The present invention relates to crystalline forms of Afatinib and its dimaleate salt. The present invention also relates to processes for the preparation of crystalline forms of Afatinib and its dimaleate salt. The present invention further relates to pharmaceutical compositions of such crystalline forms of Afatinib dimaleate and use thereof in the treatment of a patient in need thereof.

The present invention relates to crystalline forms of Afatinib and its dimaleate salt. The present invention also relates to processes for the preparation of crystalline forms of Afatinib and its dimaleate salt. The present invention further relates to pharmaceutical compositions of such crystalline forms of Afatinib dimaleate and use thereof in the treatment of a patient in need thereof.

The invention is directed to a process for preparing maleic acid or a derivative thereof, said process comprising a step b) of oxidizing 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid to maleic acid or a derivative thereof by contacting 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid with molecular oxygen (O.sub.2) in the presence of a catalyst. In a particular embodiment, step b) is preceded by a step a) of oxidizing a furanic compound according to formula I into 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid,

##STR00001##

wherein R.sup.1 is H, CH.sub.2OH, CO.sub.2H or CHO and R.sup.2 is H, OH, C.sub.1-C.sub.6 alkyl or O(C.sub.1-C.sub.6 alkyl), or esters, ethers, amides, acid halides, anhydrides, carboximidates, nitriles, and salts thereof.

The invention is directed to a process for preparing maleic acid or a derivative thereof, said process comprising a step b) of oxidizing 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid to maleic acid or a derivative thereof by contacting 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid with molecular oxygen (O.sub.2) in the presence of a catalyst. In a particular embodiment, step b) is preceded by a step a) of oxidizing a furanic compound according to formula I into 5-hydroxy-2(5H)-furanone and/or cis-β-formylacrylic acid,

##STR00001##

wherein R.sup.1 is H, CH.sub.2OH, CO.sub.2H or CHO and R.sup.2 is H, OH, C.sub.1-C.sub.6 alkyl or O(C.sub.1-C.sub.6 alkyl), or esters, ethers, amides, acid halides, anhydrides, carboximidates, nitriles, and salts thereof.

The invention is directed to a process for the preparation of maleic acid or a derivative thereof. Said process comprising an electrochemical oxidation of a furoic acid compound into maleic acid in an electrolyte solution; and optionally further comprising a step of reacting the maleic acid to the derivative thereof. In an alternative embodiment, said process comprising a first step comprising an electrochemical oxidation in an electrolyte solution of a furanic compound into one or more intermediates; followed by a second step comprising a chemo-catalytic oxidation of said intermediates to provide maleic acid or a derivative thereof.

The invention is directed to a process for the preparation of maleic acid or a derivative thereof. Said process comprising an electrochemical oxidation of a furoic acid compound into maleic acid in an electrolyte solution; and optionally further comprising a step of reacting the maleic acid to the derivative thereof. In an alternative embodiment, said process comprising a first step comprising an electrochemical oxidation in an electrolyte solution of a furanic compound into one or more intermediates; followed by a second step comprising a chemo-catalytic oxidation of said intermediates to provide maleic acid or a derivative thereof.

Provided are a fruquintinib and a saccharin salt or eutectic crystal, a fruquintinib and a malonic acid eutectic crystal or a fruquintinib and a maleic eutectic crystal, a preparation method therefor, a pharmaceutical composition containing thereof, and uses thereof in preparing drugs for treating and/or preventing diseases related to abnormal angiogenesis, such as cancer, tumors, macular degeneration, chronic inflammation and the like.

Provided are a fruquintinib and a saccharin salt or eutectic crystal, a fruquintinib and a malonic acid eutectic crystal or a fruquintinib and a maleic eutectic crystal, a preparation method therefor, a pharmaceutical composition containing thereof, and uses thereof in preparing drugs for treating and/or preventing diseases related to abnormal angiogenesis, such as cancer, tumors, macular degeneration, chronic inflammation and the like.

The present invention provides a maleate, phosphate, sulfate, hydrochloride of a cyclohexane derivative, N′-[trans-4-[2-[7-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea, as shown in Formula I and crystal forms thereof. The crystal forms have low hygroscopicity and good stability and are convenient for long-term storage and transportation; or the crystal forms have a long half-life in vivo, high bioavailability and small individual difference, and thus have obvious clinical application advantages.

##STR00001##

The present disclosure discloses an immobilized metalloporphyrin catalyst and its utilization in maleic acid preparation, belonging to the technical field of metalloporphyrin catalytic application. The immobilized metalloporphyrin catalyst is used for catalyzing furfural to prepare maleic acid and is good in catalytic effect, mild in reaction conditions and capable of greatly reducing the energy consumption required in the prior art. The catalyst disclosed by the present disclosure can provide a good microenvironment for a reaction, so that the yield and selectivity of maleic acid are increased; and according to a method disclosed by the present disclosure, the conversion ratio of furfural is 20.4%-95.6%, the yield of maleic acid is 10%-56.1%, and the selectivity is 43.6%-76.1%. Meanwhile, the catalyst is easy to separate and environmentally friendly and may be recycled for many times.