45 results about "Baricitinib" patented technology

The present invention in one embodiment provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.

The present disclosure provides a Baricitinib intermediate, a method for preparing the Baricitinib intermediate, and a method for preparing Baricitinib or a pharmaceutically acceptable salt thereof using the Baricitinib intermediate. The method for preparing the Baricitinib intermediate involves the use of a divalent palladium catalyst or a nickel catalyst and provides the Baricitinib intermediate in high yield.

The invention discloses a method for preparing baricitinib and belongs to the technical field of drug preparation. The method comprises the following steps: taking chloro-1H-pyrrolopyrimidine as an initial raw material, performing amino protection, performing 'one-pot' substitution with hydrazine hydrate and acraldehyde, and performing ring closure to obtain an intermediate 4; performing condensation on an initial raw material 1,3-dibromoacetone and ethylene glycol so as to obtain an intermediate 5, performing condensation on the intermediate 5 and ethanesulfonamide to obtain an intermediate 6, reacting the intermediate 6 and diethyl cyanomethylphosphonate in the presence of strong base so as to an intermediate 7, carrying out an addition reaction on the intermediate 4 and the intermediate7 in the presence of a catalyst, and performing deprotection, so as to obtain multiple target products 1. The process is mild in reaction conditions and simple and feasible in intermediate purification method, reaches the total yield of 40-55%, and is suitable for industrialized production.

The present invention provides a process for the preparation of baricitinib and an intermediate thereof. The present invention provides a convenient, economical, and industrially advantageous two-step process for the preparation of [4-(IH-pyrazol-4-yl)-7Hpyrrolo[2,3-d] pyrimidin-7-yl]methyl pivalate of Formula (II). The process of the present invention involves the use of an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate as a base for reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine of Formula (III) with chloromethyl pivalate of Formula (IV), and the use of an unprotected pyrazole borolane of Formula (VIII) for the conversion of (4-chloro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)methyl 2,2-dimethylpropanoate of Formula V into [4-(1H-pyrazol-4-yl)-7Hpyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula (II). The process of the present invention provides [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate of Formula (I) in high yield.

The invention discloses a pharmaceutical composition containing baricitinib and its preparation method and application. The pharmaceutical composition comprises baricitinib and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials include fillers and disintegrants. The preparation method of the pharmaceutical composition comprises: uniformly mixing a filler and a disintegrant to obtain mixed excipients; uniformly mixing the baricitinib bulk drug with the mixed excipients or granulating the baricitinib bulk drug The liquid is uniformly mixed with the mixing excipients, and the drug-loaded granules of the solid pharmaceutical composition containing baricitinib are obtained by granulation. The present invention controls the particle size of baricitinib, uses hydrophilic auxiliary materials microcrystalline cellulose, mannitol, etc. The solid pharmaceutical composition containing baricitinib has a simple preparation process and is suitable for industrialization.

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.

The invention relates to a method for separating and measuring impurities of a baricitinib bulk drug by HPLC, comprising the following steps: Step 1, taking a baricitinib bulk drug sample, using octadecylsilane-bonded silica gel as a filler, and adding water Carry out gradient elution with mobile phase A and acetonitrile as mobile phase B, and take the eluent as the detection sample; step 2, prepare the detection solution, and take the baricitinib API test sample, baricitinib reference substance, and impurity A , impurity B, impurity C, impurity D, impurity E, prepare high performance liquid chromatography analysis liquid; Step 3, carry out high performance liquid chromatography analysis to the detection liquid prepared in step 2; Obtain the content of each impurity; The comprehensive effects of analytical column, mobile phase, gradient elution procedure, flow rate and column temperature on separation and detection have optimized the detection results. It has the advantages of rapidity, simplicity, high sensitivity, accuracy and reliability, and wide applicability. It is suitable for separation and determination. Impurity content of baricitinib drug substance.

The invention relates to a preparation method for synthesizing a key intermediate 1 of Baricitinib. The preparation method comprises the following steps: generating ring closing reaction by virtue of1,3-dibromo-2,2-dimethoxypropane (SM) and ethyl sulfonamide (SM2) under an alkaline condition, and carrying out acetal deprotection under an acidic condition, so as to obtain an intermediate B; and generating witting reaction by virtue of the obtained intermediate B and diethyl cyanomethylphosphonate under the alkaline condition, so as to obtain the key intermediate 1. According to the preparationmethod, the ring closing reaction is generated by virtue of the commercial materials SM and ethyl sulfonamide under the alkaline condition, acetal deprotection is carried out under the acidic condition so as to obtain intermediate B, and witting reaction is carried out so as to obtain the key intermediate 1; the key intermediate 1 can be actually obtained only through two synthetic steps; and compared with the prior art, the preparation method has the advantages that the synthetic route is greatly shortened, the hydrogenation is avoided, and the production cost of the key intermediate 1 is lowered.