- Preparation method of baricitinib
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The invention discloses a preparation method of baricitinib. The preparation method comprises the following steps: taking 4-chloropyrrolopyrimidine as an initial raw material, protecting amino with Boc anhydride, then carrying out substitution reaction with malondialdehyde dimethyl acetal, further adjusting the acid, and adding hydrazine hydrate for cyclization to obtain a compound 4; carrying out addition reaction on the compound 5 and 2-[1-(ethylsulfonyl)-3-azacyclobutyl] acetonitrile (compound 5), and removing an amino protecting group by using trifluoroacetic acid to obtain baricitinib. According to the substitution cyclization reaction of the method, a reflux reaction in an oxygen environment in the reaction process is avoided, the reaction safety is improved, the reaction selectivity is also improved, other impurities difficult to remove are avoided, the product purity is high, and the yield is high.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF BARICITINIB
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The present invention provides an improved process for the preparation of Baricitinib of formula (I),
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- Synthesis and Characterization of Compounds Potentially Related to the Janus Kinase Inhibitor Baricitinib
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Nine compounds potentially related to the Janus kinase inhibitor Baricitinib have been identified, synthesized by conventional methods, and characterized by IR, 1H and 13C NMR, and mass spectral data.
- Dasari,Seelam,Jayachandra,Vadali,Yerva,Tondepu,Gadakar
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p. 1569 - 1574
(2019/12/28)
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- Baricitinib, novel crystal form of Baricitinib phosphate and preparation methods of Baricitinib and novel crystal form of Baricitinib phosphate
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The invention provides a Baricitinib III crystal form, a Baricitinib phosphate crystal form D, and preparation methods of the Baricitinib III crystal form and the Baricitinib phosphate crystal form D.An X-ray diffraction pattern of the Baricitinib III crystal form has diffraction peaks at diffraction angle 2 theta: 4.238 +/- 0.2 degree, 12.558 +/- 0.2 degree, 16.747 +/- 0.2 degree, 25.194 +/- 0.2degree, and 29.466 +/- 0.2 degree. An X-ray diffraction pattern of the Baricitinib phosphate crystal form D has diffraction peaks at diffraction angle 2 theta: 3.217 +/- 0.2 degree, 12.609 +/- 0.2 degree, 17.825 +/- 0.2 degree, 19.665 +/- 0.2 degree, 20.617 +/- 0.2 degree, and 22.055 +/- 0.2 degree. The crystal forms prepared through the methods of the invention have advantages of good comprehensive performances. Therefore, the curative effect and the possibility of development of the medicine kind can be improved, which is of vital importance to clinical applications of the Baricitinib medicine.
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Paragraph 0053-0054
(2018/09/08)
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- Preparation method of baricitinib
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The invention discloses a preparation method of baricitinib and belongs to the technical field of drug preparation. The method comprises that 4-chloropyrrolopyrimidine as a starting raw material is subjected to amino protection, the product, hydrazine hydrate and acrolein undergo a one-pot displacement reaction and a cyclization reaction to produce an intermediate 4, a starting raw material 1, 3-dibromoacetone and ethylene glycol undergo a condensation reaction to produce an intermediate 5, the intermediate 5 and ethyl sulfonamide undergo a condensation reaction to produce an intermediate 6, the intermediate 6 and diethyl cyanomethylphosphonate undergo a reaction under action of a strong base to produce an intermediate 7, the intermediate 4 and the intermediate 7 undergo an addition reaction under the action of a catalyst, and the product undergoes a deprotection reaction to produce a desired product 1. The preparation method needs mild reaction conditions. The intermediate purification method is simple and easy, has a total yield of 40-55% and is suitable for industrial production.
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- Preparation method of baricitinib
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The invention discloses a preparation method of baricitinib. The method comprises the following steps: performing a substitution reaction on 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (II) serving as a raw material and benzene sulfonyl chloride in the presence of an alkali to obtain an intermediate III; then, performing a Suzuki coupling reaction on the intermediate III and 4-pyrazole-4-boronic acid pinacol ester in the presence of a palladium catalytic system and an alkali to obtain an intermediate V; then performing a Michael addition reaction on the intermediate V and 3-(cyanomethylene)azetidine-1-tert-butyl formate in the presence of a catalyst to obtain an intermediate VII; then removing Boc protection from the intermediate VII under the action of hydrochloric acid to obtain an intermediate VIII; then performing a sulfoamidate reaction on the intermediate VIII and ethyl sulfonyl chloride in an organic solvent in the presence of an alkali to obtain an intermediate IX; lastly, removing benzenesulfonyl protection from the intermediate IX under the action of tetramethylammonium fluoride or tetrabutylammonium fluoride or a trihydrate of the tetramethylammonium fluoride or the tetrabutylammonium fluoride to obtain baricitinib (I). Compared with the prior art, the method has the advantages of adoption of readily-available raw materials, low cost, high product yield and easiness for industrial production.
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- New synthesis methods of JCK inhibitor baricitinib and intermediate thereof
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The present invention provides a new synthesis method of a baricitinib compound 11. According to the present invention, by using a compound 1 as a staring raw material, the amino group is protected by directly using ethanesulfonyl chloride, and direct cyclization is directly performed by using the effect of an alkali to obtain a key intermediate compound 3 so as to avoid the use of other protection groups and substantially improve the route efficiency and the atomic economy; during the compound 5 preparation, a Wittig reaction is performed by using triphenylphosphine acetonitrile so as to avoid the use of strong alkali and improve the reaction yield; the completely-new neopentyl glycol borate derivative compound 8 has good stability and good crystallinity so as to simplify the separation and purification process; and the route is simple to operate and has the high yield, the purity of the obtained product is high, and the synthesis method is suitable for amplification production. The formulas 1-11 are defined in the specification.
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- Novel synthetic method for baricitinib and intermediate thereof
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The invention discloses a novel intermediate compound 5 of baricitinib. The compound 5 has stable properties, which is favorable for separation and purification. The invention also discloses a preparation method for the compound 5 and two schemes for preparing baricitinib from the baricitinib. The two schemes are simple in operation, shortened in reaction steps, high in yield and product purity and suitable for enlarged production. The compound 5 has a structural formula as defined in the specification. In the formula, X represents halogen, e.g., chlorine, bromine or iodine.
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- PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF {1-(ETHYLSULFONYL)-3-[4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL]AZETIDIN-3-YL}ACETONITRILE
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The present invention provides processes and intermediates for the preparation of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3- yl}acetonitrile: (I)
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- Baricitinib intermediate and preparation method thereof, and method for preparing baricitinib from intermediate
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The invention discloses a baricitinib intermediate and a preparation method thereof, and a method for preparing baricitinib from the intermediate. The structure of the intermediate is disclosed as Formula (5). The preparation method of the intermediate comprises the following steps: carrying out reaction on diethyl cyanomethylphosphate and 1-boc-3-azacyclobutanone under the catalytic action of an alkali to obtain a compound 2 disclosed as Formula (2); removing the Boc group of the compound 2 to obtain a compound 3 disclosed as Formula (3); under alkaline conditions, carrying out reaction on the compound 3 and ethyl sulfonyl chloride to obtain a compound 4 disclosed as Formula (4); and in the presence of 1,8-diazabicyclo[5,4,0]hendecyne-7-ene, carrying out reaction on the compound 4 and pinacone 4-pyrazolylborate to obtain the intermediate. The method for preparing baricitinib from the intermediate comprises the following step: in the presence of a palladium catalyst and cesium fluoride, carrying out Suzuki coupling reaction on the intermediate and 6-chloro-7-deazapurine to obtain the baricitinib. The preparation method of baricitinib has the advantages of accessible raw materials and simple technique, and is suitable for industrial production.
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- PROCESS FOR THE PREPARATION OF BARICITINIB AND AN INTERMEDIATE THEREOF
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The present invention provides processes for the preparation of baricitinib of Formula I and an intermediate of Formula V. The present invention also provides the use of the intermediate of Formula V for the preparation of baricitinib.
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Page/Page column 12
(2016/09/22)
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- An efficient synthesis of baricitinib
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A highly efficient method for the synthesis of baricitinib was developed. The starting material tert-butyl 3-oxoazetidine-1-carboxylate was converted to intermediate 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile via the Horner-Emmons reaction, deprotection of the N-Boc-group and a final sulfonamidation reaction. Then the nucleophilic addition reaction was carried out smoothly to afford the borate intermediate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene under reflux. Finally, the desired compound baricitinib was obtained by the Suzuki coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with the above borate intermediate. All compounds were characterised by IR, MS, 1H NMR and 13C NMR. The overall yield in this synthetic route was as high as 49%. Moreover, this procedure is straightforward to carry out, has low cost and is suitable for industrial production.
- Xu, Jiaojiao,Cai, Jin,Chen, Junqing,Zong, Xi,Wu, Xuan,Ji, Min,Wang, Peng
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p. 205 - 208
(2016/05/11)
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- AMORPHOUS FORM OF BARICITINIB
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The present invention provides an amorphous form of baricitinib, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of JAK-associated diseases.
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Page/Page column 7
(2015/12/08)
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- AZETIDINE AND CYCLOBUTANE DERIVATIVES AS JAK INHIBITORS
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The present invention relates to azetidine and cyclobutane derivatives, as well as their compositions, methods of use, and processes for preparation, which are JAK inhibitors useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.
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Page/Page column 69
(2009/09/28)
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