1022150-11-3

Basic information

• Product Name: 1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)-
• Synonyms: 1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)-;(R)-tert-Butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate;(R)-tert-Butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (N-1);3-[4-Amino-3-(4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester;Ibrutinib Intermediates;(R)-tert-Butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-ca
• CAS NO: 1022150-11-3
• Molecular Formula: C₂₇H₃₀N₆O₃
• Molecular Weight: 486.5655
• Mol File: 1022150-11-3.mol

Chemical Properties

• Boiling Point: 673.9±55.0 °C(Predicted)
• Appearance: /
• Density: 1.31±0.1 g/cm3(Predicted)
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• PKA: 4.09±0.30(Predicted)
• CAS DataBase Reference: 1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)-(CAS DataBase Reference)
• NIST Chemistry Reference: 1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)-(1022150-11-3)
• EPA Substance Registry System: 1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)-(1022150-11-3)

Safety Data

• Hazardous Substances Data: 1022150-11-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
1-Piperidinecarboxylic acid, 3-[4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin-1-yl]-, 1,1-diMethylethyl ester, (3R)is used as an intermediate in the synthesis of pharmaceutical products for its potential applications in the treatment of erectile dysfunction and pulmonary arterial hypertension. Its unique molecular structure and stereochemistry contribute to its effectiveness in these therapeutic areas.

Upstream product

• 330786-24-8 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 143900-44-1 tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate 
• 151266-23-8 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 
• 1276110-38-3 (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester 
• 51067-38-0 4-phenoxyphenylboronic acid 
• 2380-63-4 4-Aminopyrazolo<3,4-d>pyrimidin 
• 1353993-49-3 tert-butyl (3S)-3-[[(4-methylbenzene)sulfonyl]oxy]piperidine-1-carboxylate 
• 1612774-50-1 (R)-tert-butyl 3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 
• 3473-63-0 formamidine acetic acid 
• 885275-01-4 t-butyl-3(S)-chloro-piperidine-1-carboxylate 
• 5305-40-8 2,6-dichloro-pyrimidine carbaldehyde 
• 101-55-3 4-Bromodiphenyl ether 
• 2215-77-2 4-Phenoxybenzoic acid 
• 330792-68-2 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile 

Downstream Products

• 1022150-12-4 (R)-3-(4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine 
• 1642571-07-0 (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride 
• 936563-87-0 ibrutinib 
• 1710768-30-1 (R,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)-4-(4-(2-aminoethyl)piperazin-1-yl)but-2-en-1-one 
• 1553977-08-4 (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-2,3,3-d₃-1-one 
• 1553977-42-6 3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3.4-d]pyrimidin-4-amine hydrochloride salt 
• 1412418-65-5 _{(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile} 

Relevant articles and documents

Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs)

Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.

PROCESSES AND INTERMEDIATES FOR PREPARING A BTK INHIBITOR

Disclosed is a process for the preparation of certain intermediates, e.g. a process for preparing a compound of formula (I) wherein, R1, R2 and X1 are as defined in the description, and which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

A PROCESS FOR PREPARATION OF 1H-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVES

The present invention relates to an efficient and industrially advantageous process for the preparation of 1H-pyrazolo[3,4-d] pyrimidine derivatives. In particular the present invention provides a process for the preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidine and tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate. Said compounds are important intermediates in the synthesis of ibrutinib. The method provided for preparing intermediates of ibrutinib has the advantages of a simple operation, high yield and low costs.

Preparation method of precursor of ibrutinib

The invention relates to the pharmaceutical industry, in particular to a preparation method of a drug intermediate, and specifically discloses a preparation method of a precursor of ibrutinib. The preparation method comprises the following steps: (1) reacting a compound (III) with triphenylphosphine and azodicarbonic acid diester to obtain an intermediate (III-B); (2) reacting the intermediate (III-B) with a compound (IV) under the action of a catalyst to obtain an intermediate (V-C); and (3) reacting the intermediate (V-C) under the action of hydrochloric acid to obtain (R)-3-(4-phenoxy phenyl)-1-(piperidine-3-yl)-1H-pyrazolo [3, 4-d] pyrimidine-4-amine (I). The method has the advantages of high yield, high purity, convenience in purification, simplicity and convenience in operation and the like, is suitable for industrial production, and contributes to reducing the cost to a certain extent.

Method for using zinc chloride to separate and purify ibrutinib intermediate

The invention discloses a method for using zinc chloride to separate and purify an ibrutinib intermediate, and particularly relates to a separation and purification method of the ibrutinib intermediate (3R)-4-amido-3-(4-phenoxy phenyl)-1-(1-tert-butoxy carbonyl piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. After Mitsunobu reaction for preparing the intermediate is terminated, zinc chloride is added into a mixture, heated and cooled, composition sediment of zinc chloride and triphenylphosphine oxide is removed by filtering, and the intermediate with good purity is obtained. The process omits column chromatography, and is an efficient and low-cost separation and purification method.

The compounds of structure containing conjugated zincon, its pharmaceutical composition and use thereof (by machine translation)

The present invention relates to compounds having a structure containing conjugated zincon, its pharmaceutical composition and use, and in particular relates to the general formula (I) or a salt thereof to the compound represented by the, pharmaceutical compositions thereof, and its as BTK inhibitors and/or B cell activation inhibitor, for the prevention or treatment B cell activity with abnormal and/or the use of the BTK-related diseases. The compounds of lymphoma, breast cancer, liver cancer, colon cancer, gastric cancer, such as lung cancer and cervical cancer cell has better lethal effect, note has potential for the treatment of cancer and self-immune diseases related to potential. (by machine translation)

A METHOD FOR PREPARATION OF IBRUTINIB PRECURSOR

A method for the preparation of ibrutinib's precursor, 3-(4-phenoxyphenyl)-1-((3R)-piperidin-3-il)-1H-pyrazolof [3,4-d]|pyrimidin-4-amine, involving arylation of N-protected 1-(piperidin-3-yl)pyrazolo[3,4-d]pyrimidin-4-amine in the presence of palladium catalyst, nitrogen-containing ligand, and base, with subsequent removal of the protecting groups by known methods, is reported. (Formula (II))

According to lu tini synthesis method

The invention discloses a synthesis method of ibrutinib. The method uses Suzuki coupling reaction and Kumada coupling reaction, does not need to separate the intermediate, obtains the intermediate (9) at high yield by a one-pot process, and uses mixed anhydrides instead of acryloyl chloride. The technique utilizes cheap 4-halodianisole as the initial raw material, adopts Suzuki coupling reaction and Kumada coupling reaction, and uses the one-pot process. The whole route is disclosed in the specification. The method can obtain the intermediate (9) (the chemical purity and optical purity are greater than or equal to 99%) at high yield without separating and purifying the intermediate, and avoids microwave, high temperature/high pressure and other specific reaction conditions; and the acrylic acid and mixed anhydrides generated by acyl chloride and sulfonyl chloride are used instead of the acryloyl chloride in the last step to avoid the amidation reaction of the intermediate (10) in multiple sites and reduce the generation of the byproduct, thereby obtaining the high-purity ibrutinib at high yield. The method has the advantages of short process route and lower cost, and is beneficial to the environment and suitable for industrialized scale-up production.

PROCESS FOR THE SYNTHESIS OF STABLE AMORPHOUS IBRUTINIB

Disclosed herein is a new route of synthesis and a new stable amorphous form of ibrutinib. Also disclosed are pharmaceutical compositions, oral dosage forms and the use of the amorphous ibrutinib in the treatment of mantle cell lymphoma or chronic lymphocytic leukemia.

PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE

The present invention relates to an efficient and industrially advantageous process for the preparation of pure lH-pyrazolo[3,4-d] pyrimidine derivative. In particular the present invention provides a process for the preparation of pure 4-amino-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate of ibrutinib. Particularly, the present invention provides a process for the preparation of 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, wherein none of the intermediates have been isolated, an important precursor for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d] pyrimidine.