Showing posts with label New patent. Show all posts
Showing posts with label New patent. Show all posts

Tuesday, 26 December 2017

Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd

Image result for CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD
Pexidartinib, New Patent, WO, 2017215521, Crystal Pharmatech Co Ltd
(WO2017215521) PLX3397 HYDROCHLORIDE CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017215521
CRYSTAL PHARMACEUTICAL (SUZHOU) CO., LTD
INVENTORS
CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
ZOU, Po; (CN).
ZHANG, Xiaoyu; (CN)
Novel crystalline forms of PLX3397 hydrochloride (designated as Forms CS2 and CS3), processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating giant cell tumor of the tendon sheath.
The present invention relates to a PLX3397 hydrochloride crystal form, a preparation method therefor and use thereof. The PLX3397 hydrochloride crystal form has higher solubility, larger particle size, and good stability, especially better mechanical stability, is favorable for separation of products in subsequent production, provides a better choice for preparing PLX3397-containing pharmaceutical preparations, and is very important to medicinal development.
front page image
Pexidartinib (PLX3397) is a new drug used to treat tenosynovial giant cell tumor (TGCT). Tenoid sheath giant cell tumor is a rare type of tendon sheath cancer. At present, the disease is usually treated surgically by surgical resection, and the surgical treatment of the disease may lead to the deterioration of dysfunction and serious complications. And since TGCTs have multiple types, which typically occur at bone tissue and joints, the advent of new interventional therapies is urgently needed in the clinic. The PLX3397 is currently in Phase III clinical trials and has received the FDA's breakthrough drug therapy certification. The structural formula of PLX3397 is shown in formula (I).
 
Example 1 Preparation of monohydrochloride form CS2

[0112]
Weigh 101.6 mg of PLX3397 solids in a 5 mL glass vial and add 2 mL of n-heptane at 5 ° C. Under magnetic stirring, 440 μL of 0.6 mol / L diluted hydrochloric acid was added and the reaction was carried out for 40 min. The mixture was filtered and dried to obtain an off-white solid.

[0113]
Upon testing, the solid obtained in this example is the monohydrochloride form CS2. The XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 1. The resulting solid was monohydrochloride salt of PLX3397 as determined by ion chromatography. 1 H NMR is shown in FIG. 4.

[0114]
When differential scanning calorimetry was used, the endothermic peak began to form when heated to about 72 ° C. When heated to around 227 ° C, the endothermic peak started to appear. The DSC is shown in FIG. 2.

[0115]
When subjected to thermogravimetric analysis, crystalline form CS2 has a mass loss gradient of about 8.3% when heated to 137 ° C, the TGA of which is shown in FIG. 3. Form CS2 is hydrate.
[Figure 0009]   
Fig. 1 H NMR chart of crystalline form CS3 in Example 3. Fig
//////////////Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd

Monday, 18 December 2017

IMIGLIPTIN, NEW PATENT, WO 2017211293, XUANZHU PHARMA CO., LTD.


(WO2017211293) CRYSTALLINE FORM OF SUCCINATE USED AS DIPEPTIDYL PEPTIDASE-4 INHIBITOR 
WO-2017211293, 
XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)
SHU, Chutian; (CN)


https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211293&recNum=1&tab=PCTDocuments&maxRec=&office=&prevFilter=&sortOption=&queryString=

front page image


The present invention relates to a crystalline form of a succinate used as a dipeptidyl peptidase-4 inhibitor, and a manufacturing method, pharmaceutical composition, and application thereof. The invention specifically relates to a dipeptidyl peptidase-4 inhibitor compound as represented by formula (1), a crystalline form of a succinate, wherein the succinate is an (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)methyl)benzonitrile, and a manufacturing method, pharmaceutical composition, and application thereof.




Example 1: Preparation of the succinate salt form I of the compound of formula (1)
[0056]

[0057]
The compound of formula (1) (44.6 g, 0.12 mol) was added to a 2 L round bottom flask and suspended in 1593 mL of acetonitrile. The mixture was heated to 80 ° C. and dissolved in free form. Immediately after the addition of 15.4 g A white solid precipitated, maintained at 80 ℃ for 1 hour and then cooled to room temperature, filtered and the filter cake was dried in vacuo at 40 ℃ for 10 hours, weighed 57.6g, yield 98.3%. The succinate salt Form I was tested by XRPD.
[0058]
Example 2: Preparation of the succinate salt form I of the compound of formula (1) II
[0059]
A quantity of succinate salt of the compound of formula (1) was weighed into glass vials in a total of 26 parts. A total of 26 vials of methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, Isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, Ketone, xylene, isobutyl acetate, diethyl ether). After stirring, ultrasound and other means to make the sample fully dissolved. Subsequently, about 2 mL of liquid was removed from each bottle and filtered into 26 reagent tubes numbered 1-26. The resulting 26 filtrates were distributed in two 96-well plates. One or two of the above 1-13 solvents are sequentially added into the first 96-well plate, one or two of the above-mentioned 14-26 kinds of solvents are sequentially added into the second 96-well plate, Zha Kong sealing film sealed, placed in a fume hood, the natural environment to dry. Wherein Form I is obtained in the following mixed solvent, and Form I is also precipitated in the methyl isobutyl ketone in the remaining solution after plating.
[0060]
The solvent used to prepare succinate salt Form I was prepared
[0061]
[Table 0001]
Mixed solventsSolvent 1Solvent 2
1Methyl isobutyl ketoneEther
2XyleneEther
3Isobutyl acetateEther
4EtherEther
51,4-dioxanePentane
61,4-dioxaneHeptane
71,4-dioxaneCyclohexane
81,4-dioxaneMethyl isobutyl ketone
91,4-dioxaneXylene
101,4-dioxaneIsobutyl acetate
11Butyl acetateEther
12Butyl acetate1,4-dioxane
[0062]
Example 3: Preparation of the succinate salt form II of the compound of formula (1)
[0063]
Take 8 parts of the compound of formula (1), 200mg each, placed in a 10mL round bottom flask, add the solvent in the following table to each solvent, warmed until the solvent is refluxed, after dissolving it, add 69mg (1.1eq) succinic acid and cool to At room temperature, the solid precipitated and was filtered. The resulting solid was subjected to XRPD testing as succinate crystal form II.
[0064]
[Table 0002]
Feeding amountSolvent and ratio
2mLTetrahydrofuran
3mLacetone
5.5mLAcetonitrile: water = 10: 1
2mLMethanol
4mLEthanol
1mLEthanol: water = 10: 1
2mLIsopropanol: water = 19: 1
2mLIsopropyl alcohol: water = 9: 1

Tuesday, 31 October 2017

Enclomiphene citrate, New patent, WO 2017182097, F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A

Image result for F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
Enclomiphene citrate, New patent, WO 2017182097, F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
WO-2017182097
F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
CARUANA, Lorenzo; (IT).
PADOVAN, Pierluigi; (IT).
DAL SANTO, Claudio; (IT)
Image result for F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
Enclomiphene citrate is an active pharmaceutical ingredient currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it also could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.
Enclomiphene citrate of formula (I):
has chemical name of Ethanamine, 2-[4-[(1 )-2-chloro-1 ,2-diphenyl ethenyl]phenoxy]-/V,/V-diethyl-, 2-hydroxy-1 ,2,3-propanetricarboxylate (1 : 1 ); has CAS RN. 7599-79-3, and it is also named trans-Clomiphene monocitrate, E-Clomiphene citrate or Enclomiphene monocitrate.
Enclomiphene is component of Clomiphene, an active pharmaceutical ingredient, having chemical name Ethanamine, 2-[4-(2-chloro-1 ,2- diphenylethenyl)phenoxy]-N,N-diethyl, since Clomiphene is a mixture of the geometric isomers trans-Clomiphene (i.e. Enclomiphene) and cis- Clomiphene.
The US patent 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.
In the later publication Acta Cryst. (1976), B32, pag. 291 -293, the actual geometric isomery has been definitely established by single crystal X-Ray diffraction.
Finally, in the publication "Analytical profiles of drug substances and excipients", vol. 25, (1998), pag. 85-121 , in particular at pag. 99, it is stated that prior to 1976 the cis stereochemistry was wrongly assigned to the trans-isomer of Clomiphene (E-Chlomiphene or Enclomiphene), and only after the above publication on Acta Cryst. the correct geometric isomery has been definitively assigned.
These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of US patent 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent, as confirmed by 2D H-NMR analysis (NOESY experiment). Thus, Example 31 of US3,848,030, provides, at the end, Enclomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 133-135°C. Example 32, instead provided Cis-Clomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 120-126°C.
Thus, with the aim of preparing Enclomiphene citrate, whole experiment 31 of US3,848,030 has been reworked also carrying out the crystallization of the product form a mixture of ethyl ether and ethanol, hence providing a not crystalline solid with two DSC peaks respectively at 1 14°C and 188°C, although the starting material used for the reworking example was quite a pure substance (HPLC Analysis (A A%) is 98.95% of Enclomiphene), and having a substantially the same chemical purity of that used in the prior art experiment (m.p. of our Enclomiphene BPA salt was 218°C versus 220- 222°C of the prior art Enclomiphene BPA salt of Example 31 ).
The patent US2,914,563, in example 3, discloses a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1 -ρ-(β- diethylaminoethoxy)phenyl]-1 ,2-diphenylethylene hydrochloride with N- chlorosuccinimmide in dry chloroform under reflux.
Khimiko-Farmatsevticheskii Zhurnal (1984), 18(1 1 ), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 1 1 , pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of Clomiphene citrate and some intermediates of its synthesis) discloses the trans-isomer of Clomiphene citrate, i.e. Enclomiphene citrate, characterized by:
1 H-NMR (MeOD) d 7.4-6.7 (m, 14H); 4.27 (t, 2H, -OCH2); 3.51 (t, 2H, CH2- N); 3.28 (q, 4H, 2xN-CH2)); 2.73 (2H); 2.78 (2H); 1.31 (t, 6H, 2xN-C-CHs)) Melting point: 138-139°C (98% purity by GLC);
IR spectrum, v cm-1 (suspension in mineral oil): 3640, 3430, 1720, 1710
(citrate), 1600-1555 (broad band, stilbene system); 750.
UV spectrum: λ max = 243 nm, ε 21 ,800 and λ max 300 nm, ε 1 1 ,400.
These prior art methods for the preparation of Enclomiphene citrate do not allow the preparation of Enclomiphene citrate having needle shaped crystal habit, indeed the crystallization by means of a mixture of ethyl ether and ethanol does not provide a crystalline solid having needle crystals.
Moreover, Enclomiphene citrate was described in literature with different melting points, in particular, 133-135°C and 138-139°C. Said solid forms of Enclomiphene citrate fail to comply with stabilities studies and furthermore show relatively poor solubility in water either in neutral or acid pH.
Furthermore, the prior art methods have the drawbacks related to the poor reproducibility of the process and of the solid form thus obtained.
Image result for F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
Image result for F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
EXPERIMENTAL SECTION
The starting material Clomiphene citrate can be prepared according to well-known prior art methods, or for example, as described in the example 1 of PCT/EP2015/074746 or can be purchased on the market.
[00190] Example 1 : Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.
Clomiphene citrate
[00191] A round bottom flask was charged 100 gr of Clomiphene Citrate (HPLC analysis (A/A%): 65.21 % Enclomiphene, 34.06% Z-Clomiphene) and 1000 mL of methanol. The suspension was stirred at 30°C up the complete
dissolution. Then a solution of racemic binaphthyl-phosphoric acid (abbreviated BPA) 30 gr (0.515 eq) in 30 ml_ of DMF was added. At the end of addition the mixture was stirred for 1 h at 30°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.
[00192] 50.4 gr of Enclomiphene BPA salt (III) were obtained.
[00193] HPLC Analysis (A/A%): 97.04% Enchlomiphene, 2.5% Z-Clomiphene.
[00194] Example 1 b: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.
[00195] A round bottom flask was charged 50 gr of Clomiphene Citrate and 500 ml_ of methanol. The suspension was heated at 40-45°C and stirred up to the complete dissolution. Then a solution of BPA 15 gr (0.515 eq) in 300 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.
24.1 gr of Enclomiphene BPA salt were obtained.
HPLC Analysis (A/A%): 98.96% Enchlomiphene, 0.69% Z-Clomiphene.
[00196] Example 1 c: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.
[00197] In a round bottom flask was charged 100 gr of Clomiphene Citrate and 1000 ml_ of methanol. The suspension was heated at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 30 gr (0.515 eq) in 1000 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.
47.9 gr of Enclomiphene BPA salt were obtained.
HPLC Analysis (A/A%): 98.81 % Enclomiphene, 0.79% Z-Clomiphene.
[00198] Example 1d: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric, starting from Clomiphene citrate.
[00199] In a round bottom flask was charged 150 gr of Clomiphene citrate and 1500 mL of methanol. The suspension was heater at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 45 gr (0.515 eq) in 900 mL of methanol was added. At the end of addition the mixture was
stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.
76.4 gr of E-Clomiphene BPA salt were obtained.
HPLC Analysis (A/A%): 98.82% Enchlomiphene, 0.80% Z-Clomiphene.
[00200] Example 2: Recrystallization of Enclomiphene BPA salt of formula (III) (the step A).
(Ill)
[00201] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt (III) (50 g) and having Z-isomer of 1.64 % was suspended in DMF (2.1 L/Kg of Enclomiphene BPA (III)) and methanol (1.4 L/Kg of Enclomiphene BPA salt (III)). The suspension was heated to reflux (~ 76-79°C). Further DMF (0.1 L/Kg of Enclomiphene BPA (III)) might be required to improve the solubility of the starting material. Once the starting material was completely dissolved, methanol was added as anti-solvent (3.5 L/Kg of Enclomiphene BPA (III)). The temperature was decreased to 60°C and the mixture was stirred for 2 - 3 h. Then, the temperature was further decreased to 20 °C and filtered. The wet cake was washed twice with methanol (1.5 L/Kg of Enclomiphene BPA salt (III)). The product was dried under vacuum at 60 - 70 °C for 12 - 24 h. Time of drying could be prolonged until residual DMF is < 2500 ppm.
[00202] Analysis of quality of the final product of the above mentioned example and of the same product, obtained from repetition following the same process, it is shown in the following table:
Enclomiphene BPA (III) salt Enclomiphene BPA (III) salt rixx (Starting product) (finale product)
Z-isomer = 1.64 A/A% Z-isomer = 0.07 A/A%
Z-isomer = 0.79 A/A% Z- isomer = 0.03 A/A%
[00203] Example 3: Preparation of Enclomiphene citrate of formula (I), having needle shaped crystal habit, starting from Enclomiphene BPA salt formula (III).
(II)
[00204] Into a proper 4 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt of formula (III) (400 g, assay 99.8 wt% 0.528 mol, 1 equiv.) was suspended in methyl-tert-butyl ether (MTBE, 2 L), isopropanol (IPA, 0.5 L) and water (2 L). The mixture was stirred for 15 minutes, then 0.48 L of ammonia solution 30 wt% was added and the mixture was further stirred for one hour. The aqueous phase was separated and the organic layer was washed with a solution of ammonia solution 30 wt% (0.12 L) and water (0.6 L). The aqueous phase was separated and the organic layer was finally washed with water (0.6 L). The organic solution was evaporated to residue under vacuum at 60-65°C. The residue was dissolved in 1.36 L of absolute ethanol. The assay of the solution was determined at this stage through a potentiometric titration and results in 15.125 wt% as Enclomiphene of formula (II) (0.466 mol). Then 0.24 L of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (100.8 g, 0.475 mol, 1.02 equiv.) was dissolved in absolute ethanol (1.7 L) and water (0.3 L), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 0.4 L of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 269 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.8% molar yield.
[00205] HPLC Analysis (A/A%): 99.79% Enchlomiphene, 0.04% Z-Clomiphene (i.e. Z-isomer).
[00206] Example 4: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of ethanol and water, wherein the amount of water is 15%.
(I)
[00207] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g, 0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_) and water (23 ml_), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30-40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle-shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of absolute ethanol. The product was dried under
vacuum at 65°C. At the end of drying, 20.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.4% molar yield.
[00208] HPLC Analysis (A/A%): 99.86% Enchlomiphene, 0.03% Z-Clomiphene.
[00209] Example 4a: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of isopropanol and water, wherein the amount of water is 15%.
[00210] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (40,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in isopropanol (272 ml_, 6.8 mL/g of free base), then 48 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (21.10 g, 0.100 mol, 1.02 equiv.) was dissolved in isopropanol (340 ml_, 8.5 mL/g of free base) and water (60 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of isopropanol. The product was dried under vacuum at 65°C. At the end of drying, 56.5 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 95.9% molar yield.
[0021 1] Example 4b: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-propanol and water, wherein the amount of water is 15%.
[00212] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-propanol (61 mL, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-propanol (77 ml_, 8.5 mL/g of free base) and water (14 ml_, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of 7-propanol I. The product was dried under vacuum at 65°C. At the end of drying, 1 1.7 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 88.1 % molar yield
[00213] Example 4c: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-butanol and water, wherein the amount of water is 15%.
[00214] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-butanol (61 mL, 6.8 mL/g of free base), then 1 1 mL (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-butanol (77 mL, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of 7-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.6 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 87.4% molar yield.
[00215] Example 4d: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of tert-butanol and water, wherein the amount of water is 15%.
[00216] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in te T-butanol (61 ml_, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in te T-butanol (77 ml_, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of te T-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 84.4% molar yield.
[00217] Example 5: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit. Preparation of the seed crystal.
[00218] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g,
0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_, 8.5 mL/g of free base) and water (23 mL 1.5 mL/g of free base), the solution was heated to 50°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 50°C. The dosage takes place in 30-40 minutes. At the end of the dosage, the stirring was turned off and the mixture was allowed to cool down to room temperature without stirring. The product began to crystallize at 40-30°C. Once reached 20- 25°C the stirring was turned on and the temperature was further decreased to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 13.9 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 62.3% molar yield
[00219] Example 6: Preparation of Enclomiphene citrate of formula (I), having a non-needle shaped crystals, with a mixture of acetone and water, wherein the amount of water is 15%.
Comparative example (see Fig. 8) and evidence example of the invention. Following the same process described in the example 4, substituting ethanol solvent with acetone solvent. Starting from 15,0 g of Enclomiphene of formula (II), following the above mentioned process, 22.3 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 94.2% molar yield product. For the morphology of the crystal see fig. 8.
[00220] Indeed, the microscopy analysis provides a better further evidence of the crystal habit of Enclomiphene citrate (I) of the example 6 (see Fig.8) which has a form more different than/to Enclomiphene citrate (I) having a needle shaped crystal habit, obtained according to above described examples,
1. e. 4, 4a, 4b, 4c, 4d (see Fig. 5, 6 and 7).
[00221] HPLC Analysis (A/A%): 99.63% Enchlomiphene, 0.20% Z-Clomiphene.
[00222] Example 7: Analytical method to identify and quantify Z-Clomiphene of formula (IV) into Enclomiphene of formula (II) or Enclomiphene citrate of formula (I) or Enclomiphene BPA salt of formula (III) and for determining the chemical purity.
[00223] Chromatographic conditions:
Dim. Column: 250 mm x 4.6 mm , 5 pm
Stationaly phase: Butyl sylane (USP phase L26, Vydac 4C is suggested) Temp. Column: room temperature
Mobile Phase: Methanol / water / triethylamine 55 : 45 : 0.3 v/v
Adjust at pH 2.5 with phosphoric acid
Flow: 1.0 mL/min
Detector UV a 233 nm,
Injection Volume: 10 μΙ_
Sample diluent: mobile phase.
Applying the conditions described above the expected retention times are as indicated below:

/////////////////Enclomiphene citrate, New patent, WO 2017182097, F.I.S. - FABBRICA ITALIANA SINTETICI S.P.A
File:Enclomiphene.png
Enclomiphene


Synonyms: Chloramiphene Citrate; Citrato de cloramifeno; Clomifencitrat; Clomifène, citrate de; Clomifeni Citras; Clomifeno, citrato de; Clomiphene Citrate; Klomifeenisitraatti; Klomifen Sitrat; Klomifen-citrát; Klomifén-citrát; Klomifencitrat; Klomifeno citratas; MER-41; MRL-41; NSC-35770; クロミフェンクエン酸塩
BAN: Clomifene Citrate [BANM]
USAN: Clomiphene Citrate
INN: Clomifene Citrate [rINNM (en)]
INN: Citrato de clomifeno [rINNM (es)]
INN: Clomifène, Citrate de [rINNM (fr)]
INN: Clomifeni Citras [rINNM (la)]
INN: Кломифена Цитрат [rINNM (ru)]
Chemical name: A mixture of the E and isomers of 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine dihydrogen citrate
Molecular formula: C26H28ClNO,C6H8O7 =598.1
CAS: 911-45-5 (clomifene);15690-57-0((E)-clomifene ); 15690-55-8 ((Z)-clomifene); 50-41-9 (clomifene citrate); 7599-79-3 ((E)-clomifene
citrate); 7619-53-6 ((Z)-clomifene citrate)
ATC code: G03GB02
ATC code (veterinary): QG03GB02
UNII code: 1B8447E7YI (clomifene citrate); UY5X264QZV ((Z)-clomifene citrate)
Chemical Structure of ClomifeneChemical Structure of Clomifene

NOTE:

Clomifene may be separated into its Z-and E-isomers, zuclomifene and enclomifene
.

Wednesday, 4 October 2017

WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED

WO2017163257) PROCESS FOR PREPARING PURE LH-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVE
IND-SWIFT LABORATORIES LIMITED
ARUL, Ramakrishnan; (IN).
SARIN, Gurdeep Singh; (IN).
WAS, Sandeep; (IN).
KUMAR, Vishal; (IN)
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.
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, wherein none of the intermediates have been isolated to prepare 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole, an important precursor.
Ibrutinib (IMBRUVICA), chemically known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl] prop-2-en- 1 -one is an orally administered drug that targets Bruton’s tyrosine kinase (BTK). Ibrutinib may be used for treating both B cell-related hematological cancers/ B cell chronic lymphocytic leukemia, and autoimmune diseases such as rheumatoid arthritis, Sjogrens syndrome, lupus and asthma and is represented by following chemical formula:
Ibrutinib and its pharmaceutically acceptable salts were first disclosed in US patent US7,514,444. This patent discloses a process for the preparation of Ibrutinib by involving use of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, as intermediate as shown below:
4-Amino-3-(4-phenoxyphenyl)- l H-pyrazolo[3,4-d]pyrimidine, a key intermediate of ibrutinib, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole was first disclosed in a PCT patent publication WO2001/019829 A2 as shown in below scheme.
Various other publications like US patents US7,514,444; US7.718,662; US8,883,803 and PCT publications WO2012/158843 A2; WO2013/010136A2 follow the same process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine as described above.
The process comprises the conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, which is then taken up in mixture of toluene and tetrahydrofuran and further reacted with malononitrile in the presence of diisopropylethylethylamine in toluene. The reaction mixture is stirred overnight and after completion of reaction, followed by work up 1 , 1 -dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is isolated as a residue and which is further purified.
The resulting l, l-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene is reacted with trimethylsilyldiazomethane in a mixture of acetonitrile and methanol in the presence of diisopropylethylamine as a base. The resulting reaction mixture is stirred for 2 days to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product) as an oil, which is purified by flash chromatography.
The O-methylated product is treated with hydrazine hydrate to give 3-amino-4-cyano- 5-(4-phenoxyphenyl)pyrazole, which is further reacted with formamide at a temperature of 180°C to give 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4- d]pyrimidine as pale brown-grey solid.
Since, the above process involves the isolation of intermediates and takes long time during reaction completion. Therefore, it is lengthy, not efficient. Further publication is silent about the purity of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine. Acetonitrile solvent has been used in methylation reaction, which is carcinogenic.
The cyclization reaction has been carried out at 180°C and it is observed that the cyclization reaction at high temperature of 180°C, results in grey brown solid colour of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, may be due to presence of inorganic impurities.
The said process also requires the use of expensive (trimethylsilyl)diazomethane to obtain O-methylated product, which is sensitive to air and water, and hence, the methylation reaction has to be carried out in the absence of water, under anaerobic conditions; silica and flash chromatography are also used for purifying O-methylated product. Since the above process involves complicated operation processes, which leads to high production cost and therefore is not an attractive option at industrially scale.
PCT publication WO2014/173289A1 discloses a process for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as shown below and its conversion into 4- amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine has not been disclosed.
The process involves conversion of 4-phenoxybenzoic acid to the corresponding acid chloride, followed by reaction with malononitrile in the presence of diisopropylethylethylamine in tetrahydrofuran. The reaction mixture has been stirred for 16 hours and thereafter l, l -dicyano-2-hydroxy-2-(4-phenoxyphenyl) ethene is isolated from reaction mixture. A solution of l, l-dicyano-2-hydroxy-2-(4- phenoxyphenyl)ethene in trimethoxymethane has been heated for 16 hours to give l, l-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (O-methylated product), which is then reacted with hydrazine hydrate to give 3-amino-4-cyano-5-(4-phenoxy phenyl)pyrazole.
The above process is inefficient, since it involves isolation of intermediates and takes long time to complete the reactions and purity of 3-amino-4-cyano-5-(4- phenoxypheny pyrazole has not been disclosed.
A similar approach has been described in a PCT publication WO2014/082598 A 1 for preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole and is presented as below:
The process involves conversion of 4-phenoxybenzoic acid to the corresponding acyl chloride by using sulfurous dichloride, followed by reaction with malononitrile in the presence of sodium hydride to obtain l, l-dicyano-2-hydroxy-2-(4-phenoxy phenyl)ethene, which is recrystallized from 1,4-dioxane. The hydroxy moiety is then methylated using dimethyl sulphate to give l, l-dicyano-2-methoxy-2-(4-phenoxy phenyl)ethene (O-methylated product) which is recrystallized from a mixture of hexane and ethylactetate. The solution of resulting O-methylated product in ethanol was treated with hydrazine hydrate at reflux temperature to give 3-amino-4-cyano-5- (4-phenoxy phenyl)pyrazole, followed by its recrystallization in hexane and further, its conversion into 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine was not disclosed.
The above process also involves isolation of intermediates; their purification which leads to longer time in reaction completion, and it does not disclose the purity of 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole. Further the above process involves use of sodium hydride, which is a hazardous reagent and can ignite in air during scale up. Several alternative methods have been reported in literature, wherein process for the preparation of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has been disclosed and are discussed herein.
A Chinese patent application CN103121999A discloses a process of preparation of 4- amino-3 -(4-phenoxy phenyl)- 1 H-pyrazolo[3 ,4-d] pyrimidine, as below :
The process involves reaction of 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine with (4-phenoxyphenyl)boronic acid in the presence of alkali agents and aprotic solvents to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine.
The said Chinese application is also silent about the purity of target compound and even starts with the advance intermediates, which are expensive and make the process unattractive from industrial point of view.
A similar approach has been described in US patent US8,940,893; PCT publication WO2013/1 13097A1 and WO2015/018333 A 1 for preparing 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine .
In US patent US8,940,893 and PCT publication WO2013/1 13097A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by using Combi-flash chromatography on silica gel. In PCT publication WO2015/018333A1, 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine is purified by recrystallization in ethyl acetate.
The purity of 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine has not been reported in above publications too. Further two of the above processes involve tedious step of chromatographic purification, which is not industrial viable.
Another Chinese patent application CN 103965201 A discloses a process for the preparation of 4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine, wherein 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was reacted with trimethyl tin (4- phenoxy phenyl) to give 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidine and followed by its recrystallization in isopropanol, as shown below:
The said Chinese application is also silent about the purity of 4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidine and is not cost-effective because it starts with advance intermediates, which are expensive. Therefore, said route of synthesis is not industrially applicable.
Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products.
According to ICH guidelines, process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction etc., in the manufacturing process. Typically, these limits should less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight. The limits for genotoxic impurities could be much lower depending upon the daily dose of the drug and duration of the treatment. Therefore, in the manufacture of a drug substance, the purity of the starting materials is also important, as impurities may carry forward to the active pharmaceutical ingredient such as ibrutinib.
In view of the above, most of the prior art processes involve isolation of intermediates, additional purification steps and silent about the purity or the assay of 4-amino-3-(4-phenoxy phenyl)- lH-pyrazolo[3,4-d]pyrimidine.
Thus, there is an urgent need for the development of a synthetic process which produces pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine or its acid addition salts.
The present invention fulfills the need in the art and provides an improved, industrially advantageous process for the synthesis of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine, a key intermediate in the preparation of ibrutinib, through preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole from 4-phenoxy benzoic acid using same organic solvent and none of the intermediates have been isolated.
Examples:
Example 1: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
4-Phenoxybenzoic acid (200g) was slowly added to thionyl chloride (400ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 60-65°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 60°C. Toluene (2x400ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 60°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (2000ml). Malononitile (80g) and diisopropylethylamine (320ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature 50-55°C. The reaction mass was further stirred for 30 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid ( 1.25 M) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride ( 10%) and the resulting organic layer was used directly in next reaction.
Dimethyl sulfate (200ml) and sodium bicarbonate (200g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 25-30°C, demineralized water (2000ml) was added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with toluene (1000ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). Activated carbon (20g) was added and reaction mixture was stirred for 30 minutes. The solution was filtered through hyflo bed and to the resulting organic layer hydrazine hydrate ( 120ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-50°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1 -2 hours. The resulting precipitated solid was filtered, slurry washed with dichloromethane (400ml) and finally, dried to obtain title compound of formula V ( 140g) purity 93.28% measured by HPLC.
Example 2: Preparation of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
4-Phenoxybenzoic acid (lOOg) was slowly added to thionyl chloride (200ml) at a temperature of 25-30°C and resulting reaction mixture was heated under stirring to a temperature of 50-55°C for 5 hours. Thionyl chloride was distilled off under vacuum at temperature below 50°C. Toluene (250ml) was added to the resulting oily residue and thereafter distilled out completely under vacuum below 50°C to remove traces of thionyl chloride to obtain 4-phenoxybenzoyl chloride as a viscous oil. The resulting viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (500ml). Malononitile (35.58ml) and diisopropylethylamine (160ml) were sucessively added to the reuslting solution at a temperature of 25-30°C slowly, maintaining reaction temperature around 50-55°C. The reaction mass was further stirred for 10 minutes. After completion of the reaction, the reaction mass was cooled to 25-30°C and a solution of sulfuric acid (70 ml in 1000 ml water) was added. The reaction mixture was then stirred at a temperature of 25-30°C for 30 minutes, and the layers were separated. The organic layer was washed with a solution of sodium chloride (10%) and the resulting organic layer was used directly in next reaction.
Dimethyl sulfate (95.1 1ml) and sodium bicarbonate (96.16g) were added to the resulting organic layer at a temperature of 25-30°C. Thereafter, temperature of reaction mass was raised to 80-90°C and reaction mass was stirred for 1-2 hours. After completion of reaction, the reaction mass was cooled to a temperature of 55- 60°C, demineralized water ( 1000ml) was added. The reaction mass was cooled to a temperature of 25-30°C and stirred for 10- 15 minutes. The layers were separated and the aqueous layer was extracted with toluene (500ml). All the organic layers were combined and washed with sodium chloride solution ( 10%). To the resulting organic layer hydrazine hydrate (50ml) was added at a temperature of 25-30°C. During the addition exothermicity was observed, and temperature of the reaction mass was rose up to 40-45°C. Thereafter, the reaction mass was stirred at a temperature of 25-30°C for 1-2 hours. The resulting precipitated solid was filtered, suck dried to obtain 3- amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V ( 123g) purity 86.96% measured by HPLC.
Example 3: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised and allowed to reflux to dissolve the solid completely to provide a clear solution. Then, solvent was distilled off under vacuum to obtain a residue and isopropanol (50ml) was added and after stirring for hours the solid was filtered and dried to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (26g) and having purity of 97.54 % by HPLC .
Example 4: Purification of 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (36g) was suspended in isopropanol (350ml) and temperature of the reaction mixture was raised upto reflux to dissolve the solid completely upto clear solution. Water (1050ml) was added to the solution and the reaction mixture was gradually cooled to crystallize the product. The resulting solid was filtered, washed with two volumes of isopropanol, dried in vacuum oven at a temperature of 40-45 °C to afford 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole compound of formula V (20g) and having a HPLC purity of 97.23% .
Example 5: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (20g) was suspended in formamide (100 ml) and heated at a temperature of 130°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (500ml) was added and the reaction mixture was stirred at a temperature of 25-30°C for 45 minutes. The resulting solid was filtered and acetone (200ml) was added stirred the reaction mixture for 30-45 minutes. The resulting solid was filtered, washed, dried to afford pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidine compound of formula 1 (12g) having purity 99.6% measured by HPLC.
Example 6: Preparation of pure 4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d] pyrimidine compound of formula I
3-Amino-4-cyano-5-(4-phenoxyphenyl)pyrazole (lOOg) was suspended in formamide (500ml) and heated at a temperature of 135-140°C, after completion of reaction, the reaction mixture was cooled to a temperature of 30-35°C and demineralized water (1000ml) was added and the reaction mixture was stirred at a temperature of 20-25°C for 1 hour. The resulting solid was filtered, washed with water (500ml) then successively slurry washed with toluene (2 x 500ml) and dried to afford pure 4- amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d] pyrimidine compound of formula I
(70g) having purity 99.8% measured by HPLC; assay > 98%; residue on ignition 0.05%; heavy metals < 20ppm.
Example 7: Preparation of (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7-tetraza-lH-inden-4-ylamine
Diisopropyl diazodicarboxylate (DAID, 1.2 ml,) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( l .Og,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-l ,2,5,7-tetraza- lH-inden-4-ylamine (l .Og). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-( l S)- l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)- l,2,5,7-tetraza- lH-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
Example 8: Preparation of l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3,4- d]pyrimidin-l-yl)piperidin-l-yI)prop-2-en-l-one (Ibrutinib)
To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mixture of triethylamine (O. lg) and (lS)-l-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-l,2,5,7- tetraza- lH-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The reaction mixture was stirred at 25-30°C for 18 hous and filtered. The solvent was removed under vacuum to obtain crude ibrutinib, which was further purified by column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.
Formula VI
Formula VII
Formula I
Formula II

Formula III

Formula IV

Formula V
///////WO 2017163257, NEW PATENT, IBRUTINIB, IND-SWIFT LABORATORIES LIMITED