CN109796457A - A kind of preparation method and applications of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol - Google Patents
A kind of preparation method and applications of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol Download PDFInfo
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- CN109796457A CN109796457A CN201910244644.8A CN201910244644A CN109796457A CN 109796457 A CN109796457 A CN 109796457A CN 201910244644 A CN201910244644 A CN 201910244644A CN 109796457 A CN109796457 A CN 109796457A
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- C—CHEMISTRY; METALLURGY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present invention provides a kind of preparation methods of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol, it is characterized in that, the described method comprises the following steps: (1) compound 2 reacts to obtain compound 3 with 2- ethylene halohydrin in a solvent；(2) under the effect of the catalyst, hydrogenated reaction obtains compound 4 to compound 3；(3) compound 4 is removed in vacuum acid after sloughing Boc protecting group or obtains compound 1 through alkali neutralization, is i.e. 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol reacts synthetic route under conditions of acid are as follows:Wherein, X is halogen atom.The method raw material is cheap and easily-available, and reaction condition is mild, easy to operate, high income.
Description
Technical field
The present invention relates to a kind of preparation methods of medicine intermediate, and in particular to a kind of 2- (3- (azetidine -3- base)
Piperidin-1-yl) ethyl -1- alcohol preparation method and its application in preparation of anti-tumor drugs.
Background technique
Regulatory T cells (Treg) play a significant role in tumour immunity.CCR4 (Chemokine receptor4) antagonist energy
Selectively inhibit the T in tumor tissuesreg, and lasting anti tumor immune response can be generated, it is the weight of small molecule tumour immunity
Want component part.((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azepine
Cyclobutane -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN (compound 6) is a kind of orally active CCR4 antagonist
(WO2018/022922A1).In preclinical study, it can effectively inhibit the growth of tumour when being administered alone compound 6；Combine to
When medicine, compound 6 can significantly increase immunologic test point inhibitor such as PD-1/PD-L1 and CTLA4 and immune agonist such as
The antitumous effect of anti-4-1BB.Compound 6 can also enhance is exempted from based on cell therapy strategy such as CAR-T and tumor vaccine
Epidemic disease therapeutic effect.The clinical research of immunotherapy of tumors is entered at present for the CCR4 antagonist of representative with compound 6, and has shown
Good therapeutic effect is shown, the structure of compound 6 is as follows:
2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol (compound 1) is to prepare ((R) -1- (2,4-
Dichlorophenyl) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azetidine -1- base) -1H- pyrazolo
The N-1 of [3,4-b] pyrazine -3- formonitrile HCN (compound 6) walks important intermediate, the structure of compound 1 are as follows:
Patent WO2018/022992A1 discloses 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol and (changes
Close object 1) it is prepared via a method which: 3- (piperidines -3- base) azetidinyl -1- carboxylic acid tert-butyl ester (1251006-73-1)
(compound 7) reacted with 2- ((tert-butyl dimethyl silyl) oxygen) acetaldehyde after through NaBH (OAc)3Reduction obtains compound 8；Then change
It closes object 8 and obtains compound 1 with acid condition Deprotection.
But 3- (piperidines -3- base) azetidinyl -1- carboxylic acid tert-butyl ester (compound 7) extremely difficult acquisition of commercialization, i.e.,
Make can get there is also the prominent questions of price Gao Qi；The purchase cost of starting material (compound 7) is excessively high necessarily to be caused finally
The production cost of target product such as clinical medicine compound 6 sharply rises.
Meanwhile there has been no reported literatures about the preparation of compound 7.Applicant was once explored in early-stage study
With -1 carboxylic acid tert-butyl ester (compound 2) of 3- (- 3 base of pyridine) azelidinyl in platinum/palladium catalysts such as PtO2,Pd(PPh3)4, Pd
(OAC)2Deng under the conditions of with high pressure (80atm), (60 hours) for a long time heating (80 DEG C) carry out catalytic hydrogenation, equal unreacted, not
It can obtain -1 carboxylic acid tert-butyl ester (compound 7) of target product 3- (- 3 base of pyridine) azelidinyl.
Therefore, a kind of warp of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol (compound 1) is explored
Ji, the mildly preparation method with simplicity, have important real value.
Summary of the invention
Problems to be solved by the invention
That in order to solve the above-mentioned technical problems, the present invention provides a kind of reaction raw materials is cheap and easy to get, reaction condition is mild, work
The method that skill is simple and yield highland prepares 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol (compound 1).
The solution to the problem
In order to solve the above-mentioned technical problems, the present invention provides following technical solutions:
A kind of preparation method of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol, which is characterized in that institute
State method the following steps are included:
(1) compound 2 reacts to obtain compound 3 with 2- ethylene halohydrin in a solvent；
(2) under the effect of the catalyst, hydrogenated reaction obtains compound 4 to compound 3；
(3) compound 4 is removed in vacuum acid after sloughing Boc protecting group or obtains chemical combination through alkali neutralization under conditions of acid
Object 1, i.e. 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol reacts synthetic route are as follows:
Wherein, X is halogen atom.
Preferably, the halogen atom X in step (1) in 2- ethylene halohydrin is chlorine, bromine, iodine, compound 2 and 2- ethylene halohydrin
Molar ratio be 1:0.5~3, reaction temperature be 25~120 DEG C.
Preferably, the solvent in step (1) is organic solvent, is preferably selected from acetonitrile, methanol, ethyl alcohol, ether, methyl- tert
Butyl ether, glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2- methyl tetrahydro furan
It one of mutters or a variety of.
Preferably, the catalyst in step (2) is platiniferous and/or palladium catalyst, preferably PtO2、Pd-C、Pd(OAc)2、
Pd(PPh3)4、Pd2(dba)3、Pd(dba)2、PdCl2Or PdCl2(dppf), more preferably PtO2, the matter of catalyst and compound 3
Amount is than being 0.1~20%.
Preferably, the reaction of step (2) carries out under 1~5 atmospheric pressure, preferably normal pressure, and reaction temperature is 20~120
℃。
Preferably, the acid catalyst in step (3) is Bronsted acid, preferably TFA or HCl；Reaction dissolvent is organic solvent,
Preferably methylene chloride, 1,4- dioxane or water；Alkali is inorganic base or organic base, preferably ammonium hydroxide, sodium bicarbonate, carbonic acid
One of sodium, saleratus, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or two (isopropyl) ethylamines
Or it is a variety of.
Preferably, the acid in step (3) and reaction dissolvent are TFA/DCM, HCl/1,4- dioxane or HCl/H2In O
It is any.
Preferably, the reaction temperature in step (3) is 0~100 DEG C, preferably room temperature.
The present invention also provides one kind ((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl)
Piperidines -3- base) azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN preparation method, the method packet
It includes:
(1) the step of method prepare compound 1 described in any item using claim 1-8；
(2) compound 1 and compound 5 prepare compound 6, i.e. ((R) -1- (2,4- dichlorophenyl) second under alkali effect
Base) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -
The step of 3- formonitrile HCN, the alkali are organic base or inorganic base, and reaction route is as follows:
Preferably, the catalyst in step (2) is organic base, and reaction temperature is 10~40 DEG C, preferably room temperature.
The effect of invention
1, the present invention solves prior art synthesis 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol
Raw material is not easy acquisition and expensive problem, reagent such as ethylene iodohydrin, 10%Pd-C and acid used in the present invention in technique
Such as trifluoracetic acid or hydrochloric acid are conventional reagent, cheap and easily-available；
2, the present invention and creatively find pyridine at the product of hydrogenation can be obtained after salt mildly, in high yield,
As under normal pressure, specific catalyst platiniferous and/or palladium catalyst, such as PtO are used2、Pd-C、Pd(OAc)2Or PdCl2, preferably
For PtO2, fabulous reaction yield can be obtained, react to obtain compound 1 from compound 2 through 3 steps, total recovery be up to 82% with
On；
3, the technique of synthesis 2- of the invention (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol, technique step
Rapid simple, easy to operate, all steps are not necessarily to particularly purify, and directly toward the next step, while prepared by the present invention
It is representative that obtained 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol, which is used directly for compound 6,
The synthesis of CCR4 antagonist.
Detailed description of the invention
The mass spectrogram of Fig. 1 compound 1；
The nuclear-magnetism figure of Fig. 2 compound 6；
The mass spectrogram of Fig. 3 compound 6.
Specific embodiment
The present invention provides a kind of preparation method of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol,
It the described method comprises the following steps:
(1) compound 2 reacts to obtain compound 3 with 2- ethylene halohydrin in a solvent；
(2) under the effect of the catalyst, hydrogenated reaction obtains compound 4 to compound 3；
(3) compound 4 is removed in vacuum acid after sloughing Boc protecting group or obtains chemical combination through alkali neutralization under conditions of acid
Object 1, i.e. 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol reacts synthetic route are as follows:
Wherein, X is halogen atom.
In a preferred embodiment, halogen atom X in step (1) in 2- ethylene halohydrin is chlorine, bromine, iodine, excellent
It is selected as iodine atom, the molar ratio of compound 2 and 2- ethylene halohydrin is 1:0.5~3, preferably 1:1~2, reaction temperature is 25~
120 DEG C, preferably 50~100 DEG C.
In a preferred embodiment, the solvent in step (1) is organic solvent, preferably acetonitrile, methanol, second
Alcohol, ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran
Or one of 2- methyltetrahydrofuran or a variety of.
In a preferred embodiment, the catalyst in step (2) is containing palladium and/or platinum catalyst, preferably
PtO2、Pd-C、Pd(OAc)2、Pd(PPh3)4、Pd2(dba)3、Pd(dab)2、PdCl2Or PdCl2(dppf), more preferably PtO2,
The mass ratio of catalyst and compound 3 is 0.1~20%, preferably 0.5~5%.
In a preferred embodiment, the reaction of step (2) carries out under 1~5 atmospheric pressure, preferably under normal pressure
It carries out, reaction temperature is 20~120 DEG C, preferably 40~60 DEG C.
In a preferred embodiment, the acid catalyst in step (3) is Bronsted acid, preferably TFA or HCl, acid
Catalyst is preferably excessive relative to compound 4；Reaction dissolvent is organic solvent, preferably methylene chloride, Isosorbide-5-Nitrae-dioxy six
Ring or water；Alkali is inorganic base or organic base, preferably ammonium hydroxide, sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, hydroxide
One of sodium, potassium hydroxide, calcium oxide, triethylamine or two (isopropyl) ethylamines are a variety of.
In a further preferred embodiment, acid catalyst and reaction dissolvent in step (3) are TFA/DCM, HCl/
1,4- dioxane or HCl/H2Any one of O.
In a preferred embodiment, the reaction temperature in step (3) is 0~100 DEG C, preferably room temperature.
The present invention also provides one kind ((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl)
Piperidines -3- base) azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN preparation method, the method packet
It includes:
(1) the step of using any of the above method prepare compound 1；
(2) compound 1 and compound 5 prepare compound 6, i.e. ((R) -1- (2,4- dichlorophenyl) second in the presence of alkali
Base) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -
The step of 3- formonitrile HCN, the alkali are organic base or inorganic base, and reaction route is as follows:
In a preferred embodiment, alkali in step (2) be ammonium hydroxide, sodium bicarbonate, sodium carbonate, saleratus,
One of potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, ammonium hydroxide, diethylamine, triethylamine or two (isopropyl) ethylamines
Or a variety of, preferably one of ammonium hydroxide, diethylamine, triethylamine or two (isopropyl) ethylamines or a variety of；Reaction temperature is 10
~40 DEG C, preferably room temperature.
These embodiments below do not limit the scope of the claims provided herein only for the purpose of illustrations.
It summarizes used in the present invention1H-NMR composes Bruker-400 Nuclear Magnetic Resonance, and the unit of chemical shift is million/
One, internal standard is tetramethylsilane.Coupling constant (J) is close to 0.1Hz.The abbreviation used is as described below: s, singlet；D, it is dual
Peak；T, triplet；Q, quartet；Qu, quintet；M, multiplet；Br, broad peak.Mass spectrum uses Quattro MicroTM API tri-
Weight quadrupole mass spectrometer.
The preparation of 1 compound 3 of embodiment
By -1 carboxylic acid tert-butyl ester (compound 2) (1.0g, 4.0mmoL) of 3- (- 3 base of pyridine) azelidinyl and ethylene iodohydrin
(1.1g, 6mmoL) is added in acetonitrile (10.0mL), is heated overnight under 80 DEG C of oil baths.TLC detects fully reacting, and decompression is steamed
Remove solvent.Residue washes away excessive ethylene iodohydrin with n-hexane/ethyl acetate=5/1 mixed system, obtains brown oil
1.62g, yield 100%.
1H NMR(CDCl3, 400MHz) and 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).
The preparation of 2 compound 4 of embodiment
By compound 3 (1.5g, 3.74mmoL) and PtO2(0.15g, 10%, w/w) is added in ethyl alcohol (10.0mL), in
Catalytic hydrogenation is stayed overnight under 50 DEG C of oil bath and normal pressure.TLC detects fully reacting.Filtration of catalyst, catalyst ethanol washing,
Filtrate decompression boils off solvent, and residue high vacuum dry obtains grease 980mg, yield 92%.It does not purify, is directly used in
The next step.
1H NMR(CDCl3, 400MHz) and 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]+。
The preparation of 3 compound 4 of embodiment
In addition to Pd (OAc)2Substitute PtO2Outside, the operation of embodiment 3 is the same as embodiment 2, yield 90%.
The preparation of 4 compound 4 of embodiment
In addition to substituting PtO with 10%Pd-C2Outside, the operation of embodiment 4 is the same as embodiment 2, yield 85%.This reaction may
There are problems that poor repeatability.
The preparation of 5 compound 1 of embodiment
Compound 4 (980mg, 3.45mmoL) is added to the mixing of trifluoracetic acid (2.0mL) and methylene chloride (2.0mL)
In solution, it is stirred at room temperature 2 hours.TLC detects fully reacting.Decompression boils off solvent, residue Gao Zhen under 45 DEG C of oil baths of oil bath
Sky drying 3 hours or more, obtain grease 570mg, yield 89%.It does not purify, is directly used in the next step.
1δ=4.71 (t, J=8.0Hz, 1H) H NMR (DMSO-d6,400MHz), 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]+。
The preparation of 6 compound 1 of embodiment
In addition to HCl/1,4- dioxane substitutes outside trifluoracetic acid, and residue is added to the water in post-processing
It is boiled off outside water after being neutralized with ammonium hydroxide through rotation, the operation of embodiment 6 is the same as embodiment 5.Yield is 96%.
Embodiment 7 ((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base)
Azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN (compound 6) preparation
By compound 5 (130mg, 0.37mmoL), compound 1 (136mg, 0.74mmoL) and DIPEA (111mg,
It 1.11mmoL) is added in DMF (10mL).It is stirred overnight at room temperature, TLC detects fully reacting.Decompression boils off solvent, and residue is used
Rapid column chromatography separation, eluant, eluent DCM/MeOH=10/1 obtain white solid 137mg, yield 74%.
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
(chemistry is pure): 99.3%.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring substantive content of the invention.
Claims (10)
1. a kind of preparation method of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol, which is characterized in that described
Method the following steps are included:
(1) compound 2 reacts to obtain compound 3 with 2- ethylene halohydrin in a solvent；
(2) under the effect of the catalyst, hydrogenated reaction obtains compound 4 to compound 3；
(3) compound 4 is removed in vacuum acid after sloughing Boc protecting group or obtains compound 1 through alkali neutralization under conditions of acid,
That is 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol reacts synthetic route are as follows:
Wherein, X is halogen atom.
2. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that halogen atom X in step (1) in 2- ethylene halohydrin is chlorine, bromine, iodine, compound 2 and 2- ethylene halohydrin
Molar ratio be 1:0.5~3, reaction temperature be 25~120 DEG C.
3. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that the solvent in step (1) is organic solvent, is preferably selected from acetonitrile, methanol, ethyl alcohol, ether, methyl- tert
Butyl ether, glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran or 2- methyl tetrahydro furan
It one of mutters or a variety of.
4. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that the catalyst in step (2) is platiniferous and/or palladium catalyst, preferably PtO2、Pd-C、Pd(OAc)2、Pd
(PPh3)4、Pd2(dba)3、Pd(dba)2、PdCl2Or PdCl2(dppf), more preferably PtO2, the quality of catalyst and compound 3
Than being 0.1~20%.
5. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that the reaction of step (2) carries out under 1~5 atmospheric pressure, preferably normal pressure, and reaction temperature is 20~120
℃。
6. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that the acid catalyst in step (3) is Bronsted acid, preferably TFA or HCl；Reaction dissolvent is organic solvent,
Preferably methylene chloride, 1,4- dioxane or water；Alkali is inorganic base or organic base, preferably ammonium hydroxide, sodium bicarbonate, carbonic acid
One of sodium, saleratus, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or two (isopropyl) ethylamines
Or it is a variety of.
7. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as claimed in claim 6
Method, which is characterized in that acid and reaction dissolvent in step (3) are TFA/DCM, HCl/1,4- dioxane or HCl/H2In O
It is any.
8. a kind of preparation side of 2- (3- (azetidine -3- base) piperidin-1-yl) ethyl -1- alcohol as described in claim 1
Method, which is characterized in that the reaction temperature in step (3) is 0~100 DEG C, preferably room temperature.
9. one kind ((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azacyclo-
Butane -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN preparation method, which comprises
(1) the step of method prepare compound 1 described in any item using claim 1-8；
(2) compound 1 and compound 5 prepare compound 6, i.e. ((R) -1- (2,4- dichlorophenyl) ethyl) -6- under alkali effect
(3- ((R) -1- (2- hydroxyethyl) piperidines -3- base) azetidine -1- base) -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN
The step of, the alkali is organic base or inorganic base, and reaction route is as follows:
10. one kind ((R) -1- (2,4 dichloro benzene base) ethyl) -6- (3- ((R) -1- (2- hydroxyl second as claimed in claim 9
Base) piperidines -3- base) azetidine -1- base) and -1H- pyrazolo [3,4-b] pyrazine -3- formonitrile HCN preparation method, feature exists
In the catalyst in step (2) is organic base, and reaction temperature is 10~40 DEG C, preferably room temperature.
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|---|---|---|---|
| CN201910244644.8A CN109796457B (en) | 2019-03-28 | 2019-03-28 | Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol |
| PCT/CN2019/115909 WO2020192129A1 (en) | 2019-03-28 | 2019-11-06 | Method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol and use thereof |
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| CN201910244644.8A CN109796457B (en) | 2019-03-28 | 2019-03-28 | Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020192129A1 (en) * | 2019-03-28 | 2020-10-01 | 苏州国匡医药科技有限公司 | Method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol and use thereof |
| CN114728972A (en) * | 2019-11-13 | 2022-07-08 | 拉普特医疗公司 | Crystalline forms of a C-C chemokine receptor type 4 antagonist and uses thereof |
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| WO2010111406A2 (en) * | 2009-03-24 | 2010-09-30 | Myriad Pharmaceuticals, Inc. | Compounds and therapeutic uses thereof |
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| WO2016138648A1 (en) * | 2015-03-04 | 2016-09-09 | Novartis Ag | Chemical process for preparing pyrimidine derivatives and intermediates thereof |
| CN109796457B (en) * | 2019-03-28 | 2020-03-06 | 苏州国匡医药科技有限公司 | Preparation method and application of 2- (3- (azetidin-3-yl) piperidin-1-yl) ethyl-1-ol |
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| WO2018022992A1 (en) * | 2016-07-29 | 2018-02-01 | Flx Bio, Inc. | Chemokine receptor modulators and uses thereof |
| 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 |
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| WO2020192129A1 (en) * | 2019-03-28 | 2020-10-01 | 苏州国匡医药科技有限公司 | Method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol and use thereof |
| CN114728972A (en) * | 2019-11-13 | 2022-07-08 | 拉普特医疗公司 | Crystalline forms of a C-C chemokine receptor type 4 antagonist and uses thereof |
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| WO2020192129A1 (en) | 2020-10-01 |
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