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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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OLANZEPINE VISITED PART 3/3


PART 1…..https://newdrugapprovals.org/2015/04/08/olanzepine/

PART 2….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-22/

PART 3…….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-33/

review……http://cosmos.ucdavis.edu/archives/2011/cluster8/JAIN_VINEET.pdf

WATCHOUT………..

…………….

Org. Biomol. Chem., 2013,11, 2075-2079

DOI: 10.1039/C3OB27424A

http://pubs.rsc.org/en/Content/ArticleLanding/2013/OB/c3ob27424a#!divAbstract

A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is describedvia the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.

 

Graphical abstract: Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

…………..

http://www.google.com/patents/US7329747

 

Olanzapine or 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3b][1,5]-benzodiazepine is a pharmaceutically active compound that can be represented by the formula (1).

Figure US07329747-20080212-C00002

It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water.

One synthetic route for making olanzapine starts from “des-methylpiperazine olanzapine precursor” of formula (3), which reacts with piperazine to form a “des-methyl olanzapine precursor” of formula (2) (see Jun-Da Cen, Chinese Journal of Pharmaceuticals 2001, 32(9),391-393). The compound (2) can be methylated to form olanzapine (see U.S. Pat. No. 4,115,568 for such suggestion). The methylation reaction can be carried out using formaldehyde under conditions of Eschweiler-Clarke reaction (see Jun-Da Cen) or by classical methylation agents such as methyl iodide (see WO 04-000847).

Figure US07329747-20080212-C00003

This synthetic pathway has the disadvantage that the reaction with piperazine may lead to formation of dimeric impurities and that the methylation with formaldehyde or other methylation agent may lead to side products, e.g. products of multiple methylation. All these contaminants are difficult to remove from the product. Also, methylation agents are, in general, toxic and mutagenic compounds.

An alternative of the above process was suggested in WO 04/000847 and comprises converting the compound (2) into a “formyl-olanzapine precursor” of formula (4) by a reaction with a methyl formate, and converting the compound (4) into olanzapine by a reduction with a metal borohydride.

Figure US07329747-20080212-C00004

In comparison with the preceding procedure, the alternate procedure is one step longer and suffers from the same problems in the step of making compound (2). Furthermore, the reported purity of the actually obtained olanzapine product is only 88%, which is not sufficient for pharmaceutical applications.

 

The present invention relates to the formation, purification and/or use of an N-formyl olanzapine. Accordingly, a first aspect of the present invention relates to a process, which comprises reacting a des-piperazine olanzapine of formula (3) or a salt thereof

Figure US07329747-20080212-C00005

with an N-formyl piperazine of formula (5)

Figure US07329747-20080212-C00006

to form an N-formyl olanzapine of formula (4) or a salt thereof

Figure US07329747-20080212-C00007

The reaction can be carried out in an inert solvent, generally a dipolar aprotic solvent, and is typically accomplished by heating. The N-formyl olanzapine can be converted to olanzapine.

Another aspect of the invention relates to a process for making an olanzapine salt, which comprises: reducing an N-formyl olanzapine of formula (4) or a salt thereof

Figure US07329747-20080212-C00008

with a reducing agent in a solvent to form olanzapine or a salt thereof dissolved in said solvent; reacting said dissolved olanzapine or a salt thereof with an acid to form an acid addition salt of olanzapine; and precipitating said olanzapine acid addition salt from said solution. Precipitating the salt of olanzapine can avoid the formation of technical grade olanzapine. That is, the olanzapine salt can be obtained in a purified state and then converted to olanzapine base, if desired, in high purity.

A further aspect of the present invention relates to purifying the N-formyl olanzapine, which process which comprises:

(1) dissolving and/or slurrying an N-formyl olanzapine of formula (4)

Figure US07329747-20080212-C00009

or a salt thereof in a solvent selected from the group consisting of an aliphatic alcohol, an aromatic hydrocarbon, and mixtures thereof, at a temperature of at least 35° C. to form a crystallization treatment medium;

(2) cooling said crystallization treatment medium; and

(3) isolating solid N-formyl olanzapine of formula (4) having improved purity. The steps (1)-(3) can be repeated if necessary until the desired purity is reached. Generally, such a process can achieve purity of greater than 95% and preferably greater than 98%.

An overall synthetic scheme for making olanzapine, which combines various aspects of the present invention, is set forth below:

Figure US07329747-20080212-C00010

 

Example 1

N-Formyl Olanzapine (4)

In a 1000 ml flask, a mixture of 12.0 g of “des-methylpiperazine olanzapine precursor” (compound of formula (2)) hydrochloride and 40 ml of N-formyl piperazine in a mixture of 60 ml of dimethylsulfoxide and 60 ml of toluene was heated at reflux under a nitrogen atmosphere overnight. Progress was monitored by HPLC. After cooling to 40° C., 160 ml of water was added. The resulting mixture was cooled and stirred at 0° C. The solid material was isolated by filtration and washed with 2×40 ml of water. Wet solid was dried overnight at ambient conditions and subsequently at 40° C. under vacuum.

Isolated yield: 12.19 gram, Purity (HPLC): 91.6%

Example 2

Crystallization of the Compound (4)

8.0 g of crude N-formyl olanzapine precursor (compound (4)) of a purity of about 89% (HPLC) was suspended in 50 ml of methanol and heated at 60° C. for 3 hours. The hot suspension was allowed to cool to room temperature and was subsequently cooled to 5° C. under stirring. The solid material was isolated by filtration, washed with 5 ml of cold methanol and 10 ml of cold diethyl ether and dried overnight at 40° C. under vacuum.

Yield: 3.97 g, purity 96.7% (HPLC)

……………….

PATENT

http://www.google.com/patents/WO2004056833A1?cl=en

…………………………….

http://www.google.com/patents/WO2002018390A1?cl=en

Olanzapine is represented by the following structure.

Figure imgf000003_0001

Olanzapine

Olanzapine is useful for treating psychotic patients and mild anxiety states. Preparation of Olanzapine and its acid salts, having pharmaceutical properties particularly in the treatment of disorders ofthe central nervous system has been discussed in U.S. Patent No. 5,229,382.

U.S. Patent No. 5,229,382 does not refer to any specific polymorphic crystalline form of Olanzapine. European patent specification No. 733635A1 claims Form-2 of Olanzapine. The process under this patent describes preparation of Form-2 from ethyl acetate. This patent also designated the product obtained according to the process described in U.S. Patent No. 5,229,382 as Form-1. Furthermore, EP 733635 Al discloses the d values for Form-1 and Form-2 from their X-ray Diffractograms. The values are: d value d value

Form-1 Form-2 9.94 10.26

8.55 8.57 8.24 7.47 6.88 7.12 6.37 6.14 6.24 6.07 5.58 5.48 5.30 5.21 4.98 5.12 4.83 4.98 4.72 4.76 4.62 4.71 4.53 4.47 4.46 4.33 4.29 4.22 4.23 4.14 4.08 3.98 3.82 3.72 3.74 3.56 3.69 3.53 3.58 3.38 3.50 3.25 3.33 3.12 3.28 3.08

3.21 3.06

3.11 3.01

3.05 2.87 2.94 2.81

2.81 2.72

2.75 2.64

2.65 2.60

2.63 2.59

It is noteworthy to mention that EP 0 831 098 A2 discloses the preparation of a series of dihydrates of olanzapine namely Dihydrate B, Dihydrate D and Dihydrate E.

The d values from the X-ray Diffractograms for these forms are listed in EP 0 831

098 A2. We conducted experiments to obtain Olanzapine Form I by recrystallization of olanzapine from acetonitrile using the process described in Example 1, sub example 4 of U.S. Patent No. 5,229,382. The process is described herein for reference: A mixture of 4-amino-2-methyl-10H-thieno-[ 2,3-b] [l,5]benzodiazepine HCl (100 g),

N-methyl piperizine (350ml), DMSO (465 ml) and toluene (465 ml) was heated to reflux. The reaction mass was maintained at reflux for 19 hours and then cooled to

50°C and water was added. The reaction mass was cooled to 0-10°C and stirred at the same temperature for 6 hours. The crude Olanzapine separated was filtered and dried in oven to a constant weight (76.5 g). The crude compound was added to acetonitrile (750 ml) at boiling temperature. The mixture was boiled for further 5 minutes. The mixture was filtered to remove the undissolved solid. The filtrate was treated with carbon and filtered. The filtrate was distilled to a minimum volume, cooled to 0-5 °C and maintained at the same temperature for 1.0 hour and filtered.

The compound was dried to a constant weight in an oven (51.6g).

The polymorphic form obtained from these experiments was characterized for its X-ray Powder Diffraction on Rigaku D / Max 2200. As clearly observed, the d values for this product (Fig. 1) matched with those of Olanzapine Form-2 claimed in EP 733635A1. It is therefore inferred that the recrystallization of Olanzapine in acetonitrile produces Form-2 and not Form-1.

Accordingly, the present invention provides a novel method for preparation of hydrates of olanzapine, which are different from those reported in the literature. These hydrates are named Olanzapine monohydrate-I and Olanzapine dihydrate-I for convenience.

Accordingly, the present invention also provides a novel method for preparation of Olanzapine Form-1 by recrystallization of olanzapine or its hydrates in dichloromethane . The present invention also provides a novel method for converting Olanzapine

Form-2 to Olanzapine Form-1

 

PREPARATION OF OLANZAPINE MONOHYDRATE-1

EXAMPLE 1 A mixture of 4-amino-2-methyl-10H-thieno-[2,3-b][l,5]benzodiazepine hydrochloride (20 Kg), N-methyl piperazine (42 lit), dimethyl sulfoxide (40 lit) and toluene (95 lit) was heated to reflux. The reaction mass was maintained at reflux for

17 hours and 15 minutes and then cooled to 40-50°C. Water (95 lit) was added slowly at40-50°C. The reaction mass was cooled to -0.6 to 1.2°C and stirred at the same temperature for six hours. The Olanzapine crude that separated was filtered and washed with water (10 lit). The product was dried at 30.5 to 31.8°C for 10 hrs and 50 minutes. Yield: 20 Kg. A 20 gm sample from the above material after prolonged heating for an additional 72 hours gave the product with a moisture content of 5.22%.

PREPARATION OF OLANZAPINE DIHYDRATE-I EXAMPLE 2

A mixture of 4-amino-2-methyl-l OH-thieno- [2,3-b] [ 1 ,5]benzodiazepine hydrochloride (200 g), N-methyl piperazine (420 ml), dimethyl sulfoxide (200 ml) and toluene (940 ml) was heated to reflux. The reaction mass was maintained at reflux for 12 hours and then cooled to 40°C. Water (940 ml) was added slowly at 40-44°C. The reaction mass was cooled to 0-5°C and stirred at the same temperature for five hours. The Olanzapine crude that separated was filtered and washed with water (100 ml). The solid obtained was dried atmospherically (25-35°C) for 24 hours (Yield :

241 g).

PREPARATION OF FORM-1

EXAMPLE 3 Crude 2-methyl-4-(4-methyl- 1 -piperazinyl)- 1 OH-thieno- [2,3 -b] [ 1 ,5] benzodiazepine (35.0 g) was suspended in dichloromethane (160.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (3.5 g) followed by filtration. Upon completion of this step the filtrate was cooled to 0 to 5°C and stirred at the same temperature for one hour. The separated solid was filtered and washed with chilled dichloromethane (10.0ml). The product obtained on drying in oven at 65 to 70°C to a constant weight gave Form-1 of Olanzapine (Yield 22.0 g).

CONVERSION OF FORM-2 TO FORM-1 EXAMPLE 4 The stirred suspension of pure form-2 of 2-methyl-4-(4-methyl-l-piperazinyl)-

10H-thieno-[2,3-b][l,5]benzodiazepine (20.0 g) in dichloromethane (90.0 ml) was heated to reflux to obtain a clear solution. The clear solution was filtered and the filtrate was then cooled to 3 to 5°C and stirred at same temperature for one hour. The crystalline solid separated was filtered and washed with dichloromethane (4.0 ml). Subsequent drying at 60 to 70°C to a constant weight yielded Olanzapine Form-1. (Yield: 12.7 g).

PREPARATION OF FORM-1 FROM MONOHYDRATE-I OF OLANZAPINE

EXAMPLE 5 Monohydrate-I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3- b][l,5] benzo- diazepine (25.0 g) prepared as per Example- 1 was suspended in dichloromethane (325.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (2.5 g) followed by filtration. Upon completion of this step the filtrate was distilled to a minimum volume and then cooled to 2 to 4°C and stirred at the same temperature for 90 minutes. The product separated was filtered arid washed with chilled dichloromethane (10 ml). The product obtained on drying in oven at 60 to 70°C to a constant weight gave Form-1 of Olanzapine (Yield 16.5 g)

PREPARATION OF FORM-1 FROM DIHYDRATE-I OF OLANZAPINE

EXAMPLE 6 Dihydrate-I of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3-b][l,5] benzodiazepine (40.0 g) prepared as per Example-2 was suspended in dichloromethane (520.0 ml). The suspension was heated to reflux to obtain a clear solution. The resultant solution was then treated with carbon (4.0 g) followed by filtration. Upon completion of this step the filtrate was distilled to a minimum volume and the left over reaction mass was cooled to 0 to 2°C and stirred at the same temperature for one hour. The separated solid was filtered and washed with dichloromethane (10.0ml). The product obtained on drying in oven at 65 to 70°C to a constant weight renders Form-1 of Olanzapine (Yield 26.0 g).

The aforementioned crystalline forms in examples 1 to 6 have been examined for their structural and analytical data viz., Powder X-Ray Diffraction, Differential Scanning Calorimetry, and Infrared Absorption Spectroscopy. The results obtained are discussed and the respective drawings attached (Fig. 2 -19).

………………………………..

 http://www.google.com/patents/EP2292624A1?cl=en

  • Olanzapine is a pharmaceutical active substance from the group of antipsychotics, applicable for the treatment of different mental diseases and conditions, such as, for example, disorders of the central nervous system, schizophrenia, hallucination, acute mania, depression, and the like.
  • Chemically, it belongs to the group of the benzodiazepines and is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (formula 1).

    Figure imgb0001
  • Olanzapine and analogues thereof are encompassed for the first time within a general formula in the patent GB 1,533,235 and specifically described in EP 454 436 B1 . The patents disclose two different one-step processes for olanzapine preparation. The first described process is a reaction of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride with N-methylpiperazine in an organic solvent, such as anisole, toluene, dimethyl formamide or dimethyl sulfoxide, preferably at a temperature from 100 to 150°C to yield olanzapine (Scheme 1).

    Figure imgb0002
  • The second process disclosed in EP 454 436 B1 is the reaction of N-methylpiperazine with methyl-2-(2-aminoanilino)-5-methylthiophene-3-carboxylate in the presence of titanium tetrachloride (Scheme 2).

    Figure imgb0003
  • The same patent also mentions the formation of acid addition salts of olanzapine and their potential use as intermediates in olanzapine purification process and for a pharmaceutical use.
  • As disclosed in EP 454 436 B1 and US equivalent US 5,229,382 , olanzapine obtained according to the first synthesis (Scheme 1) is purified by recrystallization from acetonitrile, whereas olanzapine prepared according to the second route (Scheme 2) is further purified by column chromatography on Florisil® and recrystallization from acetonitrile. This purification procedure lacks on industrial applicability.
  • Some other synthetic approaches for the preparation of olanzapine describe two steps for creating 4-methylpiperazinyl side chain (Scheme 3). Firstly, 4-amino-2-methyl-10H-thieno [2,3-b][1,5] benzodiazepine hydrochloride reacts with piperazine to yield 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (i.e. N-desmethylolanzapine; Bioorganic & Medicinal Che-mistry Letters, Vol. 7, No. 1, pp. 25-30, 1997), then the methyl group is introduced either by reductive N-methylation (using formaldehyde and metal boron hydride -WO 04/000847) or by nucleophylic substitution reaction with methyl iodide (WO 05/090359). The two-step approach reduces the dark colour appearance but it does not solve the problem of purification from similar by-products.

    Figure imgb0004
  • It is well known to a skilled person that most chemical reactions are not completely finished, may be reversible or are driven simultaneously with some other parallel reactions. Starting materials or side reaction products are usually found as impurities in the isolated main product which should therefore be further purified. The simplest way of purification includes various recrystallization and precipitation procedures which are usually less effective if the impurities have physico-chemical properties very similar to the main product.
  • In the case where olanzapine is prepared according to the one step processes disclosed in EP 454 436 B1 , the starting material, 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine, is found as an impurity in the final product olanzapine.
  • In the case of preparation of olanzapine via the two-step process, as disclosed also in the patent application WO 04/000847 , the presence of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine hydrochloride is not critical but various other similar compounds could be found as impurities, such as 4-(4-formylpiperazinyl)-2-methyl-10H-thieno[2,3-b][1,5]-benzo diazepine and N-desmethylolanzapine. In the case of preparation of olanzapine by a two-step process with methyl iodide, an overmethylated N,N-dimethylpiperazinium analogue can be formed.
  • A further undesired impurity which accompanies olanzapine is obtained when olanzapine compound is dissolved in methylene chloride. It is so called olanzapine-CM, being (E)-1-(chloromethyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium chloride). Olanzapine-CM is formed by alkylation of olanzapine with methylene chloride in methylene chloride solution, for example during evaporation of methylene chloride before the crystallization (Scheme 4).

    Figure imgb0005
  • According to the Regulatory Toxicology and Pharmacology 44, pp. 198-211, 2006, classification of potential genotoxic impurities, olanzapine-CM is a potential genotoxic substance due to its R-CH2-Cl structural element, which is known to be involved in reactions with DNA.
  • For all impurities that have a thienobenzodiazepine ring system as a part of the molecule skeleton and because it represents a great part of the molecule, said ring system is crucial for the similarity of physico-chemical properties of said impurities compared to olanzapine.
  • Different salts and crystal forms of an active pharmaceutical ingredient are an important tool for modulating pharmacokinetic properties but can be also a tool for purification.
  • WO 04/089313 discloses olanzapine acid salts, solvates and co-crystals and their use as active pharmaceutical ingredients in formulations. The preparation of fumaric, maleic and malonic acid addition salts of olanzapine is disclosed in WO 04/089313 . Olanzapine acid addition salts disclosed in this application exhibit specific aqueous solubility from 50 µg/ml to 100 mg/ml.
  • WO 05/090359 discloses a method for the purification of olanzapine which has on one hand been prepared by the one-step-process according to Scheme 1, and on the other hand by the process according to Scheme 3, by preparing an addition salt of at least one carboxylic salt, purification of said salt and transfer into purified olanzapine.
  • Neutral olanzapine can be isolated in various crystal forms, hydrates and other solvates. However crystal forms I and II are the most often mentioned as an active pharmaceutical ingredient. Both forms were first disclosed in EP 733 635 alleging that form II is thermodynamically more stable than form I which had been prepared already by the basic patent procedures ( EP 454 436 B1 ).
  • Crystal Growth & Design, Vol. 3, No. 6, pp. 897-907, 2003 discloses anhydrates and hydrates of olanzapine.
  • Olanzapine form I is thermodynamically less stable but it can possess specific kinetic properties which can be applied in designing a final dosage form. Many procedures are known how to prepare it but a person skilled in the art can soon find that the use of methylene chloride is unavoidable to develop a repeatable process. Because this solvent is used in the final step of preparation of olanzapine form I, previous purification methods cannot prevent the presence of the impurity olanzapine-CM in the final product.
  • WO 03/101997 A1 discloses a process for the preparation of a pure olanzapine form I by an addition of methyl-piperazine to the hydrochloride salt of the corresponding benzodiazepine derivative. The purification of olanzapine is conducted by recrystallization. Olanzapine-CM is not disclosed as a disturbing side product which can be removed by recrystallization.
  • WO 02/18390 discloses a process for the preparation of hydrates of olanzapine and the conversion thereof into crystalline forms of olanzapine by recrystallization from methylene dichloride. It is not disclosed that essentially pure olanzapine can be obtained by the removal of olanzapine-CM.
  • WO 04/056833 A1 discloses a process for the preparation of essentially pure olanzapine by removing olanzapine-CM, which is obtained from a solution of olanzapine in methylene chloride, by treating this solution with SiO2, followed by the removal of SiO2. According to the examples, olanzapine is obtained having a purity of 99.92 %, whereas olanzapine-CM is present in an amount of 0.05 %, corresponding to 500 ppm. But SiO2 is acidic, so it adsorbs well also the basic olanzapine what leads to considerable losses of the mother compound.
  • Olanzapin-CM has to be removed in order to obtain essentially pure olanzapine with a high purity which can be further used in pharmaceutical applications. It has been found that olanzapine cannot be efficiently separated from its highly related impurities, in particular from olanzapine-CM, using repeated crystallizations of crude olanzapine. It would therefore be desirable to develop a purification process, in order to provide pharmaceutically acceptable pure and discoloured olanzapine, in particular to provide pharmaceutically acceptable pure olanzapine, being essentially free of the olanzapine-CM impurity. A further object of the present invention is to provide a process for the purification of olanzapine which can also and preferably be conducted in a large scale synthesis.

Example 1 – Synthesis of olanzapine oxalic salt

    • [0093]
      A solution of 12.0 g of N-desmethylolanzapine in 90 mL of THF and 36 mL of dimethylacetamide (DMAc) is cooled to approx. -20 °C. At -20 °C, 8.19 g of diisopropylamine is added to the solution and afterwards, 8.14 g of methyl iodide is added over 30 min. After stirring the reaction mixture for 65 minutes at -20 °C, 6.4 mL of concentrated hydrochloric acid in 50 mL of water and a solution of 6.36 g of thiourea in 50 mL of water is added and the reaction mixture is stirred for 15 minutes at 20 °C. Then THF is evaporated off and 120 mL of methylene chloride is added and the pH is adjusted to 8.6 with a 40 % water solution of NaOH. After the separation of the phases, the water phase is washed twice with 60 and 30 mL of methylene chloride. The organic phases are combined and 380 mg of acetic anhydride is added and the mixture is stirred for 5 minutes. Then 6.20 g of oxalic acid in 24 mL of methanol is added within 15 minutes. The resulting suspension is stirred for about 1 hour at approx. 20 °C and afterwards 1 hour at approx. 0 °C. The product is isolated by filtration, washed with 100 mL of methylene chloride and dried for 15 hours at 25 °C in vacuo. Yield: 15 g (93 %).

Example 2 – Formation of olanzapine form I

    • [0094]
      5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. After the solution is concentrated in vacuo to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

      HPLC-Purity: 99.9 %
      olanzapine-CM 380 ppm
      IR Form I
      XRD Form I

Example 3 – Formation of olanzapine form I (scale up)

    • [0095]
      24 kg of olanzapine oxalate is dissolved in 240 L of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 2.4 kg of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 L of water. The filtrate and wash water are combined and after the addition of 300 L of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 15 minutes, the layers are separated and the water phase is extracted twice with 50 L of methylene chloride. The organic layers are combined and washed twice with 100 L of water. After the solution is concentrated in vacuo to the volume of 50 L, the solution is immediately cooled to -15 °C. The resulting suspension is stirred for 30 minutes, then olanzapine is isolated by filtration. The wet cake is washed with 10 L of methylene chloride of the temperature of -20 °C. The product is dried for 10 hours at 100 °C in vacuo.

      HPLC-Purity: 99.7 %
      olanzapine-CM 1000 ppm
      IR Form I
      XRD Form I

Example 4 – Formation of olanzapine form I

      (

Al2O3 fluidized bed adsorption

      )

    • [0096]
      5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. After 0.2 g of Al2O3 is added and the methylene chloride suspension is stirred for 5 minutes, Al2O3 is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

      HPLC-Purity: 99.9 %
      olanzapine-CM 214 ppm
      IR Form I
      XRD Form I

Example 5 – Formation of olanzapine form I (Al2O3 fluidized bed adsorption

      )

    • [0097]
      5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Afterwards, the methylene chloride solution is concentrated to 30 mL and 0.2 g of Al2O3is added. After stirring for 5 minutes, Al2O3 is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

      HPLC-Purity: 99.9 %
      Olanzapine-CM 321 ppm
      IR Form I
      XRD Form I

Example 6 – Formation of olanzapine form I (Al2O3 fluidized bed adsorption

      )

    • [0098]
      5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Then the methylene chloride solution is concentrated to 30 mL and 1 g of Al2O3 is added. After stirring for 5 minutes, Al2O3 is filtered off and the methylene chloride solution is concentrated to the volume of 15 mL. The solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of a temperature of -20 °C. The product is dried for four hours at 100 °C in vacuo.

      HPLC-Purity: 99.9 %
      olanzapine-CM 138 ppm
      IR Form I
      XRD Form I

Example 7 – Formation of olanzapine form I (Al2O3 short column adsorption)

    • [0099]
      5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Then the methylene chloride solution is concentrated to 30 mL and filtered through 20 g of Al2O3 (h = 2 cm). After the methylene chloride solution is concentrated to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of-20 °C. The product is dried for four hours at 100 °C in vacuo.

      HPLC-Purity: 99.9 %
      olanzapine-CM 162 ppm
      IR Form I
      XRD Form I

Example 8 – Formation of olanzapine form I (Al2O3 short column adsorption)

  • [0100]
    5 g of olanzapine oxalate is dissolved in 50 mL of water and the pH of the solution is adjusted to 2.0 by the addition of 6 N HCl. To the resulting clear solution of olanzapine oxalate, 0.5 g of charcoal is added. After stirring for 5 minutes, the charcoal is filtered off and the cake is washed with 10 mL of water. The filtrate and wash water are combined and after the addition of 60 mL of methylene chloride, the pH of the combined mixture is adjusted to 9.0 by the addition of a 40 % water solution of NaOH. After stirring for 5 minutes, the layers are separated and the water phase is extracted twice with 10 mL of methylene chloride. The organic layers are combined and washed twice with 20 mL of water. Afterwards, the methylene chloride solution is concentrated to 30 mL and filtered through 20 g of Al2O3 (h = 5 cm). After the methylene chloride solution is concentrated to the volume of 15 mL, the solution is immediately cooled on an ice/salt bath. The resulting suspension is stirred for 15 minutes, and then olanzapine is isolated by filtration. The wet cake is washed with 3 mL of methylene chloride of the temperature of-20 °C. The product is dried for four hours at 100 °C in vacuo.

    HPLC-Purity: 99.9 %
    olanzapine-CM 73 ppm
    IR Form I
    XRD Form I

    Table 1. Comparison and overview of beneficial effect of Al2O3 treatment

    Ex. Scale Treatment Mass (Al2O3) [g] Al2O3 pad height [cm] CM assay [ppm]
    2 5 g none / / 380
    3 24 kg none / / 1000
    4 5 g fluidized bed adsorption 0.2 / 214
    5 5 g fluidized bed adsorption (concentrated to 30 mL) 0.2 / 321
    6 5 g fluidized bed adsorption (concentrated to 30 mL) 1.0 / 138
    7 5 g short column adsorption (concentrated to 30 mL) 20 2 162
    8 5 g short column adsorption (concentrated to 30 mL) 20 5 73

    Table 2. As comparative data, olanzapine obtained by processes according to the prior art comprises the following amounts of olanzapine-CM:

    No. prior art amount of olanzapine-CM
    1 WO 2005/090359 , lab. scale 300 – 400 ppm
    2 WO 2005/090359 , industrial scale 800 – 2000 ppm
    3 WO 2004/056833 <0.15%

………………………………

 

 

Cited Patent Filing date Publication date Applicant Title
EP0454436B1 Apr 24, 1991 Sep 13, 1995 Lilly Industries Limited Pharmaceutical compounds
EP0733635A1 Mar 22, 1996 Sep 25, 1996 Eli Lilly And Company Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation
GB1533235A Title not available
US5229382 May 22, 1992 Jul 20, 1993 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
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WO2003101997A1 May 30, 2003 Dec 11, 2003 Geneva Pharmaceuticals Inc Process of preparation of olanzapine form i
WO2004000847A1 Jun 10, 2003 Dec 31, 2003 Adamed Sp Zoo A process for the preparation of olanzapine and an intermediate therefor
WO2004056833A1 Dec 15, 2003 Jul 8, 2004 Adamed Sp Zoo A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine
WO2004089313A2 Mar 31, 2004 Oct 21, 2004 Magali Bourghol Hickey Novel olanzapine forms and related methods of treatment
WO2005090359A2 Mar 17, 2005 Sep 29, 2005 Lek Pharmaceuticals Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof
WO2008139228A2 * May 14, 2008 Nov 20, 2008 Generics Uk Ltd Process for the purification of olanzapine
Reference
1 BIOORGANIC & MEDICINAL CHE-MISTRY LETTERS vol. 7, no. 1, 1997, pages 25 – 30
2 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 7, no. 1, 1997, pages 25 – 30
3 CRYSTAL GROWTH & DESIGN vol. 3, no. 6, 2003, pages 897 – 907
4 REGULATORY TOXICOLOGY AND PHARMACOLOGY vol. 44, 2006, pages 198 – 211
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EP2264016A2 Jul 14, 2004 Dec 22, 2010 Jubilant Organosys Limited A process for producing pure form form of 2-Methyl-4-(4-Methyl-1-Piperazinyl)-10h-thieno[2,3-B][1,5] benzodiazepine
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US7323459 Dec 24, 2003 Jan 29, 2008 Teva Pharmaceutical Industries Ltd. Dissolving olanzapine in a solution of acetic acid and water; filtering the solution; stirring the solution; precipitating the crystalline form by adding a base; and isolating the crystals
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US7538213 May 16, 2003 May 26, 2009 Institut Farmaceutyczny Condensation of molar excess of N-methylpiperazine with 4-amine-2-methyl-10H-thieno [2,3-b][1,5]benzodiazepine hydrochloride in dimethylsulfoxide; recovery and purification with methylene chloride
US7745429 Jul 14, 2003 Jun 29, 2010 Krka, D.D. Novo Mesto Crystal forms of olanzapine and processes for their preparation
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US7829700 Sep 5, 2005 Nov 9, 2010 Shasun Chemicals And Drugs Limited Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine
US7834176 Jan 26, 2006 Nov 16, 2010 Sandoz Ag Polymorph E of Olanzapine and preparation of anhydrous non-solvated crystalline polymorphic Form I of 2-methyl-4(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine (Olanzapine Form I) from the polymorphic Olanzapine Form E
WO2002018390A1 * Mar 7, 2001 Mar 7, 2002 Ramesh Chakka Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine
WO2003097650A1 * May 16, 2003 Nov 27, 2003 Urszula Fraczek Methods for preparation of olanzapine polymorphic form i
WO2003101997A1 * May 30, 2003 Dec 11, 2003 Geneva Pharmaceuticals Inc Process of preparation of olanzapine form i
WO2004006933A2 * Jul 14, 2003 Jan 22, 2004 Krka D D Novo Mesto Crystal forms of olanzapine and processes for their preparation
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US5229382 * May 22, 1992 Jul 20, 1993 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
US5703232 * Jan 16, 1996 Dec 30, 1997 Eli Lilly And Company Process and solvate of 2-methyl-thieno-benzodiazepine
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WO2007144901A1 * Jun 12, 2007 Dec 21, 2007 Jubilant Organosys Ltd Process for stabilization of olanzapine polymorphic form i
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WO2011009831A1 Jul 19, 2010 Jan 27, 2011 Lek Pharmaceuticals D.D. Process for the purification of olanzapine
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US7829700 Sep 5, 2005 Nov 9, 2010 Shasun Chemicals And Drugs Limited Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine

 

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
 
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Cited Patent Filing date Publication date Applicant Title
WO1996038151A1 May 30, 1995 Dec 5, 1996 Lilly Co Eli Method for treating cognitive dysfunction
WO1999016312A1 * Sep 25, 1998 Apr 8, 1999 Lilly Co Eli Method for treating sexual dysfunction
WO2001047933A1 Dec 22, 2000 Jul 5, 2001 Cipla Ltd New polymorphic forms of olanzapine
WO2002018390A1 Mar 7, 2001 Mar 7, 2002 Ramesh Chakka Process for preparation of hydrates of olanzapine and their conversion into crystalline forms of olanzapine
WO2003097650A1 May 16, 2003 Nov 27, 2003 Urszula Fraczek Methods for preparation of olanzapine polymorphic form i
WO2003101997A1 * May 30, 2003 Dec 11, 2003 Geneva Pharmaceuticals Inc Process of preparation of olanzapine form i
WO2004056833A1 Dec 15, 2003 Jul 8, 2004 Adamed Sp Zoo A process for the preparation of a pharmaceutically pure polymorphic form i of olanzapine
WO2005107375A2 * Apr 4, 2005 Nov 17, 2005 Jyothi Basu Abbineni Process for the preparation of olanzapine form-i
WO2006006180A1 * Jul 14, 2004 Jan 19, 2006 Akshat Bhatnagar A PROCESS FOR PRODUCING PURE FORM OF 2-METHYL-4-(4-METHYL-1-PIPERAZINYL)-10H-THIENO[2,3-b][1,5]BENZODIAZEPINE
WO2006010620A2 Jul 28, 2005 Feb 2, 2006 Krka Tovarna Zdravil D D Novo Olanzapine salts and their conversion to olanzapine free base
EP0454436A1 Apr 24, 1991 Oct 30, 1991 Lilly Industries Limited Pharmaceutical compounds
EP0454436B1 Apr 24, 1991 Sep 13, 1995 Lilly Industries Limited Pharmaceutical compounds
EP0733635B1 Mar 22, 1996 Aug 16, 2001 Eli Lilly And Company Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation
US5637584 Mar 24, 1995 Jun 10, 1997 Eli Lilly And Company Solvate of olanzapine
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OLANZEPINE VISITED PART 2/3


PART 1…..https://newdrugapprovals.org/2015/04/08/olanzepine/

PART 2….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-22/

PART 3…….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-33/

WATCHOUT………..

 

…………………….

PATENT

 http://www.google.com/patents/US7459449

Olanzapine is a pharmaceutically active compound that can be represented by formula (1).

Figure US07459449-20081202-C00001

It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water; i.e., solubility at pH 6.8=0.02 mg/ml.

The olanzapine base is known to exist in various crystalline modifications and in various hydrated forms that are generally stable at ambient conditions; see for example EP 733635 and corresponding U.S. Pat. No. 5,736,541; WO 98-11893; and EP 831098. Having so many different forms is considered to be a disadvantage as repeated production of olanzapine substance may give rise to unpredictable amounts of the respective modifications in the product, which in turn can influence the properties of the product such as in tabletting and/or releasing of the active from the tablets after ingestion.

WO 99-16313 discloses olanzapine pamoate as a pharmaceutical agent. It is a compound that is also insoluble in water and is useful particularly in intramuscular depot forms. However, like the free base, the pamoate salt exists in several forms including hydrates, solvates, and in different counter ion ratios.

WO 03-007912 discloses an amorphous lyophilized olanzapine in a reconstitutable parenteral formulation. The olanzapine is “intimately mixed” with a stabilizer and a solubilizer. The stabilizer is preferably lactose and the solubilizer includes organic acids and most preferably tartaric acid. The composition is formed by lyophilizing, i.e. a type of freeze drying, a solution of olanzapine, the stabilizer and the solubilizer to form the intimate mixture. The resulting lyophilized amorphous product can be reconstituted with parenteral diluents to make an injectable composition. Whether the tartaric acid salt of olanzapine is present in the lyophilized product is unclear.

For instance, the “des-methyl olanzapine” (2) may be methylated by formic acid/formaldehyde (Chinese Journal of Pharmaceuticals 2001, 32, 391-393) to form an olanzapine reaction mixture.

Figure US07459449-20081202-C00002

Similarly, the “des-piperazine olanzapine” (3) can be treated with N-methylpiperazine in DMSO under conditions of olanzapine formation to produce a reaction mixture containing olanzapine.

Figure US07459449-20081202-C00003

In a third process, the “formyl-olanzapine” (4) is reduced by a reducing agent, for instance by a borohydride agent (WO 2004/000847) or by hydrogen under the presence of a hydrogenation catalyst.

Figure US07459449-20081202-C00004

The starting compounds (2), (3), and (4) are known compounds and may be obtained by procedures known in the art.

EXAMPLE 16A

Olanzapine Benzoate by Methylation of Desmethyl Olanzapine

Figure US07459449-20081202-C00005

In a 100 ml flask, equipped with a magnetic stirrer, 0.5 g desmethyl olanzapine was dissolved in 5 ml DMSO. Then, 0.142 g formic acid (37% in water) and 0.082 g formic acid (98%) were added and the resulting mixture was heated at 80° C. for 2 hours. After cooling to room temperature, 20 ml ethyl acetate and 20 ml water were added. The organic layer was washed with 2*20 ml water and 20 ml saturated aqueous NaCl, dried (Na2SO4) and concentrated at reduced pressure to a volume of about 10 ml. Then, 0.200 g benzoic acid dissolved in 2 ml ethyl acetate was added dropwise to the crude olanzapine solution. An off-white/yellow solid formed which was isolated by filtration and dried over weekend at 40° C. in vacuo. Isolated yield: 0.58 gram (80%). 1H-NMR: expected compound; trace of ethyl acetate present.

EXAMPLE 16B

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00006

In a 250 ml flask, equipped with a magnetic stirrer, 4.3 g of N-desmethylpiperazine-olanzapine was refluxed in a mixture of 15 ml N-methylpiperazine, 20 ml DMSO, and 20 ml toluene under a nitrogen atmosphere for 20 hours. The mixture was cooled and 50 ml water was added. The aqueous layer was extracted three times with 150 ml ethyl acetate and the combined organic layers were washed 3 times with 100 ml water and once with 100 ml aqueous saturated sodium chloride. After drying over Na2SO4, the organic layer was concentrated to about 100 ml and 1.6 g benzoic acid was added. After a few minutes, a yellow solid was formed. Stirring was continued at 4° C. for 1 hour. The solid material was isolated by filtration, washed with 5 ml ethyl acetate and 10 ml diethyl ether, and dried overnight at 40° C. in vacuum. Isolated yield: 4.61 g (80%; based on benzoic acid).

EXAMPLE 16C

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00007

In a 2000 ml flask, 50 g of desmethyl olanzapine was dissolved in 450 ml of DMSO. Then, 13.04 g of formaldehyde (37% in water) and 7.59 g of formic acid (98%) were added and the resulting mixture was heated at 80° C. for 2 hours. The crude reaction mixture was poured into a mixture of 1000 ml of ethyl acetate and 1000 ml of ice-cooled water. The aqueous layer was separated and extracted with 2×500 ml of ethyl acetate. The combined organic layers were washed with 3×500 ml of water and 500 ml of saturated aqueous NaCl, dried (Na2SO4) and concentrated at reduced pressure to a volume of about 1000 ml. To the warm solution, 20.4 g of benzoic acid was added in one portion under stirring. An off-white/yellow solid was formed. Stirring was continued overnight at room temperature and subsequently for 2 hours at 4 C. The yellow solid was isolated by filtration, washed with 30 ml of cold ethyl acetate and 100 ml of diethyl ether and dried overnight at 60° C. in vacuo. Isolated yield: 60.25 g. Assay (HPLC): 99.1%.

EXAMPLE 16D

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00008

In a 3000 ml flask, 86 g of desmethylpiperazine-olanzapine hydrochloride was refluxed in a mixture of 300 ml of N-methylpiperazine, 400 ml of DMSO, and 400 ml of toluene under a nitrogen atmosphere for 5 hours. The mixture was cooled to 50° C. and poured into a mixture of 2000 ml of ethyl acetate and 2000 ml of ice-cooled water. The aqueous layer was extracted with 2×500 ml of ethyl acetate and the combined organic layers were washed with 3×500 ml of water and with 500 ml of aqueous saturated sodium chloride. After drying over Na2SO4, the organic layer was concentrated to about 1500 ml and 39.6 g of benzoic acid was added in one portion. After a few minutes, a yellowish solid was formed. Stirring was continued overnight at room temperature. The solid material was isolated by filtration, washed with 50 ml of ethyl acetate and 200 ml of diethyl ether, and dried overnight at 60° C. in vacuum. Yield: 86.35 gram.

EXAMPLE 16E

Olanzapine Benzoate from Formyl Olanzapine

Figure US07459449-20081202-C00009

In a 250 ml flask, 3.0 g of N-formyl olanzapine precursor (compound (4)) was suspended in 45 ml of dry toluene and cooled to 0C. Under nitrogen atmosphere, 5.4 ml of Red-Al™ solution (70 wt % solution of sodium dihydrido-bis(2-methoxyethoxy) aluminate in toluene) was added dropwise under stirring. The resulting mixture was allowed to warm up to room temperature. Then 5.0 ml of Red-Al solution was added dropwise at this temperature. After stirring for 5 hours at room temperature, the reaction mixture was poured into 100 ml of water and immediately 100 ml of ethyl acetate was added. The mixture was filtered over a P3-filter to remove insoluble material. The biphasic filtrate was allowed to stand for separating the layers and the aqueous layer was removed and washed with 2×50 ml of ethyl acetate. The combined organic layers were washed with 2×50 ml of water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a volume of about 50-60 ml. Then, 1.12 g of benzoic acid was added in one portion and the resulting mixture was stirred at 4° C. for 4 hours. The formed solid was isolated by filtration, washed with 5 ml of cold ethyl acetate and 10 ml of cold diethyl ether, and dried overnight at 40 C under vacuum. Yield: 2.75 gram, purity (HPLC): 94.8%.

………………

PATENT

http://www.google.com/patents/WO2003101997A1?cl=en

EXAMPLE 1 ULTRA-PURE OLANZAPINE FORM I

Figure imgf000004_0001

A three necked flask, fitted with a nitrogen gas inlet and a water condenser with calcium chloride guard tube, is charged with 4-amino-2-methyl-10H-theino[2,3-b][1 ,5] benzodiazepine HCI (5.0 g, 0.0188 mol), 1-methylpiperazine (13.0 mL, 0.11 mol, 99.0%, Aldrich Chemicals, USA) and anhydrous dimethyl sulfoxide (30.0 mL, Aldrich Chemicals, USA, water< 0.1%). The reaction mixture is stirred at 112-115°C (oil bath temperature 115°C) for 16 hours under continuous flow of nitrogen to drive away the ammonia gas generated during the reaction. The reaction is monitored by HPLC and it is found that within 16 hours 97% product is formed. The reaction mixture is cooled to room temperature (24- 25°C) and added dropwise to a mixture of dichloromethane.water-methanol (190:190:15, 395 mL). After addition, the reaction mixture is stirred for 30 minutes at room temperature. The resulting mixture is yellowish hazy with a dark brown organic layer settled at the bottom of the flask. The dark brown colored dichloromethane layer is separated from the aqueous hazy phase.

After separating the organic layer, the aqueous hazy phase is again extracted with dichloromethane (1×100.0 mL). The combined dichloromethane phases (total volume 290.0 mL) are extracted twice with 50 % aqueous acetic acid solution (1×100 mL, 1×75.0 mL). A dark orange color acetic acid layer is separated. The pH of the acetic acid solution is found to be around 3.0-3.5 when tested by litmus paper. Combined aqueous acetic acid solution is basified, to pH 7.5-8.5, using 40% aqueous sodium hydroxide solution under cold conditions (0-10°C). After attaining the desired pH of the solution, 200 mL dichloromethane is added and stirred. The content is transferred to a separating funnel and is vigorously shaken. The dichloromethane layer is separated and the aqueous phase is again extracted with dichloromethane (1×75.0 mL). The combined dichloromethane extracts are washed with cold saturated sodium chloride solution (1×30.0 mL) and dried over anhydrous sodium sulfate. Removal of solvent on a rotary evaporator with a water bath temperature of 45°C, gives a dark orange brown viscous liquid. To this viscous liquid, 80-85.0 mL dry toluene is added.

The toluene containing crude olanzapine is transferred into a dry 250 mL single necked round bottom flask. Methanolic sodium hydroxide solution (0.32 g sodium hydroxide dissolved in 3.0-4.0 mL methanol by sonication) is added and the mixture is heated in an oil bath at 60°C for 2 hours. After the stipulated time, 20-25 % of the total volume of solvent is evaporated on a rotary evaporator, with a 55-60°C water bath, to ensure the complete removal of dichloromethane and trace amounts of water, resulting in a final volume of between 55-60 mL. The hot solution is removed from the water bath and cooled in an ice bath with stirring. Within 2-3 minutes, the solution is quickly seeded with previously prepared ultra pure olanzapine Form I, as determined by X-Ray and IR, with stirring. Stirring is continued for 40-45 minutes. The yellowish solid obtained in the solution is filtered off, washed with 1.5-2.0 mL dichloromethane and dried on a vacuum pump for 50-60 minutes to give 4.85 g ( 82.4 % yield) of olanzapine Form I. The solid obtained is crushed to a fine powder and air dried to remove traces of dichloromethane. Karl Fisher analysis indicates 5000-8000 ppm water content. The material is dried in an oven at 65°C for 1.5-2.0 hours and analyzed for water (670-860 ppm water). The weight of the title product is 4.80 g (82 % yield), HPLC purity = 99.83%, polymorphic purity is 100% as no detectable polymorph II is observed by X-ray and IR, as shown in Example 3.

The HPLC conditions are as follows: Column: SymmetryC18 , 4.6 x 250 mm λmax 254 nm

Flowrate : 1.0 mL/min. Run Time: 70 minutes

The buffer comprises 5.4 g potassium phosphate; 0.5 g heptanesulfonic acid sodium salt and 0.5 g 1-octanesulfonic acid sodium salt dissolved in 500 mL Dl water and adjusted the pH to 2.6 using cone, phosphoric acid. The mobile phase was 500 mL buffer/300 mL acetonitrile/200 mL methanol. The final pH of the mobile phase is about 3.6. The concentration of the standard is 100μg/mL; the injection volume is 15 μl; and RT = 4.6—4.7 min.

EXAMPLE 2 RECRYSTALLIZATION

From the dried yellowish solid prepared according to Example 1 , 2.0 g (0.0064 mol) is transferred into a single necked round bottom flask provided with a magnetic stirrer. To the solid, 40.0 mL dry toluene and methanolic sodium hydroxide solution (0.052 g sodium hydroxide pellets dissolved in 2.0 L methanol by sonication) are added. To this mixture 3.5-4.0 mL dichloromethane is added.

The mixture is heated for 5-10 minutes in an oil-bath at 60-65°C until a clear solution is obtained. After heating, the solution is transferred into an ice bath and seeded with previously prepared ultra-pure olanzapine Form I. The solution is stirred for 30-35 minutes at 0-10°C. The yellowish solid obtained is filtered on vacuum pump and washed with 2.0-2.5 mL dichloromethane. The solid is dried on a vacuum pump for 40-45 minutes. The solid obtained is crushed into a fine powder and air dried to remove traces of dichloromethane. The air dried material is further dried in the oven at 65°C for 1.5-2.0 hours and analyzed for water content. Karl Fisher study shows 670-860 ppm water content. The weight of olanzapine Forml is 1.93 g (95.0 % crystallization yield) of 99.96 % HPLC purity. EXAMPLE 3 X-RAY POWDER DIFFRACTOMETRY STUDY

Olanzapine Form I prepared according to Example 1 is analyzed by X-ray, IR, and DSC and found to conform to a commercially available reference standard olanzapine Form I. DSC of the olanzapine Form I prepared according to the present invention shows an endotherm peak at 195°C.

…………………

http://www.google.com/patents/CN102268010A?cl=en

Currently, the preparation of olanzapine, mainly in the following three ways:

1.4-amino-2-methyl–10H- thieno [2,3-b] [1,5] – benzodiazepine hydrochloride and N- methylpiperazine, in a nitrogen atmosphere Toluene and DMSO as solvent at reflux for 20h, after-treatment to give the product, recrystallized from acetonitrile to give crystals of olanzapine, a yield of 33% (US5229382).

 

Figure CN102268010AD00041

[0013] The process route fewer steps, simple process, raw materials, but a long reaction time, the use of toxic solvents, pollution, low yield, industrial production adversely.

[0014] CN1906201A discloses the use of no solvent or low boiling organic solvent method for preparing olanzapine, pointed N- methylpiperazine with 4-amino-2-methyl -10H- thieno [2,3-b] [l, 5] molar ratio _ benzodiazepine hydrochloride of 3: 1~8: 1,110~145 ° C after the reaction at least polonium, water was added, at least two organic solvents, or water and at least one organic solvent precipitation olanzapine. This improved process reaction time is shortened, reducing energy consumption and cost, but an excess of starting material N- methylpiperazine unrecovered, resource waste problems still exist.

[0015] 2. 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride, to generate demethylolanzapine piperazine is reacted with level, and then obtained by methylation of olanzapine, recrystallized from ethanol to obtain refined product yield of 68% (CN1420117A).

[0016]

Figure CN102268010AD00042

[0017] The method for preparing olanzapine via a two-step process is relatively complicated and the reaction time is still long; Further, more by-products: The first step is easy to form dimeric product, a second step Iddo methylation.

[0018] 3. 4-amino-2-methyl -10H- thieno [2,3-b] [1,5] – benzodiazepine and N, N- two – (2_ haloethyl ) _ methylamine in alkaline catalyst, solvent reflux 3~IOh obtained crude olanzapine, yield 75% to 92%. Wherein, X = Br or Cl, the catalyst is sodium alkoxide, sodium hydroxide, sodium amide, sodium hydroxide, inorganic bases (CN101168544A).

[0019]

Figure CN102268010AD00051

[0020] This method is simple, shorten the reaction time and therefore reduce energy consumption, but the raw material N, N- two – (2-halo-ethyl) _ methylamine not easy, if more raw material preparation is bound to increase the cost of production.

The present invention is olanzapine preparation method:

[0024]

Figure CN102268010AD00052

 

Example 1 olanzapine [0030] Implementation

[0031] To a 250ml three-necked flask of 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 20. OOg (0 075mol.) , N_-methylpiperazine 75. 30g (0. 75mol), nitrogen and stirred and heated to reflux the reaction cell. Under stirring, the reaction mixture was poured into 200ml of water to precipitate a pale yellow solid powder, stirring was continued for lh, filtered and dried to give olanzapine product 23. 30g, yield 99.4%, purity 99. 0% (HPLC).

2 olanzapine refined example [0032] Implementation

[0033] Example 1 was 23. 30g olanzapine product was transferred into 250ml single neck flask was added MOml ethanol, stirred and heated to reflux to make the product the whole solution. 0. 20g of activated carbon was added to the system, reflow bleaching treatment 30min, filtered, and the filtrate cooled to room temperature and crystallization, filtration and dried to give a yellow crystalline powder 16. 32g, yield 70.0%, the purity of 99. 8% (HPLC), high performance liquid phase chromatogram, see photos.

Olanzapine Preparation Example 3 [0034] Implementation

[0035] To a three-necked flask IOOOml 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 150. 03g (. 0 56mol) , N- methylpiperazine 339. 29g (3. 39mol), nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 70% excess N- methylpiperazine to give Olanzapine crude solid.

[0036] 400ml of ethanol was added to the three-necked flask and heated to reflux for solid all dissolved. Then dissolved under stirring in ethanol olanzapine solution was poured IOOOml water to precipitate a pale yellow solid powder was filtered and dried to give olanzapine product 173. 87g, yield 99.4%, purity 98. 9% (HPLC).

Preparation 4 olanzapine [0037] Implementation

[0038] To a 250ml three-necked flask of 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 10. OOg (0 038mol.) , N_-methylpiperazine 39. 63g (0. 40mol) and diethylene glycol dimethyl ether 30ml, nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 80% excess of N- methylpiperazine and diethylene glycol dimethyl ether mixture to give solid crude olanzapine.

[0039] 40ml of ethanol was added to the three-necked flask and heated to reflux all dissolved solids. Then under stirring to dissolve olanzapine solution was poured into 200ml of water in ethanol, a yellow powder precipitated solid was filtered and dried to give olanzapine product 11.79g, yield 99.3%, purity 98. 7% (HPLC).

Olanzapine Preparation Example 5 [0040] Implementation

[0041] To a 250ml bottle of three 4-amino-2-methyl–10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 20. OOg (0. 075mol) , N_-methylpiperazine 62. 34g (0. 62mol), nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 75% excess N- methylpiperazine to give Olanzapine crude solid.

[0042] 60ml of ethanol was added to the three-necked flask and heated to reflux all dissolved solids. Then under stirring to dissolve olanzapine solution was poured into 600ml of ethanol in water to precipitate a pale yellow solid powder was filtered and dried to give olanzapine product 23. 37g, yield 99.7%, purity 99. 0% (HPLC). [0043] Example 6 olanzapine refined

[0044] Example 5 was 23. 37g olanzapine product was transferred into 250ml single neck flask was added ^ Oml ethanol, stirred and heated to reflux to make the product the whole solution. 0. 03g of activated carbon is added to the system and 0. 03g diatomite, reflow bleaching treatment 15min, filtered, and the filtrate cooled to room temperature and crystallization, filtration and dried to give a yellow crystalline powder 16. 76g, yield 71.7%, purity 99.7% ( HPLC).

 

………………….

http://www.google.com/patents/EP0733635B1?cl=en

 

Example 1

      Technical Grade olanzapine

    • Figure 00100001
    • In a suitable three neck flask the following was added:

      Dimethylsulfoxide (analytical):
      6 volumes
      Intermediate 1 :
      75 g
      N-Methylpiperazine (reagent) :
      6 equivalents

      Intermediate 1 can be prepared using methods known to the skilled artisan. For example, the preparation of the Intermediate 1 is taught in the ‘382 patent.

    • A sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction. The reaction was heated to 120°C and maintained at that temperature throughout the duration of the reaction. The reactions were followed by HPLC until ≤ 5% of the intermediate 1 was left unreacted.
    • After the reaction was complete, the mixture was allowed to cool slowly to 20°C (about 2 hours). The reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath. To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20°C for 30 minutes. Three volumes of water was added slowly over about 30 minutes. The reaction slurry was cooled to zero to 5°C and stirred for 30 minutes. The product was filtered and the wet cake was washed with chilled methanol. The wet cake was dried in vacuo at 45°C overnight. The product was identified as technical olanzapine.
      Yield: 76.7%; Potency: 98.1%

Example 2

    Form II

  • A 270 g sample of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in anhydrous ethyl acetate (2.7 L) . The mixture was heated to 76°C and maintained at 76°C for 30 minutes. The mixture was allowed to cool to 25°C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using x-ray powder analysis. Yield: 197 g.
  • The process described above for preparing Form II provides a pharmaceutically elegant product having potency > 97%, total related substances < 0.5% and an isolated yield of > 73%.

………………….

Impurities

Olanzapine N-oxide (Olanzapine Impurity D)

…………..

Synthesis and characterization of impurities of an anti-psychotic drug substance, Olanzapine (08-3022UP)
Poornachander Thatipalli, Ramesh Kumar, Chandrasekhar Bulusu, Ramesh Chakka, Pratap R. Padi, Anjaneyulu Yerra and Satyanarayana Bollikonda
Full Text: PDF (226K)
pp. 195 – 201

 

 

 

 

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P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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OLANZEPINE VISITED PART 1/3


Olanzapine3Dan2.gif

Olanzapine

Olanzapine, LY170053
CAS : 132539-06-1
 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
2-Methyl-4-(4-methyl-1-piperazinyl)-10Hthieno[2,3-b][1,5]benzodiazepine
Manufacturers’ Codes: LY-170053
Trademarks: Zyprexa (Lilly)
Molecular Formula: C17H20N4S
Molecular Weight: 312.43
Percent Composition: C 65.35%, H 6.45%, N 17.93%, S 10.26%
Properties: Crystals from acetonitrile, mp 195°. Practically insol in water.
Melting point: mp 195°
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Other Tricyclics; Serotonin-Dopamine Antagonist.

Olanzapine (sold under the brand names Zyprexa, Zypadhera and Lanzek or in combination with fluoxetine, Symbyax) is anatypical antipsychotic. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder.[4]

Olanzapine is structurally similar to clozapine and quetiapine, but is classified as a thienobenzodiazepine. The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company; the drug went generic in 2011. Sales of Zyprexa in 2008 were $2.2B in the US, and $4.7B worldwide.[5]

Zyprexa (olanzapine) 10 mg tablets (AU)

Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of all atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride. Olanzapine also had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.[60] P-glycoprotein transports a number of drugs across a number of different biological membranes including the blood-brain barrier, which could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein.[61]

Olanzapine is a potent antagonist of the muscarinic M3 receptor,[65] which may underlie its diabetogenic side effects.[64][66] Additionally, olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.[67] [27]

Displaying image002.png

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Dosage forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 milligrams. Zyprexa (and generic olanzapine) is available as an orally-disintegrating “wafer” which rapidly dissolves in saliva. It is also available in 10 milligram vials for intramuscular injection.[4]

Research

Olanzapine has been investigated for use as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV). A 2007 study demonstrated its successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly-emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone.[85]

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk forschizophrenia. The study examined 60 patients with prodromalschizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.[86] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[87]

1H NMR PREDICT

Olanzapine NMR spectra analysis, Chemical CAS NO. 132539-06-1 NMR spectral analysis, Olanzapine H-NMR spectrum

13C NMR PREDICT

Olanzapine NMR spectra analysis, Chemical CAS NO. 132539-06-1 NMR spectral analysis, Olanzapine C-NMR spectrum

OLA 1

OLA 2

COSY

OLA COSY

HMBC

OLA HMBC

…………………………………..WILL BE UPDATED

UV

Displaying image034.png

IR

Displaying image035.png

1H NMR

Displaying image040.png

Displaying image042.png

Displaying image044.png

13C NMR

Displaying image045.png

MASS

 Displaying image046.png

 

 Displaying image049.png

Displaying image050.png

Displaying image058.png

…………………………………….

INTERMEDIATE/S USED IN SYNTHESIS AND REFERENCE

LEK PHARMACEUTICALS D.D. Patent: WO2005/90359 A2, 2005 ; Location in patent: Page/Page column 21 ;

Apotex Pharmachem Inc. Patent: US2008/319189 A1, 2008 ; Location in patent: Page/Page column 2 ;

LEK PHARMACEUTICALS D.D. Patent: WO2005/90359 A2, 2005 ; Location in patent: Page/Page column 21 ;

Leyva-Perez, Antonio; Cabrero-Antonino, Jose R.; Corma, Avelino Tetrahedron, 2010 , vol. 66, # 41 p. 8203 – 8209

SEE

WATSON PHARMACEUTICALS, INC. Patent: WO2004/94390 A1, 2004 ; Location in patent: Page 15 ;

WO2006/6180 A1, ; Page/Page column 11 ;

Russian Journal of Bioorganic Chemistry, , vol. 31, # 4 p. 378 – 382

Russian Journal of Bioorganic Chemistry, , vol. 31, # 4 p. 378 – 382

WO2006/6180 A1, ; Page/Page column 11 ;

US5605897 A1, ;

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PATENT

http://www.google.com.na/patents/EP1730153B1?cl=en

Figure 2 shows the NMR spectrum of the solvate according to the invention. The peaks were assigned as follows (1H NMR; CDCl3, 300 MHz) :

Chemical shift δ Assignement
1.20 (3H, d) CH3 – isopropanol
2.30 (3H, s) 4′-CH3
2.34 (3H, s) 2- CH3
2.20-2.40 (2H, br s) H – water
2.49 (4H, m) 3′-CH2
3.52 (4H, m) 2′-CH2
4.03 (0.5H, dq) CH – isopropanol
5.02 (H, broad s) 10-NH
6.29 (H, broad s) 3-CH
6.29-7.05 (4H, m) 6, 7, 8, 9-H
  • Olanzapine has shown to have high activity with regard to the central nervous system and is also useful for the treatment of schizophrenia, schizophreniform disorders, acute mania, mild anxiety states and psychosis.
  • Various polymorphic and pseudopolymorphic forms, such as solvates, of olanzapine have become known. Some of them are useful for conversion to other desirable forms.
  • The British patent GB 1 533 235 discloses antipsychotically effective thienobenzodiazepines by a generic formula which also covers olanzapine.
  • US patent 5,229,382 discloses olanzapine explicitly. The described process for its synthesis involves a crystallization from acetonitrile.
  • EP-B-733 635 claims crystalline form II olanzapine, and this polymorphic form is said to be more stable than the material obtained according to US 5,229,382 which is designated “form I olanzapine”. Both the form I and the form II of olanzapine are characterized by e. g. X-ray data. The preparation of the more stable form II of olanzapine is effected by dissolving technical grade olanzapine in ethyl acetate and crystallization from the resulting solution by any conventional process such as seeding, cooling, scratching the glass of the reaction vessel or other common techniques.
  • WO 02/18390 discloses the monohydrate form I and the dihydrate form I of olanzapine, a process for production thereof and a process for production of form I of olanzapine which comprises the steps of stirring olanzapine monohydrate form I or crude olanzapine or form II of olanzapine in methylene chloride at reflux, cooling, filtering and drying. It is also described that a repeating of the process described in US 5,229,382 Example 1, subexample 4 did not lead to formation of form I of olanzapine.
  • WO 03/101997 relates to processes for preparation of form I of olanzapine by regulation of the pH-value of the solution.
  • WO 03/055438 discloses the preparation of form I olanzapine by crystallization from ethanol and subsequent conversion of the obtained ethanol solvate.
  • US patent 5,637,584 discloses the (mono)methylene chloride solvate form of olanzapine and a method for its conversion to the polymorphic form I of olanzapine.
  • EP-B-733 634 discloses three specific solvates of olanzapine, namely the methanol, ethanol and 1-propanol solvates and a process for production of form II olanzapine by drying such a solvate.
  • WO 03/097650 describes two new, mixed solvate forms, the water/methylene chloride solvate and the water/DMSO solvate, methods for preparing them, and their transformation to polymorphic form I.
  • WO 2004/006933 discloses a process for the preparation of form I olanzapine, as well as various pseudopolymorphic forms, namely the isopropanol solvate, and the acetonitrile/methylene chloride/water and acetonitrile/water mixed solvates of olanzapine, and the polymorphic form A.

Preparation of the water-isopropanol mixed solvate of olanzapine Example 1

  • A mixture of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride (26.6 g), 1-methylpiperazine (92 ml), dimethylsulfoxide (120 ml) and toluene (120 ml) was refluxed for 4 hours. The solution was cooled to 95°C and 200 ml were distilled off under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, and the solution was further cooled to 0°C and water (36 ml) was added to initialize crystallization. After the crystallization was completed, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to obtain a clear solution. Ethylenediaminotetraacetic acid disodium salt (3 g) was added and the suspension was stirred for one hour. Undissolved material was removed by hot filtration. The clear solution was cooled to 25°C and water (6 ml) was added to start crystallization. The suspension was cooled to 0°C and after completion of the crystallization the product was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 22.84 g. Loss on drying (140°C): 13.6%. Water content (Karl Fischer): 5.12%.

Example 2

  • A mixture of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride (26.6 g), 1-methylpiperazine (92 ml), dimethylsulfoxide (36 ml) and toluene (120 ml) was refluxed for 4 hours. The solution was cooled to 95°C and 80 ml were distilled off under vacuum. The residue was cooled to room temperature, and isopropanol (180 ml) was added. The solution was further cooled to 0°C and water (36 ml) was added to initialize crystallization. After the crystallization was completed, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to obtain a clear solution. Ethylenediaminotetraacetic acid disodium salt (3 g) was added and the suspension was stirred for one hour. Undissolved material was removed by hot filtration. The clear solution was cooled to 35 °C and water (6 ml) was added to start crystallization. The suspension was cooled to 0°C, upon finalization of the crystallization, the product was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 21.98 g. Loss on drying (140°C): 13.2 %. Water content (Karl Fischer): 5.09%. Assay of isopropanol (GC): 8.55 %.

Example 3

  • A mixture of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride (26.6 g), 1-methylpiperazine (92 ml), dimethylsulfoxide (36 ml) and toluene (120 ml) was refluxed for 4 hours. The solution was cooled to 95°C and 120 ml were distilled off under vacuum. The residue was cooled to room temperature, and isopropanol (180 ml) was added. The solution was further cooled to 0°C and water (36 ml) was added to initialize crystallization. After completion of the crystallization, the precipitate.was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to obtain a clear solution. Ethylenediaminotetraacetic acid disodium salt (3 g) was added and the suspension was stirred for one hour. Undissolved material was removed by hot filtration. The clear solution was cooled to 35°C and water (6 ml) was added to start crystallization. The suspension was cooled to 0°C, upon completion of the crystallization, the product was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 24.35 g. Loss on drying (140°C): 13.5%. Water content (Karl Fischer): 5.05%.

Example 4

  • Anhydrous olanzapine (10 g) was suspended in isopropanol (108 ml) and heated to reflux to obtain a clear solution. The solution was slowly cooled. Water (6 ml) was added at 57°C to start crystallization. The suspension was cooled to 0°C, upon finalization of the crystallization, the product was filtered off and washed with isopropanol (5 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 10.97 g. Loss on drying (140°C): 13.3%. Water content (Karl Fischer): 5.13%.

Example 5

  • 60 g of olanzapine obtained from mother liquors was suspended in isopropanol (650 ml) and heated to reflux to obtain a clear solution. Ethylenediaminotetraacetic acid disodium salt (7.9 g) was added and the suspension was stirred for one hour. Undissolved material was removed by hot filtration. The clear solution was cooled to 25°C and water (16 ml) was added to start crystallization. The suspension was cooled to 0°C and, upon completion of the crystallization, the product was filtered off and washed with isopropanol (50 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 57.64 g. Loss on drying (140°C): 13.5%. Water content (Karl Fischer): 5.26%.

Example 6

  • The solution of 2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine (41.86 g, 0.11 mmol) (prepared according to WO 2004/065390 ), pyridinium p-toluenesulfonate (55.29 g, 0.22 mmol) and sulfur (11.99 g, 0.374 mmol) in benzonitrile (1100 mL) was stirred at 140°C for 11 h, cooled to 90°C and concentrated to an oily residue. The residue was diluted with dichloromethane and isopropanol (250 mL, 1 : 1). The precipitate was filtered off and washed with dichloromethane and isopropanol (20 ml, 1 : 1). The filtrate was extracted with HCl (250 ml, 2 M). The organic phase was further extracted with HCl (2 X 100 ml, 1 M). The combined aqueous phases were cooled in an ice bath and made alkaline by using 5 M NaOH. The obtained turbid solution was left in a refrigerator over night resulting in a suspension. This was separated by filtration and washed with isopropanol (2 X 25 ml). The wet material was suspended in isopropanol (215 ml) and heated to reflux to obtain a clear solution. The solution was hot filtered. Water (6.5 ml) was added to induce crystallization. The obtained’suspension was cooled to 0°C, and upon completion of crystallisation, the product was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to a constant weight. Yield: 18.61 g. Loss on drying (140°C): 12.8 %. Water content (Karl Fischer): 5.29 %.

Example 7

  • The solution of 2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine (3.805 g, 10 mmol) (prepared according to WO 2004/065390 ), pyridinium p-toluenesulfonate (5.026 g, 20 mmol) and sulfur (1.122 g, 35 mmol) in benzonitrile (100 ml.) was stirred at 140°C for 8.5 h, cooled to 90°C and concentrated to an oily residue. The residue was diluted with isopropanol (50 ml) and dimethyl sulfoxide (5 ml). The precipitate was filtered off and washed with isopropanol (5 ml). Water (10 ml) and sodium hydroxide (1.00 g, 25 mmol) were added to the filtrate. The mixture was stirred at room temperature until the sodium hydroxide had dissolved. The turbid solution was left in a refrigerator over night resulting in a suspension. This was filtered off and washed with isopropanol (5 mL). The wet material was suspended in isopropanol (25 mL) and the suspension was heated to reflux. Then solids were hot filtered. Water (0.75 mL) was added to the filtrate to induce crystallization. The resulting suspension was cooled to 0°C, and upon completion of crystallisation, the product was filtered off and washed with isopropanol (1 mL). The product was then dried at room temperature under vacuum to a constant weight. Yield: 0.738 g.

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PAPER

http://www.biomedcentral.com/1471-2210/12/8

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Scheme 1

Synthesis of compounds 8a, 8b, and 8c. Reagents and conditions: (i) 1-fluoro-2-nitrobenzene, NaH, THF, rt, 20 h, 60%; (ii) SnCl2, EtOH, 80°C, 1 h, 80%; (iiia) N-methylhomopiperazine (5 equiv), no solvent, microwave heating, 80°C, 4 h,65%; (iiib) N-methylhomopiperazine (5 equiv), no solvent, microwave heating, 120°C, 3 h, 55%; (iiic) N-methylpiperazine (10 equiv), N-methylpiperazine hydrochloride (10 equiv), DMSO, 110–120°C, 20 h, 56%.

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Literature References:

Serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. Prepn: J. K. Chakrabarti et al., EP 454436; eidem, US 5229382 (1991, 1993 both to Lilly). PRODUCT PATENT

Comparative pharmacology: N. A. Moore et al., Curr. Opin. Invest. Drugs 2, 281 (1993). HPLC determn in human plasma: J. T. Catlow et al., J. Chromatogr. B 668, 85 (1995).

Clinical evaluation in schizophrenia: D. S. Baldwin, S. A. Montgomery, Int. Clin. Psychopharmacol. 10, 239 (1995); in mania of bipolar disorder: M. Tohen et al., Am. J. Psychiatry 156, 702 (1999).

Review of pharmacology and clinical experience: B. C. Lund, P. J. Perry, Expert Opin. Pharmacother. 1, 305-323 (2000).

External links

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.




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