitable for industrial production.
In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
In a second aspect, the present invention provides a process for preparing intermediate compound 08, which comprises reacting compound 07 with a base to obtain compound 08,
the method can obtain a compound 08 with a novel structure, and can better prepare a target compound.
In some embodiments, the base is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium carbonate, potassium carbonate;
in some embodiments, the molar ratio of compound 07 to base is from 1:1.0 to 1: 2.0; or the molar ratio is 1:1.2-1: 1.5.
In some embodiments, the reaction solvent of the reaction is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, DMF.
In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 100 ℃; or the reaction temperature is 50-80 ℃.
In some embodiments, the compound 07 can be obtained by resolution of compound 06,
in some embodiments, the compound 06 is resolved with a resolving agent, L-DBTA, using methanol or acetone as a solvent.
In some embodiments, the compound 06 is resolved with a resolving agent, L-DTTA, using methanol or acetone as a solvent.
In some embodiments, the reaction temperature for the resolution is from 40 ℃ to 80 ℃; or the reaction temperature is 50-70 ℃.
In some embodiments, the resolving agent equivalent weight is from 0.5eq to 1.0 eq.
In a third aspect, the present invention provides a process for preparing intermediate compound 06, which comprises reacting compound 05 with 4-chloro-7-tosyl-7H-pyrrolo [2,3-D ] pyrimidine in the presence of a base to obtain compound 06,
the method can obtain the compound 06 with a novel structure, and can better prepare a target compound.
In some embodiments, in the method of preparing intermediate compound 06, the base is at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate;
in some embodiments, in the process for preparing intermediate compound 06, the reaction solvent for the reaction is water;
in some embodiments, in the method of preparing intermediate compound 06, the reaction temperature of the reaction is between 50 ℃ and 180 ℃; or the reaction temperature is 80-150 ℃; or the reaction temperature is 100-130 ℃.
In some embodiments, in the process for preparing intermediate compound 06, a salt of compound 05 is reacted with the base to produce compound 5.
In a fourth aspect, the present invention provides a compound of the formula,
the compound has a novel structure, and can be used for better preparing a target compound and obtaining PF-06651600.
A fifth aspect. The invention provides a method for preparing a compound PF-06651600, which comprises the steps of reacting a compound 09 with acryloyl chloride or acrylate in a reaction solvent in the presence of alkali to obtain a compound PF-06651600,
wherein the reaction solvent can be at least one of water and tetrahydrofuran,
in some embodiments, the base may be at least one of sodium bicarbonate, potassium phosphate, potassium hydrogen phosphate, sodium carbonate,
in some embodiments, the reaction may be at a reaction temperature of-10 ℃ to 50 ℃, or at a reaction temperature of 0 ℃ to 30 ℃, or at a reaction temperature of 10 ℃ to 20 ℃.
The compound PF-06651600 obtained by the method has high yield, high purity and mild reaction conditions, and is suitable for industrial production.
In some embodiments, a method for preparing a PF-06651600 intermediate is provided by the following reaction scheme:
the resolving agent used in the preparation method is low in price, expensive reagents are avoided, the resolving safety is high, the reaction is mild, the reagents are easy to obtain, the product purity is high, the yield is high, the operation is safe, the column chromatography purification is avoided, and the industrial production is facilitated.
In a sixth aspect, the present invention provides a process for preparing compound 05, which comprises reacting compound 04 with an acid to prepare compound 05 or a salt thereof,
wherein the acid is hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or sulfuric acid. The method is beneficial to further preparing the compound 04 to obtain the compound 05 with a novel structure, so that PF-06651600 is easier to obtain, and the method has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the compound 04 to acid molar ratio is from 1:1 to 1: 6; or the molar ratio is 1:2-1: 5.
In a seventh aspect, the present invention provides a process for preparing intermediate compound 04. A process for preparing compound 04 includes reaction between compound 03 and phenylmethylamine in reaction solvent, post-treating to obtain compound 04,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 04 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of making compound 04, the reaction solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, ethylene glycol dimethyl ether. The method has the advantages of mild reaction conditions, safe operation, easily obtained reagents and low production cost.
In some embodiments, the molar ratio of compound 03 to benzylamine is from 1:1 to 1: 20; or the molar ratio is 1:5-1: 15; or mole of
The ratio was 1: 10.
In some embodiments, in the method of making compound 04, the reaction temperature of the reaction is between 20 ℃ and 80 ℃.
In some embodiments, in the method of making compound 04, the reaction time of the reaction is 4 hours to 48 hours; or the reaction time is 12 to 40 hours; or the reaction time is 24 hours to 30 hours.
In an eighth aspect, the present invention provides a process for preparing compound 03, which comprises reacting compound 02 with R-Cl in the presence of a base to obtain compound 03,
wherein R is a leaving group which may be methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The method is beneficial to obtaining the intermediate compound 03 with a novel structure, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, in the method of preparing compound 03, the base is at least one of triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate.
In some embodiments, the molar ratio of compound 02 to base is from 1:2 to 1: 3. The method is favorable for better enabling the compound 02 to react completely and obtaining the target compound with high yield.
In some embodiments, in a method of making compound 03, the reaction temperature of the reaction is-10 ℃ to 10 ℃; or the reaction temperature is 0-10 ℃.
In a ninth aspect, the present invention provides a process for preparing compound 02, which comprises reacting compound 01 with a reducing agent in a solvent to obtain compound 02,
wherein the reducing agent is sodium borohydride, potassium borohydride, red aluminum, lithium aluminum hydride (LiAlH)4). The method is beneficial to obtaining the intermediate compound 02 with a novel structure, ensures the raw material of the compound 03 to be obtained, and has the advantages of mild reaction conditions, safe operation and low production cost.
In some embodiments, the molar ratio of compound 01 to reducing agent is from 1:3 to 1: 8; or the molar ratio is 1:4-1: 5.
In some embodiments, in the method of making compound 02, the solvent is at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran.
In some embodiments, in the method of making compound 02, the reaction temperature of the reaction is between-10 ℃ and 10 ℃.
In a tenth aspect, the present invention provides a compound selected from the group consisting of the compounds of the formula,
wherein R is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. The compound has a novel structure, is favorable for better preparing a target compound and is favorable for preparing PF-06651600.
In some embodiments, a method for preparing a PF-06651600 intermediate is provided by the following reaction scheme:
wherein R is a leaving group which is methylsulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
The reaction route takes D-Boc-pyroglutamic acid ethyl ester as a raw material, and PF-06651600 is obtained through format ring opening, reduction reaction, hydroxyl sulfonylation, cyclization, deprotection and/or salification, substitution reaction, resolution, Ts removal protection, debenzylation and amidation. The preparation method has the advantages of low cost and production cost reduction, and the chiral center is introduced into the raw material, so that the pressure of subsequent compounds to be resolved is reduced. The preparation method has the advantages of mild reaction conditions, easily obtained reagents, high product purity, high yield and safe operation, and can be used for industrial production.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the terms "some embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound 01" and "compound represented by formula (01)" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means hour, g means g, ml means ml, eq means equivalent, M means mol/L, THF means tetrahydrofuran, 2Me-THF means 2-methyltetrahydrofuran, MeOH means methanol, EtOH means ethanol, CH means3CN represents acetonitrile, DCM represents dichloromethane, DMF represents N, N-dimethylformamide, EA represents ethyl acetate, Boc2O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, NaBH4Represents sodium borohydride, NaOH represents sodium hydroxide, Ms represents methylsulfonyl, Ts or Tos represents p-toluenesulfonyl, L-DBTA represents L- (-) -dibenzoyltartaric acid monohydrate, L-DTTA represents di-p-methylbenzyltartaric acid, NaBH4Denotes sodium borohydride, NH4Cl represents ammonium chloride, NaHCO3Denotes sodium bicarbonate, Na2CO3Representing sodium carbonate, DME glycol dimethyl ether, palladium hydroxide/C palladium hydroxide/carbon and TEA triethylamine.
EXAMPLE 1 preparation of (R) -2- (N-Boc-amino) -5-carbonyl-hexanoic acid ethyl ester (Compound 01)
Under the protection of nitrogen, 60g (1.0eq, 233.2mmol) of Boc-D-pyroglutamic acid ethyl ester and 500ml of THF are sequentially added into a 1000ml three-neck flask, stirred at room temperature, dissolved and cleared, cooled to-40 ℃, slowly added with 110ml (1.4eq, 330mmol) of MeMgBr format reagent, slowly heated to-20 ℃ after finishing dropping, and subjected to TLC central control. After the reaction of the raw materials is finished, 300ml of saturated NH is added dropwise4And (3) quenching the Cl solution, separating liquid, extracting an aqueous phase by 300ml of ethyl acetate, combining organic phases, washing the organic phases by 500ml of water once, performing decompression spin-drying, adding 300ml of N-heptane, cooling, crystallizing, stirring, filtering and drying to obtain 63.7g of (2R) -2- (N-Boc-amino) -5-carbonyl-ethyl hexanoate as an off-white solid with the yield of 93%. GC-MS: M/z:274.1(M +),1H NMR(400MHz,CDCl3)δ5.16(d,J=6.5Hz,1H),4.15(q,J=7.1Hz,3H),2.61–2.41(m,2H),2.16–2.02(m,4H),1.84(td,J=14.4,8.0Hz,1H),1.40(s,9H),1.24(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ207.32,172.27,155.42,79.76,61.33,52.92,39.29,29.85,28.22,26.46,14.07。
EXAMPLE 2 preparation of (R) -2- (N-Boc-amino) -1, 5-hexanediol (Compound 02)
Adding 0160 g (1.0eq, 219.5mmol) of compound and a mixture of 240ml of absolute ethanol and 240ml of THF into a 1000ml four-mouth bottle at room temperature, stirring for dissolving, cooling to-5 ℃, and adding 33.2g (4.0eq, 878mmol) of NaBH in batches4Stirring for 2h under the condition of heat preservation, slowly heating to room temperature for reaction, controlling by TLC until the raw materials completely react, cooling to-10 ℃, slowly dropwise adding 300ml of saturated ammonium chloride solution to quench the reaction, separating out a large amount of solids, filtering, extracting the filtrate with 300ml of EA, spin-drying, adding 200ml of dissolved solution, adding 200ml of DCM for extraction twice, spin-drying under reduced pressure, adding N-heptane for low-temperature crystallization, carrying out suction filtration, and carrying out vacuum pumping on the solids to obtain 46.1g of (2R) -2- (N-Boc-amino) -1, 5-hexanediol white solids with the yield of 90%. GC content is 100%. LC-MS, M/z (ESI), 256.3(M + Na)+)+,1H NMR(400MHz,CDCl3)δ5.07(s,1H),3.81(dd,J=11.1,5.0Hz,1H),3.70(dd,J=13.9,7.0Hz,1H),3.59(s,2H),3.18(d,J=27.1Hz,1H),2.70(s,1H),1.77–1.46(m,4H),1.44(s,9H),1.19(d,J=6.1Hz,3H)。
EXAMPLE 3 preparation of (R) -1, 5-dimethylsulfonic acid-2- (N-Boc-amino) hexane (Compound 03-Ms)
Under the protection of nitrogen, 0245 g (1.0eq, 192.9mmol) of the compound and 250ml of DCM are added into a 1000ml four-opening bottle, the mixture is stirred and dissolved at room temperature, the temperature is reduced to 0 ℃, 48.8g (2.5eq, 482.2mmol) of TEA is added, the mixture is stirred for 0.5h, the reaction temperature is controlled to be lower than 0 ℃, a DCM solution of 48.6g (2.2eq, 424.4mmol) of MsCl is added dropwise, the mixture is kept warm after the dropwise addition, TLC is monitored until the raw materials are completely reacted, 250ml of water is added for quenching, liquid separation is carried out, the DCM layer is washed once by using 250ml of saturated NaHCO3 and aqueous solution respectively, and the mixture is reduced in pressure and rotary evaporated to dryness at room temperature to obtain 72.8g of (R) -1, 5-dimethyl sulfonic acid-2- (N-Boc-amino) hexane. LC-MS, M/z (ESI), 412.0(M + Na)+)+,1H NMR(400MHz,CDCl3)δ4.82(d,J=8.8Hz,2H),4.20(dd,J=14.4,10.6Hz,2H),3.86(d,J=28.2Hz,1H),3.02(d,J=10.6Hz,6H),1.70(dd,J=23.5,14.0Hz,4H),1.50–1.36(m,12H).
EXAMPLE 4 preparation of (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine (Compound 04)
Under the protection of nitrogen, 198mL (10eq,1797mmol) of benzylamine is added into a 1000mL three-necked bottle, the temperature is raised to 45 ℃ under the protection of nitrogen, 70g of compound 03-Ms (1.0eq,179.8mmol) are dissolved in 140mL of 2-MeTHF, the 2-MeTHF is slowly dripped into the system of the benzylamine, the temperature is raised to 60 ℃ after the dripping is finished, the reaction is carried out for 24-48h, the TLC is controlled to be finished, the solvent is removed by reduced pressure distillation, 200mL of DCM is added, the temperature is reduced to 0 ℃, glacial acetic acid is dripped to adjust the system to be neutral, 200mL of water is used for washing three times, the DCM is dried by reduced pressure rotation, and (5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine brown yellow oily46.5g, yield 85%. The oil was used directly in the next reaction. LC-MS M/z (ESI) 305.3(M + H)+,1H NMR(400MHz,CDCl3)δ7.41–7.30(m,5H),5.48(d,J=5.7Hz,1H),4.52(s,1H),4.06(d,J=13.5Hz,1H),3.76(s,1H),3.32(d,J=13.5Hz,1H),2.71(d,J=11.2Hz,1H),2.41(dd,J=12.3,6.1Hz,1H),2.25(d,J=10.4Hz,1H),1.76(d,J=11.7Hz,1H),1.60(dd,J=10.4,6.5Hz,2H),1.44(s,9H),1.24(d,J=5.8Hz,3H).
EXAMPLE 5 preparation of (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride (Compound 05 hydrochloride)
At room temperature, adding EA140mL into a 500mL single-neck bottle containing 0446.5 g of 1.0eq, 152.7mmol) of the compound to dissolve, dropwise adding 230mL (4.5eq,690mmol) of 3M HCl solution of EA, stirring at room temperature for removing Boc salt, monitoring by HPLC until the reaction is complete, transferring the reaction solution into a 1000mL four-neck bottle, adding 370mL of water, stirring, separating, washing the aqueous phase once with 370mL of EA to obtain a pale yellow (5R) -2-methyl-5-amino-1-benzylpiperidine hydrochloride aqueous solution, wherein the yield is 100% of theoretical yield, and directly using the solution in the next reaction. LC-MS M/z (ESI) 205.2(M + H)+,1H NMR(400MHz,MeOD)δ7.35(dt,J=14.8,7.2Hz,4H),7.25(t,J=7.0Hz,1H),4.03(d,J=13.2Hz,1H),3.28(s,1H),2.73(dd,J=12.4,5.2Hz,1H),2.59(s,1H),2.39(dd,J=12.4,2.6Hz,1H),1.87–1.69(m,3H),1.62(dt,J=21.9,8.0Hz,1H),1.34(dd,J=19.9,7.4Hz,2H),1.24(d,J=6.3Hz,3H)。
EXAMPLE 6 preparation of (5R) -5- ((7-tosyl-7H-pyrrolo [2,3] pyrimidine) amino) -2-methyl-1-benzylpiperidine (Compound 06)
To a 1000ml four-necked flask containing an aqueous solution of Compound 05-HCl at room temperature, Na was added2CO3Adjusting pH to neutral, adding Na2CO325.9g(1.6eq,244.4mmol), dissolved with stirring for 0.5H, and added with 4-chloro-7-tosyl-7H-pyrrole [2,3-D ]]46g (0.98eq, 149mmol) of pyrimidine, stirring at room temperature for 0.5H, heating to 120 ℃, stirring overnight, controlling the reaction in HPLC to be complete, cooling to 60 ℃, dropwise adding 370ml of EA, continuing to stir and cool to room temperature after dropwise adding, separating liquid, extracting the aqueous phase once with 200ml of EA, combining EA layers, washing the organic phase twice with 300ml of water, and performing reduced pressure spin-drying to obtain (5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine foamy solid 57.8g, yield 80%, purity 95%. LC-MS M/z (ESI) 476.2(M + H)+,1H NMR(400MHz,DMSO)δ8.13(d,J=5.3Hz,1H),7.93(t,J=8.2Hz,2H),7.50(dt,J=20.7,8.4Hz,2H),7.44–7.34(m,2H),7.26(t,J=4.7Hz,3H),7.15(dt,J=22.7,7.0Hz,2H),6.88(d,J=32.2Hz,1H),4.14(d,J=29.3Hz,1H),3.94(d,J=13.8Hz,0.5H),3.19(d,J=13.8Hz,0.5H),2.93–2.71(m,1H),2.44(d,J=7.7Hz,1H),2.33(s,3H),1.82(dd,J=25.6,14.9Hz,1H),1.76–1.49(m,3H),1.40–1.25(m,1H),1.08(dd,J=47.6,6.2Hz,3H)。
EXAMPLE 7 preparation of (2S,5R) -5- ((7-tosyl-7H-pyrrolo [2,3] pyrimidine) amino) -2-methyl-1-benzylpiperidine (Compound 07)
Adding 500mL of methanol and 24.5g (0.65eq, 68mmol) of L-DBTA24 into a 1000mL single-neck bottle filled with 0650g (1.0eq, 105mmol) of the compound at room temperature, stirring and dissolving, heating to 40-80 ℃, reacting for 12-48h, separating out a large amount of solid, cooling to room temperature, crystallizing, stirring for 4-8h, filtering, leaching with methanol, adding DCM300mL and 5% Na into the solid2CO3The solution (300 ml) is stirred and dissolved, separated, washed and the DCM layer is dried by spinning under reduced pressure to obtain (2S,5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine as a white foamy solid 20.5g in 41% yield with 98% purity ee>98.5%。LC-MS:m/z(ESI):476.2(M+H)+,1H NMR(400MHz,DMSO)δ8.13(s,1H),7.93(d,J=8.2Hz,2H),7.69(d,J=6.5Hz,1H),7.52(d,J=3.8Hz,1H),7.41(d,J=8.1Hz,2H),7.27(d,J=7.2Hz,2H),7.16(dt,J=23.7,7.0Hz,3H),7.03(s,1H),4.18(s,1H),2.80(d,J=6.0Hz,1H),2.46(d,J=6.5Hz,2H),2.34(s,3H),1.67(t,J=20.0Hz,2H),1.56(d,J=9.1Hz,1H),1.22(s,3H),1.02(d,J=6.4Hz,3H)。
Adding 50mL of acetone and 2.45g (0.65eq, 6.8mmol) of L-DBTA into a 1000mL single-neck flask containing 065 g (1.0eq, 10.5mmol) of the compound at room temperature, stirring for dissolving, heating to 40-80 ℃, reacting for 12-48h, precipitating a large amount of solid, cooling to room temperature, crystallizing, stirring for 4-8h, filtering, leaching with acetone, adding 30mL of DCM and 5% of Na into the solid, stirring for 4-8h, filtering, leaching with acetone, and adding 30mL of DCM and 5% of Na into the solid2CO3The solution (30 ml) is stirred and dissolved, separated, washed and the DCM layer is dried by spinning under reduced pressure to obtain (2S,5R) -5- ((7-tosyl-7H-pyrrole [2,3]]Pyrimidine) amino) -2-methyl-1-benzylpiperidine 1.8g as a white foamy solid in 36% yield and 97% purity ee>98%。LC-MS:m/z(ESI):476.2(M+H)+。
EXAMPLE 8 preparation of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1-benzylpiperidine (Compound 08)
At room temperature, 150mL of 2-MeTHF and 150mL of NaOH2.18g (1.3eq, 54.5mmol) are added into a 500mL single-neck bottle containing 0720 g (1.0eq, 26.4mmol) of the compound, stirred and dissolved, the temperature is raised to 50-90 ℃, the reaction is controlled to be complete in HPLC, the temperature is reduced, the pressure is reduced, the mixture is dried, 100mL of DCM and 100mL of water are added, stirred and extracted, liquid separation is carried out, the organic phase is washed once by 100mL of water, and the pressure is reduced, so that 12.8g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1-benzylpiperidine is obtained as a light brown solid, the yield is 95%, and the purity is 98%. LC-MS M/z (ESI) 322.25(M + H)+,1H NMR(400MHz,MeOD)δ8.06(d,J=10.7Hz,1H),7.39(d,J=7.1Hz,2H),7.29(t,J=7.2Hz,2H),7.26–7.21(m,1H),7.09(t,J=6.7Hz,1H),6.59(d,J=3.0Hz,1H),4.33(s,1H),4.05(t,J=14.0Hz,1H),3.51(d,J=12.9Hz,1H),2.83(dd,J=11.7,6.3Hz,1H),2.77(s,1H),2.62(d,J=10.9Hz,1H),1.94–1.64(m,4H),1.27(d,J=6.4Hz,3H).。
Example 9(2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine (compound 09)
At room temperature, 125mL of isopropanol, 10-20% of palladium hydroxide/C (relative to the mass ratio of the compound 08), 2.6g of glacial acetic acid (1.1eq, 43.3mmol) and 12.5mL of water are added into a 250mL single-neck bottle containing 0812.5 g of the compound (1.0eqq, 38.9mmol), hydrogen is replaced, normal pressure hydrogenation is carried out, the mixture is heated to 50-80 ℃ for reaction, HPLC is controlled to be complete in reaction, suction filtration is carried out, a filter cake is leached by isopropanol, and filtrate is obtained to be dried by spinning to obtain 9g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methylpiperidine light brown solid, the yield is 95.0%, and the purity is 98%. LC-MS M/z (ESI) 232.3(M + H)+。
EXAMPLE 10 preparation of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine (Compound PF-06651600)
To a 250ml single-neck flask containing 099 g (1.0eq, 38.9mmol) of compound was added saturated NaHCO at room temperature3Cooling 90ml of solution and 90ml of THF (tetrahydrofuran), slowly dropwise adding 4.23g (1.2eq, 46.7mmol) of acryloyl chloride at 0-20 ℃, controlling the reaction temperature to be complete in HPLC (high performance liquid chromatography), transferring to a 500ml reaction bottle, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M (1eq, 39mmol) of EA solution for salification, controlling in TLC (thin layer chromatography), adding 100ml of water for extraction twice, combining water phase and saturated NaHCO, and performing liquid-liquid separation3Adjusting the pH value to be neutral, cooling, crystallizing, filtering, and drying to obtain 9.4g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine white solid with the yield of 84.7%, the purity of 99% and the ee value of 99%. LC-MS M/z (ESI) 286.3(M + H)+,1H NMR(400MHz,DMSO)δ11.53(s,1H),8.10(d,J=10.8Hz,1H),7.47–7.25(m,1H),7.08(s,1H),6.80(dd,J=30.9,17.3Hz,1H),6.58(s,1H),6.09(dd,J=16.7,2.0Hz,1H),5.67(dd,J=10.5,1.9Hz,1H),4.79(s,0.5H),4.54(d,J=13.2Hz,0.5H),4.37(s,0.5H),4.21–3.94(m,1.5H),3.07–2.89(m,0.5H),2.63(dd,J=23.2,11.5Hz,0.5H),1.94–1.54(m,4H),1.20(dd,J=22.4,6.5Hz,3H).
To a 250ml single-neck flask containing 099 g (1.0eq, 38.9mmol) of compound was added saturated NaHCO at room temperature3Cooling 90ml of solution and 90ml of THF (tetrahydrofuran), slowly dropwise adding 4.67g of acryloyl ethyl ester (1.2eq, 46.7mmol) at 0-20 ℃, controlling the reaction in HPLC (high performance liquid chromatography) until the reaction is complete, transferring to a 500ml reaction bottle, adding 100ml of EA for extraction twice, combining organic layers, cooling, dropwise adding 13ml of 3M hydrochloric acid (1eq, 39mmol) EA solution for salification, controlling in TLC (thin layer chromatography), adding 100ml of water for extraction twice, combining water phase and saturated NaHCO, and performing combined extraction3Adjusting the pH value to be neutral, cooling, crystallizing, filtering, and drying to obtain 8.9g of (2S,5R) -5- ((7H-pyrrole) amino) -2-methyl-1- (3-acryloyl) piperidine white solid with the yield of 80.2%, the purity of 95% and the ee value of 98%. LC-MS M/z (ESI) 286.3(M + H)+。
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.