44 results about "Baricitinib" patented technology

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 provides a baricitinib polymorph A. The baricitinib polymorph A is characterized in that diffraction peaks are arranged on an XRPD (X Ray Powder Diffraction) map when values of 2 theta are equal to 12.46, 13.921, 14.94, 15.359, 16.26, 16.639, 17.36, 19.08, 20.321, 21.961, 22.381, 24.118, 25.42, 27.441, 28.381, 29.321, 29.799, 32.675, 33.14, 33.563, 33.923 and 41.6, wherein an error range of the values of the 2 theta is +/- 0.2. The baricitinib polymorph A provided by the invention has good high-temperature stability, good high-humidity stability and good illumination stability, can be applied to medicine for treating or preventing diseases related to JAK (Janus Kinase) and has better biological availability; meanwhile, provided qualitative and quantitative information has important significance in further studying the therapeutic effect of such solid medicine.

The invention discloses a pyrrolomiazine compound shown as the general formula I (please see the formula in the description) and pharmaceutically-acceptable salt or solvate of the pyrrolomiazine compound, and further discloses preparation methods and application of the pyrrolomiazine compound shown as the general formula I and the pharmaceutically-acceptable salt or solvate of the pyrrolomiazine compound. The prepared pyrrolomiazine compound can be quickly converted into a stock drug baricitinib in plasma and has the better solubility, the higher bioavailability and the enhanced drug efficacy compared with the stock drug.

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.

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.

The invention provides Baricitinib trifluoroacetate crystal forms A and B in the formula (I) (please see the formula in the description). The XRPD atlas of the crystal form A has diffraction peaks at the positions representing that 2theta equals to 8.60, 10.12, 10.72, 14.02, 16.66, 17.24, 17.84, 18.90, 19.54, 20.26, 21.54, 21.94, 23.40, 23.78, 24.66, 25.64, 25.98, 26.32, 27.12, 28.16, 30.34 and 31.12, and the XRPD atlas of the crystal form B has diffraction peaks at the positions representing that 2theta equals to 5.34, 9.00, 10.08, 10.70, 16.12, 17.44, 17.80, 18.92, 19.48, 20.22, 21.56, 22.68, 23.42, 23.98, 25.84, 27.22, 28.76, 29.46 and 32.66, wherein the error range of 2theta is +/-0.2. The stability of the Baricitinib trifluoroacetate crystal forms A and B is better than that of a Baricitinib trifluoroacetate semi-crystal, and the medicine processing of the crystal forms A and B and the application of the crystal forms A and B in a medicine composition are facilitated. The Baricitinib trifluoroacetate crystal forms A and B can be applied in medicine for treating immunity diseases, inflammatory diseases or cancers; meanwhile, qualitative and quantitative information is provided, and important significance is achieved for further studying the treatment effect of such type of solid medicine.

The invention discloses a drug composition containing baricitinib and a preparation method and application of the drug composition. The drug composition comprises the baricitinib and an auxiliary material which can be received pharmaceutically, wherein the auxiliary material comprises a filling agent and a disintegrating agent. The preparation method of the drug composition comprises the steps that the filling agent and the disintegrating agent are evenly mixed, so that the mixed auxiliary material is obtained; and then a baricitinib crude drug and the mixed auxiliary material are evenly mixed or pelletizing liquor containing the baricitinib crude drug is evenly mixed with the mixed auxiliary material, and drug-carrying pellets of the solid drug composition containing the baricitinib are obtained through pelletizing. According to the drug composition containing the baricitinib and the preparation method and application of the drug composition, the solid drug composition which can be dissolved out rapidly in vitro and contains the baricitinib is prepared by controlling the particle size of the baricitinib, using microcrystalline cellulose, mannitol and the like in the hydrophilic auxiliary material as the filling agent, and using croscarmellose sodium and the like as the disintegrating agent; and the preparation technique is simple and suitable for industrialization.

The invention belongs to the field of pharmaceutical and chemical industry, and particularly relates to a preparation method for a Baricitinib intermediate. The preparation method is characterized in that a key intermediate 2-[1-ethyl sulfonyl-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-parazole-1-ethyl] azacyclobutyl-3-yl) acetonitrile is prepared through reaction of a 4-parazole boride and 2-[1-(ethyl sulfonyl-3-azacyclobutaneylidene) acetonitrile, and nitrogen on a pyrazolone ring of 4- parazole boride does not need to be protected, so that a follow-up step of removing a corresponding a protective group is avoided, and therefore, the whole reaction route is short, raw materials are obtained easier, the production cost is low, and the preparation method is especially suitable for industrial production.

The invention relates to new application of a medicament, in particular to application of Baricitinib in preparation of a medicament for treating senile calcific heart valve disease. The research of the invention shows that: by inhibiting a JAK pathway and selectively activating a substrate-STAT of the Baricitinib, the substrate-STAT is translocated to the nucleus so as to act on downstream targetgenes such as cyclin D1, BCL-xL, C-MYC, P21 WAF1/ CIP1 and the like, and the cell proliferation, differentiation and apoptosis is regulated, so that degeneration, fibrosis, thickening and calcification of heart valve connective tissues of a patient are obviously improved, and cardiomyocytes are protected. Compared with the prior art, the medicament can reduce various indexes of patients with thesenile calcific heart valve disease, improve the disease condition and improve the life quality of the patients with the senile calcific heart valve disease.

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 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.

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a Baricitinib cream and a preparation method and application thereof. The Baricitinib cream comprises Baricitinib or pharmaceutically acceptable salt thereof and polyethylene glycol-7 stearate. In the preparation process of the Baricitinib cream, the Baricitinib cream which is fine and smooth, has the particle size meeting the quality requirement of Chinese pharmacopoeia for the cream and is good in coating performance can be prepared through low-speed stirring; and the cream has better high-temperature-resistant stability, and oil-water separation is not prone to occurring. Therefore, the Baricitinib cream is more suitable for industrial production and better in stability.

The invention relates to a method for preparing a spherical baricitinib crystal. The method for preparing the spherical baricitinib crystal comprises the following steps: adding baricitinib into water, heating to 40-50 DEG C, dissolving, and filtering; keeping the filtrate at a temperature range of 5-15 DEG C, adding 95% ethanol which is 0.2-0.3 time of the volume of filtrate obtained at the firststep while stirring, culturing a crystal for 1-2.5 hours at a constant temperature, and stirring; continuously stirring, cooling to subzero 5 to 0 DEG C, continuously culturing the crystal for 1.5-2hours at the constant temperature, and stirring; carrying out suction filtration, washing filtrate cakes, and drying at 50-60 DEG C. By adopting the technical scheme of the invention, the spherical baricitinib crystal is obtained, and the spherical baricitinib crystal has very good flowability and is free of adhesion in the pressing process.

The invention discloses a novel drug application of baricitinib. More specifically, the application refers to the application of the baricitinib or pharmaceutically acceptable salt or ester thereof inpreparation of drugs for promoting the proliferation of cardiomyocytes. Experimental results show that the baricitinib can promote the proliferation of the cardiomyocytes of rats. Thus, the baricitinib can be used for the related fields in preparing the drugs for promoting the proliferation of the cardiomyocytes and the drugs for treating or preventing heart diseases; and a novel drug and treatment idea can be provided for treating or preventing the heart diseases such as myocardial infarction.

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.

The invention relates to a method for separating and determining impurities in a baricitinib bulk drug by using HPLC (High Performance Liquid Chromatography). The method comprises the following steps:step 1, taking a baricitinib bulk drug sample, carrying out gradient elution by using octadecylsilane chemically bonded silica as a filler, water as a mobile phase A and acetonitrile as a mobile phase B, and taking eluent as a detection sample; step 2, performing preparation of a detection liquid: taking a baricitinib bulk drug detection sample, a baricitinib reference substance, an impurity A, an impurity B, an impurity C, an impurity D and an impurity E, and preparing a high performance liquid chromatography analysis liquid; and step 3, carrying out high performance liquid chromatography analysis on the detection liquid prepared in the step 2; obtaining the content of each impurity. According to the method, the comprehensive influence of an analysis column, a mobile phase, a gradient elution program, a flow rate and a column temperature on separation detection is comprehensively considered, so that a detection result is optimized; and the method has the advantages of rapidness, simplicity, convenience, high sensitivity, accuracy, reliability and wide applicability, and is suitable for separating and determining the impurity content of the baricitinib bulk drug.

The present disclosure relates to crystalline forms of Baricitinib and processes for preparation thereof. The present disclosure also relates to pharmaceutical composition containing these crystalline forms and use of these crystalline forms for preparing JAK inhibitor drugs and preparing drugs treating rheumatoid arthritis. The crystalline forms of the present disclosure have one or more improved properties compared with crystalline forms of the prior art and have significant values for future drug optimization and development.