CN109796457B - Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol - Google Patents

Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol Download PDF

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CN109796457B
CN109796457B CN201910244644.8A CN201910244644A CN109796457B CN 109796457 B CN109796457 B CN 109796457B CN 201910244644 A CN201910244644 A CN 201910244644A CN 109796457 B CN109796457 B CN 109796457B
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梅德盛
刘爱风
孙靖
汪奎
孙高睿
陈林瑞
施佳
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Suzhou State Pharmaceutical Technology Co Ltd
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Abstract

The invention provides a 2- (3- (azetidin-3-yl) piperidine-1-yl group) A process for the preparation of ethyl-1-ol, characterized in that it comprises the following steps: (1) reacting the compound 2 with 2-halogenated ethanol in a solvent to obtain a compound 3; (2) carrying out hydrogenation reaction on the compound 3 under the action of a catalyst to obtain a compound 4; (3) removing Boc protecting group of the compound 4 under the condition of acid, and removing acid in vacuum or neutralizing with alkali to obtain a compound 1, namely 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, wherein the reaction synthesis route is as follows:
Figure DDA0002010710020000011
wherein X is a halogen atom. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple and convenient operation and high yield.

Description

Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol
Technical Field
The invention relates to a preparation method of a medical intermediate, in particular to a preparation method of 2- (3- (azetidine-3-yl) piperidine-1-yl) ethyl-1-ol and application thereof in preparing an anti-tumor medicament.
Background
Regulatory T cells (T)reg) Has important function in tumor immunity. CCR4 (chemokine receptor 4) antagonists selectively inhibit T in tumor tissueregAnd can generate durable anti-tumor immune response, which is an important component of small-molecule tumor immunity. ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b]Pyrazine-3-carbonitrile (compound 6) is an orally effective CCR4 antagonist (WO2018/022922A 1). In preclinical studies, given aloneThe compound 6 can effectively inhibit the growth of tumors; when administered in combination, Compound 6 significantly enhances the anti-tumor effects of immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA4, as well as immune agonists such as anti-4-1 BB. Compound 6 can also enhance the immunotherapeutic effect of cell-based therapeutic strategies such as CAR-T and tumor vaccines. CCR4 antagonists, represented by compound 6, have now entered clinical studies in tumor immunotherapy and have shown good therapeutic efficacy, and the structure of compound 6 is as follows:
Figure BDA0002010708000000011
2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol (compound 1) is an important intermediate in step N-1 for the preparation of ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile (compound 6), the structure of compound 1 being:
Figure BDA0002010708000000021
patent WO2018/022992a1 discloses that 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol (compound 1) is prepared by the following method: 3- (piperidin-3-yl) azetidinyl-1-carboxylic acid tert-butyl ester (1251006-73-1) (Compound 7) reacted with 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde and then passed through NaBH (OAc)3Reducing to obtain a compound 8; then, compound 8 is deprotected under acidic conditions to give compound 1.
Figure BDA0002010708000000022
However, commercial tert-butyl 3- (piperidin-3-yl) azetidinyl-1-carboxylate (compound 7) is extremely difficult to obtain and has a significant problem of high cost performance even if it is available; the high procurement costs of the starting material (compound 7) necessarily lead to a drastic increase in the production costs of the final target product, such as the clinical drug compound 6.
Meanwhile, there is no literature on the preparation of compound 7And (6) reporting. In earlier studies, the Applicant has sought to use tert-butyl 3- (pyridin-3 yl) azetidinyl-1-carboxylate (Compound 2) in platinum/palladium catalysts such as PtO2,Pd(PPh3)4，Pd(OAC)2Catalytic hydrogenation was carried out under high pressure (80atm) and long-term (60 hours) heating (80 ℃) under the same conditions, and the target product, i.e., tert-butyl 3- (pyridin-3 yl) azetidinyl-1-carboxylate (compound 7), was not obtained.
Figure BDA0002010708000000031
Therefore, the method for preparing the 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol (compound 1) is economical, mild and simple and has important practical value.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the invention provides a method for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol (compound 1) with cheap and easily obtained reaction raw materials, mild reaction conditions, simple process and high yield.
Means for solving the problems
In order to solve the technical problems, the invention provides the following technical scheme:
a process for the preparation of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, comprising the steps of:
(1) reacting the compound 2 with 2-halogenated ethanol in a solvent to obtain a compound 3;
(2) carrying out hydrogenation reaction on the compound 3 under the action of a catalyst to obtain a compound 4;
(3) removing Boc protecting group of the compound 4 under the condition of acid, and removing acid in vacuum or neutralizing with alkali to obtain a compound 1, namely 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, wherein the reaction synthesis route is as follows:
Figure BDA0002010708000000041
wherein X is a halogen atom.
Preferably, in the step (1), the halogen atom X in the 2-halogenated ethanol is chlorine, bromine or iodine, the molar ratio of the compound 2 to the 2-halogenated ethanol is 1: 0.5-3, and the reaction temperature is 25-120 ℃.
Preferably, the solvent in step (1) is an organic solvent, preferably one or more selected from acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran.
Preferably, the catalyst in step (2) is a platinum and/or palladium containing catalyst, preferably PtO2、Pd-C、Pd(OAc)2、Pd(PPh3)4、Pd2(dba)3、Pd(dba)2、PdCl2Or PdCl2(dppf), more preferably PtO2The mass ratio of the catalyst to the compound 3 is 0.1-20%.
Preferably, the reaction in the step (2) is carried out under 1-5 atmospheric pressures, preferably normal pressure, and the reaction temperature is 20-120 ℃.
Preferably, the acid catalyst in step (3) is a protic acid, preferably TFA or HCl; the reaction solvent is an organic solvent, preferably dichloromethane, 1, 4-dioxane or water; the base is inorganic base or organic base, preferably one or more of ammonia water, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or di (isopropyl) ethylamine.
Preferably, the acid and reaction solvent in step (3) is TFA/DCM, HCl/1, 4-dioxane or HCl/H2Any one of O.
Preferably, the reaction temperature in the step (3) is 0-100 ℃, and preferably room temperature.
The present invention also provides a process for the preparation of ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile comprising:
(1) a step of preparing compound 1 by the method according to any one of claims 1 to 8;
(2) compound 1 and compound 5 the procedure for the preparation of compound 6, i.e., ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile, under the action of a base, which is an organic or inorganic base, is as follows:
Figure BDA0002010708000000051
preferably, the catalyst in the step (2) is organic base, the reaction temperature is 10-40 ℃, and room temperature is preferred.
ADVANTAGEOUS EFFECTS OF INVENTION
1. The invention solves the problems that the raw materials are difficult to obtain and the price is high in the process of synthesizing 2- (3- (azetidine-3-yl) piperidine-1-yl) ethyl-1-ol in the prior art, and the reagents used in the invention, such as 2-iodoethanol, 10% Pd-C and acids, such as trifluoroacetic acid or hydrochloric acid, are conventional reagents which are cheap and easy to obtain;
2. the present inventors have found that the salification of pyridine gives the product of the hydrogenation reaction in a mild and high yield, e.g. at atmospheric pressure, using a specific catalyst comprising platinum and/or palladium, e.g. PtO2、Pd-C、Pd(OAc)2Or PdCl2Preferably PtO2Excellent reaction yield can be obtained, the compound 1 is obtained from the compound 2 through 3 steps of reaction, and the total yield is up to more than 82%;
3. the process for synthesizing the 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol has simple process steps and simple and convenient operation, all the steps do not need special purification and can be directly reacted in the next step, and meanwhile, the 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol prepared by the method can be directly used for synthesizing CCR4 antagonists represented by a compound 6.
Drawings
FIG. 1 Mass Spectroscopy of Compound 1;
FIG. 2 nuclear magnetic map of Compound 6;
FIG. 3 mass spectrum of Compound 6.
Detailed Description
The invention provides a preparation method of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, which comprises the following steps:
(1) reacting the compound 2 with 2-halogenated ethanol in a solvent to obtain a compound 3;
(2) carrying out hydrogenation reaction on the compound 3 under the action of a catalyst to obtain a compound 4;
(3) removing Boc protecting group of the compound 4 under the condition of acid, and removing acid in vacuum or neutralizing with alkali to obtain a compound 1, namely 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, wherein the reaction synthesis route is as follows:
Figure BDA0002010708000000061
wherein X is a halogen atom.
In a preferred embodiment, in the step (1), the halogen atom X in the 2-halogenated ethanol is chlorine, bromine or iodine, preferably iodine atom, the molar ratio of the compound 2 to the 2-halogenated ethanol is 1: 0.5-3, preferably 1: 1-2, and the reaction temperature is 25-120 ℃, preferably 50-100 ℃.
In a preferred embodiment, the solvent in step (1) is an organic solvent, preferably one or more of acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran.
In a preferred embodiment, the catalyst in step (2) is a palladium and/or platinum containing catalyst, preferably PtO2、Pd-C、Pd(OAc)2、Pd(PPh3)4、Pd2(dba)3、Pd(dab)2、PdCl2Or PdCl2(dppf), more preferably PtO2The mass ratio of the catalyst to the compound 3 is 0.1 to 20%, preferably 0.5 to 5%.
In a preferred embodiment, the reaction of step (2) is carried out at 1 to 5 atmospheres, preferably at atmospheric pressure, and the reaction temperature is 20 to 120 ℃, preferably 40 to 60 ℃.
In a preferred embodiment, the acid catalyst in step (3) is a protic acid, preferably TFA or HCl, preferably in excess relative to compound 4; the reaction solvent is an organic solvent, preferably dichloromethane, 1, 4-dioxane or water; the base is inorganic base or organic base, preferably one or more of ammonia water, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or di (isopropyl) ethylamine.
In a more preferred embodiment, the acid catalyst and reaction solvent in step (3) is TFA/DCM, HCl/1, 4-dioxane or HCl/H2Any one of O.
In a preferred embodiment, the reaction temperature in step (3) is 0 to 100 ℃, preferably room temperature.
The present invention also provides a process for the preparation of ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile comprising:
(1) a step of preparing compound 1 by any of the above methods;
(2) compound 1 and compound 5 the procedure for the preparation of compound 6, i.e., ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile, under the action of a base, which is an organic or inorganic base, is as follows:
Figure BDA0002010708000000081
in a preferred embodiment, the base in step (2) is one or more of ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, ammonia, diethylamine, triethylamine or di (isopropyl) ethylamine, preferably one or more of ammonia, diethylamine, triethylamine or di (isopropyl) ethylamine; the reaction temperature is 10-40 ℃, and room temperature is preferred.
The following examples are for illustrative purposes only and do not limit the scope of the claims provided herein.
Summary of the invention1H-NMR spectra Bruker-400 NMR spectrometer with chemical shifts in parts per million and internal standard tetramethylsilane. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s, single multiplet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak. Mass Spectrometry A Quattro MicroTM API triple quadrupole mass spectrometer was used.
EXAMPLE 1 preparation of Compound 3
Figure BDA0002010708000000082
Tert-butyl 3- (pyridin-3 yl) azetidinyl-1-carboxylate (Compound 2) (1.0g, 4.0mmoL) and 2-iodoethanol (1.1g,6mmoL) were added to acetonitrile (10.0mL) and heated overnight in an 80 ℃ oil bath. TLC detection shows complete reaction, and the solvent is evaporated under reduced pressure. The residue was washed with a mixed system of n-hexane/ethyl acetate (5/1) to remove excess 2-iodoethanol, whereby 1.62g of a brown oil was obtained in 100% yield.
1H NMR(CDCl3,400MHz)δ＝9.23(s,1H),9.04(d,J＝8.0Hz,1H),8.53(d,J＝8.0Hz,1H),8.13(dd,J1＝4.0Hz,J2＝8.0Hz,1H),4.96-4.94(m,2H),4.46(t,J＝8.0Hz,2H),4.16-4.12(m,2H),4.05-4.01(m,2H),3.83(t,J＝4.0Hz,3H),1.45(s,9H)。
EXAMPLE 2 preparation of Compound 4
Figure BDA0002010708000000091
Mixing Compound 3(1.5g,3.74mmoL) with PtO2(0.15g, 10%, w/w) was added to ethanol (10.0mL) and catalytically hydrogenated overnight in an oil bath at 50 ℃ under normal pressure. The reaction was complete by TLC. Filtering to remove catalyst, washing catalyst with ethanol, evaporating the filtrate under reduced pressure to remove solvent, and drying the residue under high vacuum to obtain 980mg of oily substance with yield92 percent. The product was used in the next reaction without purification.
1H NMR(CDCl3,400MHz)δ＝3.98-3.93(m,2H),3.78-3.71(m,2H),3.69-3.65(m,3H),3.11-3.02(m,2H),2.76-2.73(m,2H),2.30-1.77(m,8H),1.43(s,9H).ESI-MS:285.2[M+H]+。
EXAMPLE 3 preparation of Compound 4
Figure BDA0002010708000000092
Except for Pd (OAc)2Substitution of PtO2In addition, the procedure of example 3 was the same as in example 2, and the yield was 90%.
EXAMPLE 4 preparation of Compound 4
Figure BDA0002010708000000101
Except that 10% Pd-C was used instead of PtO2In addition, the procedure of example 4 was the same as in example 2, and the yield was 85%. This reaction may have a problem of poor reproducibility.
EXAMPLE 5 preparation of Compound 1
Figure BDA0002010708000000102
Compound 4(980mg, 3.45mmoL) was added to a mixed solution of trifluoroacetic acid (2.0mL) and dichloromethane (2.0mL), and stirred at room temperature for 2 hours. The reaction was complete by TLC. The solvent was evaporated under reduced pressure and the residue dried under high vacuum in an oil bath at 45 ℃ for more than 3 hours to give 570mg of an oil in 89% yield. The product was used in the next reaction without purification.
1H NMR(DMSO-d6,400MHz)δ＝4.71(t,J＝8.0Hz,1H),3.98-3.70(m,6H),3.50-3.35(m,2H),3.12-3.07(m,1H),2.93-2.78(m,1H),2.65-2.49(m,3H),2.09-2.00(m,1H),1.90-1.82(m,1H),1.73-1.64(m,2H),1.02-0.92(m,1H).ESI-MS:185.0[M+H]+。
EXAMPLE 6 preparation of Compound 1
Figure BDA0002010708000000111
Example 6 was carried out as in example 5, except that HCl/1, 4-dioxane was used instead of trifluoroacetic acid, and the residue was added to water in the workup and neutralized with aqueous ammonia and then water was distilled off by rotation. The yield thereof was found to be 96%.
Example 7 preparation of ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile (Compound 6)
Figure BDA0002010708000000112
Compound 5(130mg,0.37mmoL), Compound 1(136mg,0.74mmoL) and DIPEA (111mg,1.11mmoL) were added to DMF (10 mL). Stir at rt overnight and check by TLC for reaction completion. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography using DCM/MeOH 10/1 to give 137mg of a white solid in 74% yield.
1H NMR(CD3OD,400MHz)δ＝7.92(s,1H),7.45(dd,J1＝J2＝4.0Hz,1H),7.34(dd,J1＝4.0Hz,J2＝8.0Hz,1H),7.28(dd,J1＝4.0Hz,J2＝8.0Hz,1H),6.42(q,J＝8.0Hz,1H),4.30-4.24(m,2H),4.01-3.95(m,2H),3.77(t,J＝8.0Hz,2H),3.69-3.65(m,1H),3.24-3.16(m,1H),2.89(brs,2H),2.64-2.60(m,1H),2.49(brs,1H),2.24(brs,1H),2.00-1.97(m,1H),1.88-1.86(m,5H),1.72-1.65(m,1H),1.10-1.04(m,1H).ESI-MS:500.0[M+H]+. HPLC (chemical purity): 99.3%.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (16)

1. A process for the preparation of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, comprising the steps of:
(1) reacting the compound 2 with 2-halogenated ethanol in a solvent to obtain a compound 3;
(2) carrying out hydrogenation reaction on the compound 3 under the action of a catalyst to obtain a compound 4, wherein the catalyst is a platinum and/or palladium-containing catalyst;
(3) removing Boc protecting group of the compound 4 under the condition of acid, and removing acid in vacuum or neutralizing with alkali to obtain a compound 1, namely 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol, wherein the reaction synthesis route is as follows:
Figure FDA0002346286270000011
wherein X is a halogen atom.
2. The method for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the halogen atom X in the 2-haloethanol in the step (1) is chlorine, bromine or iodine, the molar ratio of the compound 2 to the 2-haloethanol is 1: 0.5-3, and the reaction temperature is 25-120 ℃.
3. The process for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the solvent in step (1) is an organic solvent.
4. The process for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the solvent in step (1) is one or more selected from acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran.
5. The process according to claim 1, wherein the catalyst used in step (2) is PtO2、Pd-C、Pd(OAc)2、Pd(PPh3)4、Pd2(dba)3、Pd(dba)2、PdCl2Or PdCl2(dppf) the mass ratio of the catalyst to the compound 3 is 0.1 to 20%.
6. The process according to claim 5, wherein the catalyst used in step (2) is PtO2。
7. The method for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the reaction in step (2) is carried out under 1 to 5 atmospheres at a temperature of 20 to 120 ℃.
8. The process for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 7, wherein the reaction of step (2) is carried out under normal pressure.
9. The process for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the acid catalyst in step (3) is a protonic acid, the reaction solvent is an organic solvent, and the base is an inorganic base or an organic base.
10. The process according to claim 1, wherein the acid catalyst in step (3) is TFA or HCl, the reaction solvent is dichloromethane, 1, 4-dioxane or water, and the base is one or more of ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or di (isopropyl) ethylamine.
11. The process according to claim 9, wherein the acid and the reaction solvent in step (3) are TFA/DCM, HCl/1, 4-dioxane or HCl/H2Any one of O.
12. The method for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 1, wherein the reaction temperature in step (3) is 0 to 100 ℃.
13. The process for preparing 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol according to claim 12, wherein the reaction temperature in step (3) is room temperature.
14. A process for the preparation of ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile comprising:
(1) a step of preparing compound 1 by the method according to any one of claims 1 to 13;
(2) compound 1 and compound 5 the procedure for the preparation of compound 6, i.e., ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile, under the action of a base, which is an organic or inorganic base, is as follows:
Figure FDA0002346286270000031
15. the method for preparing ((R) -1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile according to claim 14, wherein the catalyst in step (2) is an organic base and the reaction temperature is 10-40 ℃.
16. The process according to claim 14, wherein the reaction temperature in step (2) is room temperature, and wherein the reaction temperature is in the range of from about 1- (2, 4-dichlorophenyl) ethyl) -6- (3- ((R) -1- (2-hydroxyethyl) piperidin-3-yl) azetidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazine-3-carbonitrile.
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