EA042764B1 - METHODS FOR OBTAINING (R)-(+)-TIPIFARNIBA - Google Patents

Description

I. Technical field to which the invention belongs

Provided herein are methods for preparing the desired enantiomer of 6-[amino(4chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)- quinolinone, also known as tipifarnib.

II. State of the art

Farnesyl transferase inhibitors block the main post-translational modification of the Ras protein, thereby preventing its localization to the inner surface of the plasma membrane and subsequent activation of downstream effectors. Although initially developed as a strategy to target Ras in cancer, farnesyl transferase inhibitors have subsequently been recognized to act through additional and more complex mechanisms that may extend beyond Ras, involving GTP-binding proteins, kinases, centromeres-binding proteins, and probably other farnesylated proteins.

A particular farnesyl transferase inhibitor that has been described is (R)-(+)-6[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl) -1-methyl-2(1 H)-quinolinone, also known as R115777 or (R)-(+)-tipifarnib. See WO 97/21701, the disclosure of which is incorporated herein by reference in its entirety. (R)-(+)-tipifarnib is a potent, selective and orally bioavailable farnesyl transferase inhibitor. It is one of the most promising farnesyl transferase inhibitors and is currently known to be in clinical trials, being one of the agents entering phase III trials.

(R)-(+)-tipifarnib has been found to have very strong activity against neoplastic diseases. Antitumor activity was observed in solid tumors as well as in hematological malignancies.

The synthesis of (R)-(+)-tipifarnib as originally described in WO 97/21701 is shown in Scheme 1.

Scheme 1.

O o ''γ ιθχθθ Cl-^^ N (1) SS W. he J cr (II) u^m^z θΓ jOlXi or (ill) J cr CH _a (IV) θ' W, nh ₂ J XjYXi CHi (V) .01 Stage 1 N-methylimidazole, n-BuLi, CiSiEt ₃ , THE, -78 °C. '° (Yield 52%) ,01 Stage 2 SOCI _Z ^f O ,CI Stage a NH ₄ 0H4~HF (yield 62%) 'o XI Stage 4 Chiral chromatography _h (Yield 32.5%) O XI 'o

- 1 042764

In this synthesis, tipifarnib is initially synthesized as a racemate (step 3). The enantiomers are then separated to give (R)-(+)-tipifarnib, albeit in only 32.5% yield.

The approach described above highlights a characteristic disadvantage of methods based on the separation of the racemate. Namely, the unwanted (S)-(-)-enantiomer is discarded, resulting in low yield and additional production costs. Thus, there is a need for improved methods for the synthesis of (R)-(+)-tipifarnib.

III. The essence of the invention

This description provides methods for obtaining the desired enantiomer 6-[amino(4chlorophenyl)( 1 -methyl-1 H-imidazol-5 -yl)methyl] -4-(3 -chlorophenyl)-1 -methyl-2( 1 H)- quinolinonα, also known as tipifarnib. One embodiment involves synthesizing racemic tipifarnib, crystallizing the desired enantiomer from the racemate, isolating crystals of the desired enantiomer from the mother liquor, and racemizing and recycling the unwanted enantiomer in the mother liquor.

One embodiment is summarized and represented by Scheme 2, which is a synthesis scheme for the preparation of (R)-(+)-typipfarnib using racemic synthesis of tipifarnib, crystallization to separate the racemic mixture of tipifarnib, and racemization and recycling of the mother liquor back to the intermediate stage of the racemic synthesis. Scheme 2.

In another embodiment, summarized in Scheme 3, an alternative synthesis procedure is used to recycle the mother liquor (VIb) back to the racemic synthesis intermediate.

Scheme 3.

IV. Detailed description

Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art. All publications and patents referenced herein are incorporated by reference in their entirety.

- 2 042764

A. Definitions.

The terminology descriptions below refer to the terms used here unless otherwise noted.

The term stereochemical formula refers to a three-dimensional representation of a molecule as such or in projection. A pair of stereochemical formulas are matched when superimposed when they can be brought to match by nothing more than translation and non-free rotation.

The term chirality refers to the geometric property of an inflexible object, such as the spatial arrangement of atoms, not matching its mirror image when superimposed. If an object coincides with its mirror image when superimposed, then the object is described as achiral.

The term enantiomer refers to one of a pair of molecular compounds that are mirror images of each other and do not match when superimposed.

The term optical activity refers to the ability of a material sample to rotate the plane of polarization of a beam of transmitted plane polarized light. This optical rotation is a sufficient but not essential feature of systems containing unequal amounts of the corresponding enantiomers. An enantiomer that causes clockwise rotation when viewed in the direction of an oncoming light beam, under certain conditions, is called dextrorotatory, and its chemical name or formula is indicated by the prefix (+); the enantiomer that causes rotation in the opposite direction is left-handed and is indicated by the prefix (-).

The enantiomer may also be denoted by the prefix (R) or (S) which is derived by applying the Cahn-Ingold-Prelog precedence rules commonly described in R. S. Cahn, C. K. Ingold, V. Prelog, Angew. Chem. 78, 413-447 (1966), Angew. Chem. Intemat. Ed. Eng. 5, 385-415, 511 (1966); and V. Prelog, G. Helmchen, Angew. Chem. 94, 614-631 (1982), Angew. Chem. Internat. Ed. Eng. 21, 567-583 (1982).

The term enantiopure or enantiomerically pure refers to a sample in which all molecules have the same chirality in the range of detection.

The term racemic mixture or racemate refers to an equimolar mixture of a pair of enantiomers. The racemic mixture does not exhibit optical activity.

The term enantiomeric excess refers to the difference in mole fractions of two opposite enantiomers in a composition. Enantiomeric excess is often expressed as a percentage.

The term acid refers to both Brönsted acid and Lewis acid. A Bronsted acid is a molecular compound capable of donating a hydron to a Bronsted base. A Lewis acid is a molecular compound that is an electron pair acceptor and therefore capable of reacting with a Lewis base to form a Lewis adduct by sharing the electron pair provided by the Lewis base.

The term base refers to both the Bransted base and the Lewis base. A Brønsted base is a molecular compound capable of accepting a hydron from a Brønsted acid. A Lewis base is a molecular compound capable of donating an electron pair and thus capable of coordinating with a Lewis acid to form a Lewis adduct as a result.

The term hydron is the general name of the H ⁺ cation, used without taking into account the mass of the nucleus of the hydrogen atom.

The term salt refers to a chemical compound consisting of a combination of cations and anions.

The term chiral resolving agent refers to a reagent used to convert a mixture of enantiomers to diastereomers, usually by forming a well-crystallized diastereomeric salt.

The term solvent refers to a liquid in which a solute is dissolved to form a solution.

The term miscibility refers to the ability of a mixture to form one single phase. Miscibility may be limited to certain ranges of temperature, pressure and composition.

The terms process and method are used interchangeably to refer to the process described herein for the preparation of a compound. Modifications of the processes and methods described herein (eg, starting materials, reagents, protecting groups, solvents, temperatures, reaction times and/or purifications) that are well known to those skilled in the art are also covered by the invention.

The term resolution, optical resolution, or chiral resolution is used interchangeably to refer to any process by which a racemic mixture is separated into its two constituent enantiomers.

The term crystallization refers to the formation of a crystalline solid from a solution, melt, vapor, or other solid phase, typically by lowering the temperature or by evaporating the solvent.

The term mother liquor refers to that part of the solution that remains after crystallization.

- 3 042764 from solution. It is a liquid obtained by filtering the formed crystals.

The term extraction refers to the process of transferring a substance from any matrix into a suitable liquid phase. In particular, it refers to liquid-liquid extraction, which is the process of transferring a solute from a liquid phase to another immiscible or partially miscible liquid phase upon contact with it.

The term reaction is used to denote the contact of one reactant, reagent, solvent, catalyst, or reactive group with another reactant, reagent, solvent, catalyst, or reactive group. Unless otherwise indicated, reactants, reagents, solvents, catalysts, and reactive groups may be added individually, simultaneously or separately, and/or may be added in any order. They may be added in the presence or absence of heat, and may optionally be added under an inert atmosphere (eg N2 or Ar). In some embodiments, the implementation of the term reaction may also refer to the formation of in situ or intramolecular reaction, when the reactive groups are in the same molecule.

The term approximately or approximately denotes the margin of error for a particular value as established by those skilled in the art, which depends in part on how that value is measured or determined. In some embodiments, the term approximately or approximately means an error within 1, 2, 3, or 4 standard deviations. In some embodiments, the term about or approximately means being within 50, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.05% of a set value, or range.

The term compound includes its salt, solvates (eg, hydrates), co-crystals, and polymorphs.

The term solvate means a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent that are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, without limitation, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, without limitation, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

The term polymorph refers to solid crystalline forms of a compound or complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties.

Where the stereochemistry of a structure or part of it is not indicated, for example by bold or dashed lines, the structure or part of it should be interpreted as encompassing all stereoisomers of the structure.

B. Methods of obtaining.

In some embodiments, the present invention provides a process for preparing the desired enantiomer of tipifarnib, comprising the steps of: (i) obtaining a starting material containing tipifarnib that is not enantiopure at the desired enantiomer; (ii) converting the starting material from step (i) into a racemic mixture of tipifarnib; and (iii) isolating the desired enantiomer of tipifarnib from the racemic mixture of tipifarnib from step (ii). In one embodiment, the method is shown in Scheme 2. In one embodiment, the method is shown in Scheme 3.

In one embodiment, the desired enantiomer of tipifarnib is (R)-(+)-tipifarnib. In one embodiment, as shown in Scheme 2, the desired enantiomer of tipifarnib is (R)-(+)-tipifarnib. In another embodiment, as shown in Scheme 3, the desired enantiomer of tipifarnib is (R)-(+)-tipifarnib.

In some embodiments, the implementation of the source material of stage (i) contains a mother liquor from the crystallization process. In some embodiments, the starting material of step (i) contains an enantiomeric excess of the undesired enantiomer of tipifarnib. In one embodiment, the unwanted enantiomer of tipifarnib is (S)-(-)-tipifarnib. In another embodiment, as shown in Scheme 2, the unwanted enantiomer of tipifarnib is (S)-(-)-tipifarnib. In another embodiment, as shown in Scheme 3, the undesired enantiomer of tipifarnib is (S)-(-)-tipifarnib.

In some embodiments, the starting material from step (i) contains an acid salt of tipifarnib. In some embodiments, the acid is an enantiopure chiral organic acid. In some embodiments, the acid is a chiral resolving agent. In one embodiment, the acid is (-)-dibenzoyl-L-tartaric acid. In another embodiment, as shown in Scheme 2, the acid is (-)-dibenzoyl-L-tartaric acid. In another embodiment, as shown in Scheme 3, the acid is (-)-dibenzoyl-b-tartaric acid.

In some embodiments, step (ii) of converting the starting material to a racemic

- 4 042764 a mixture of tipifarnib includes the steps of: (ii)(a) reacting the starting material with sodium nitrite in a reaction solvent to obtain a mixture of products; (ii)(b) isolating the racemic alcohol of formula (II) from the mixture of products from step (ii)(a); and (ii)(c) converting the racemic alcohol from step (ii)(b) to a racemic mixture of tipifarnib. In one embodiment, the steps are shown in Scheme 2.

In some embodiments, step (ii) converting the starting material to a racemic mixture of tipifarnib comprises the steps of: (ii) (a) heating the starting material in an aqueous reaction solvent to obtain a mixture of products; (ii)(b) isolating the racemic alcohol of formula (II) or (IIa) from the mixture of products from step (ii)(a); and (ii)(c) converting the racemic alcohol from step (ii)(b) to the tipifarnib racemic mixture of formula (IV). In one embodiment, the steps are shown in Scheme 3.

In some embodiments, the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof. In one embodiment, the reaction solvent of step (ii)(a) is a mixture of an organic solvent and water. In some embodiments, the mixture has a volume ratio of organic solvent to water in the range of 20:1 to 3.5:1. In another embodiment, the volume ratio of organic solvent to water is 4:1. In one embodiment, as shown in Scheme 2, the volume ratio of organic solvent to water is 4:1. In some embodiments, the mixture has a volume ratio of organic solvent to water in the range of 6:1 to 2:1. In one embodiment, the volume ratio of organic solvent to water is 2:1. In another embodiment, as shown in Scheme 3, the volume ratio of organic solvent to water is 2:1.

In some embodiments, the implementation of the organic solvent is miscible with water. In some embodiments, the organic solvent is acetone, acetonitrile, methanol, t-amyl alcohol, or a mixture thereof. In one embodiment, the organic solvent is acetone. In another embodiment, the organic solvent is acetonitrile. In another embodiment, as shown in Scheme 2, the organic solvent is acetone. In some embodiments, the organic solvent is acetonitrile, methyl ethyl ketone, acetone, DMF, or a mixture thereof. In one embodiment, the organic solvent is methyl ethyl ketone. In one embodiment, as shown in Scheme 3, the organic solvent is methyl ethyl ketone.

In some embodiments, the implementation of the reaction in stage (ii)(a) proceeds at a temperature in the range from about 20 to about 75°C. In one embodiment, the reaction in stage (ii)(a) proceeds at a temperature of about 20°C. In another embodiment, the reaction in stage (ii)(a) proceeds at a temperature of 20°C. In another embodiment, as shown in Scheme 2, the reaction proceeds at a temperature of 20°C. In some embodiments, the implementation of the reaction in stage (ii)(a) proceeds at a temperature in the range from about 60°C to about 80°C. In one embodiment, the reaction in stage (ii)(a) proceeds at a temperature of about 80°C. In another embodiment, the reaction in stage (ii)(a) proceeds at a temperature of about 76°C. In another embodiment, as shown in Scheme 3, the reaction proceeds at a temperature of about 76°C.

In some embodiments, the reaction in step (ii)(a) proceeds in the presence of an additive. In some embodiments, the additive is an acid. In one embodiment, the acid is sulfuric acid. In another embodiment, the acid is hydrochloric acid. In another embodiment, the acid is 50% sulfuric acid. In another embodiment, the acid is 37% hydrochloric acid.

In some embodiments, step (ii)(b) isolates the racemic alcohol of formula (II) as a salt. In one embodiment, step (ii)(b) isolates the racemic alcohol of formula (II) as the hydrochloride salt. In another embodiment, step (ii)(b) isolates the salt of formula (IIa). In another embodiment, as shown in Scheme 2, the salt of formula (IIa) is isolated. In another embodiment, as shown in Scheme 3, the salt of formula (IIa) is isolated.

In some embodiments, step (ii)(b) isolating the racemic alcohol of formula (II) from the product mixture from step (ii)(a) comprises the steps of: adjusting the pH of the product mixture with a base; extracting the product mixture with an extraction solvent; and crystallization of the racemic alcohol of formula (II).

In some embodiments, the pH of the product mixture is adjusted to a range of about 5 to about 10. In one embodiment, the pH of the product mixture is adjusted to about 10. In one embodiment, the pH of the product mixture is adjusted to about 8. In another embodiment, the pH of the product mixture is adjusted to 10.

In some embodiments, the base is sodium hydroxide or ammonium hydroxide. In one embodiment, the base is sodium hydroxide. In another embodiment, the base is 10% aqueous sodium hydroxide.

In some embodiments, the extraction solvent is isopro

- 5 042764 pilacetate or 2-methyltetrahydrofuran. In one embodiment, the extraction solvent is isopropyl acetate.

In some embodiments, the racemic alcohol crystallizes as the hydrochloride salt. In one embodiment, as shown in Scheme 2, the racemic alcohol crystallizes as the hydrochloride salt of formula (IIa). In another embodiment, as shown in Scheme 3, the racemic alcohol crystallizes as the hydrochloride salt of formula (IIa).

In some embodiments, step (ii) converting the starting material to a racemic mixture of tipifarnib comprises the steps of: (ii) (a) reacting the starting material with sodium nitrite in a reaction solvent to obtain a mixture of products; (ii)(b) isolating the racemic alcohol of formula (II) from the mixture of products from step (ii)(a); and (ii)(c) converting the racemic alcohol from step (ii)(b) to a racemic mixture of tipifarnib. In one embodiment, the steps are shown in Scheme 2.

In some embodiments, the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof. In one embodiment, the reaction solvent of step (ii)(a) is a mixture of an organic solvent and water. In some embodiments, the mixture has a volume ratio of organic solvent to water in the range of 20:1 to 3.5:1. In another embodiment, the volume ratio of organic solvent to water is 4:1. In another embodiment, as shown in Scheme 2, the volume ratio of organic solvent to water is 4:1.

In some embodiments, the implementation of the organic solvent is miscible with water. In some embodiments, the organic solvent is acetone, acetonitrile, methanol, t-amyl alcohol, or a mixture thereof. In one embodiment, the organic solvent is acetone. In another embodiment, the organic solvent is acetonitrile. In another embodiment, as shown in Scheme 2, the organic solvent is acetone.

In some embodiments, the implementation of the reaction in stage (ii)(a) proceeds at a temperature in the range from about 20 to about 75°C. In one embodiment, the reaction in stage (ii)(a) proceeds at a temperature of about 20°C. In another embodiment, the reaction in stage (ii)(a) proceeds at a temperature of 20°C. In another embodiment, as shown in Scheme 2, the reaction proceeds at a temperature of 20°C.

In some embodiments, the reaction in step (ii)(a) proceeds in the presence of an additive. In some embodiments, the additive is an acid. In one embodiment, the acid is sulfuric acid. In another embodiment, the acid is hydrochloric acid. In another embodiment, the acid is 50% sulfuric acid. In another embodiment, the acid is 37% hydrochloric acid.

In some embodiments, step (ii)(b) isolates the racemic alcohol of formula (II) as a salt. In one embodiment, step (ii)(b) isolates the racemic alcohol of formula (II) as the hydrochloride salt. In another embodiment, step (ii)(b) isolates the salt of formula (IIa). In another embodiment, as shown in Scheme 2, the salt of formula (IIa) is isolated.

In some embodiments, step (ii)(b) isolating the racemic alcohol of formula (II) from the product mixture from step (ii)(a) comprises the steps of: adjusting the pH of the product mixture with a base; extracting the product mixture with an extraction solvent; and crystallization of the racemic alcohol of formula (II).

In some embodiments, the pH of the product mixture is adjusted to a range of about 5 to about 10. In one embodiment, the pH of the product mixture is adjusted to about 10. In another embodiment, the pH of the product mixture is adjusted to 10.

In some embodiments, the base is sodium hydroxide or ammonium hydroxide. In one embodiment, the base is sodium hydroxide. In another embodiment, the base is 10% aqueous sodium hydroxide.

In some embodiments, the extraction solvent is isopropyl acetate or 2-methyltetrahydrofuran. In one embodiment, the extraction solvent is isopropyl acetate.

In some embodiments, the racemic alcohol crystallizes as the hydrochloride salt. In one embodiment, as shown in Scheme 2, the hydrochloride salt (IIa) of the racemic alcohol is crystallized.

In some embodiments, step (iii) isolating the desired enantiomer of tipifarnib from the racemic mixture comprises: (iii) (a) crystallizing the desired enantiomer of tipifarnib from the racemic mixture of tipifarnib in the presence of a chiral resolving agent; and (iii)(b) isolating crystals of the desired enantiomer of tipifarnib from the mother liquor. In one embodiment, the steps are shown in Scheme 2. In another embodiment, the steps are shown in Scheme 3.

In some embodiments, the chiral resolving agent of step (iii)(a) is

- 6 042764 is an enantiopure chiral organic acid. In one embodiment, the chiral resolving agent of step (iii)(a) is (-)-dibenzoyl-L-tartaric acid. In another embodiment, as shown in Scheme 2, the chiral resolving agent of step (sh)(a) is (-)-dibenzoyl-L-tartaric acid. In another embodiment, as shown in Scheme 3, the chiral resolving agent of step (iii)(a) is (-)-dibenzoyl-L-tartaric acid.

In some embodiments, the stock solution of step (iii)(a) contains an enantiomeric excess of the undesired enantiomer of tipifarnib. In one embodiment, the unwanted enantiomer of tipifarnib is (S)-(-)-tipifarnib. In another embodiment, as shown in Scheme 2, the unwanted enantiomer of tipifarnib is (S)-(-)-tipifarnib. In another embodiment, as shown in Scheme 3, the undesired enantiomer of tipifarnib is (S)-(-)-tipifarnib.

In some embodiments, the implementation of the method further includes: (iv) recycling the mother liquor of stage (iii)(b) for use as a starting material in stage (i). In some embodiments, steps (i)-(iv) may be performed in multiple cycles. In one embodiment, the method is shown in Scheme 2. In another embodiment, the method is shown in Scheme 3.

In some embodiments, the present invention provides a process for preparing the desired enantiomer of tipifarnib, comprising the steps of: (i) obtaining a starting material containing tipifarnib that is not enantiopure at the desired enantiomer; (ii)(a) reaction of the starting material with sodium nitrite to obtain a mixture of products; (ii)(b) isolating the racemic alcohol of formula (II) from the mixture of products from step (ii)(a); (ii)(c) converting the racemic alcohol from step (ii)(b) to the racemic mixture of tipifarnib; (iii)(a) crystallizing the desired enantiomer of tipifarnib from the tipifarnib racemic mixture of step (ii)(c) in the presence of a chiral resolving agent; (iii)(b) recovering crystals of the desired enantiomer of tipifarnib from the mother liquor of step (sh)(a); and (iv) recycling the mother liquor of step (iii)(b) for use as the starting material in step (i). In one embodiment, the method is shown in Scheme 2.

In some embodiments, the present invention provides a method for preparing the desired enantiomer of tipifarnib, comprising the steps of: (i) obtaining a racemic mixture of tipifarnib; (ii) crystallizing the desired enantiomer of tipifarnib from the tipifarnib racemic mixture of step (i) in the presence of a chiral resolving agent; (iii) recovering crystals of the desired enantiomer of tipifarnib from the mother liquor; (iv) converting any remaining tipifarnib in the mother liquor from step (iii) to racemic alcohol of formula (II); (v) converting the racemic alcohol from step (iv) to the racemic mixture of tipifarnib; and (vi) recycling the racemic mixture of tipifarnib from step (v) back to step (i). In one embodiment, the method is shown in Scheme 2. In another embodiment, the method is shown in Scheme 3.

In some embodiments, the present invention provides a process for converting an enantiomerically enriched amine of formula (IV) comprising: (i) reacting an enantiomerically enriched amine of formula (IV) or a salt thereof with sodium nitrite in a 4:1 mixture of acetone and water at 20° C. obtaining a mixture of products; (ii) adjusting the pH of the product mixture to about 10 with sodium hydroxide; (iii) extracting the product mixture with isopropyl acetate; (iv) adding 1.5 equivalents of concentrated hydrochloric acid; and (v) isolating the racemic alcohol of formula (IIa) by crystallization. In one embodiment, the method provided here suppresses the formation of the main impurity of formula (VII). In another embodiment, the method is shown in Scheme 2.

In some embodiments, the present invention provides a process for converting an enantiomerically enriched amine of formula (IV) comprising: (i) heating an enantiomerically enriched amine of formula (IV) or a salt thereof in a 2:1 mixture of methyl ethyl ketone and water at 76° C. to obtain a mixture of products ; (ii) adjusting the pH of the product mixture to about 8 with sodium hydroxide; (iii) extracting the product mixture with isopropyl acetate; (iv) adding concentrated hydrochloric acid; and (v) isolating the racemic alcohol of formula (IIa) by crystallization. In one embodiment, the method is shown in Scheme 3.

V. Examples

Some embodiments are illustrated by the following non-limiting examples. The following description is presented to illustrate certain aspects of the present invention and is not intended to limit the scope of the present invention. Changes may be made to the embodiments in light of the detailed description below. Although con

- 7 042764 Specific embodiments are described here for purposes of illustration, various modifications of the methods described herein for carrying out the invention, which are obvious to those skilled in the art, are contemplated within the scope of the claims. All publications, patents, and patent applications cited herein are incorporated herein by reference, as if each such publication, patent, or patent application were specifically and separately indicated to be incorporated herein by reference.

Here and below, equiv. or X means equivalent or equivalents; h means hour or hours; IPC stands for In-Process Control; But. means not found; RT means retention time; pace. means temperature, and V means volume or volumes.

Example A1.

Synthesis of (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy-(1-methyl-1H-imidazol-5yl)methyl]-1-methyl-2(1H)-quinolinone monohydrochloride ( IIa).

As shown in Scheme 2, the conversion from 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1Н)quinolinone (I) to monohydrochloride (±)-4-(3-chlorophenyl)- 6-[(4-chlorophenyl)hydroxy(1-methyl-1nimidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone (IIa) consists of two consecutive steps.

The first stage was the condensation of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (I) with 1-methyl-imidazole in the presence of n-butyllithium in 23% hexane and chlorotriethylsilane using tetrahydrofuran as a solvent. After completion of the reaction, the reaction mixture was diluted with water and neutralized with acetic acid. After separation of the layers, water was added to the organic layer and neutralized with sodium hydroxide. The layers were separated and the organic layer was evaporated.

In the second step, the residue was diluted with 2-propanone. The formation of salt (IIa) of hydrochloric acid was carried out by adding hydrochloric acid. The product crystallized. The precipitate was separated, washed with 2-propanone, and dried.

In particular, the hydrochloride (IIa) was obtained as follows.

1) A minimum of 1.7 liters of tetrahydrofuran and 1.75 mol of 1-methylimidazole were charged into the reactor, stirred and cooled.

2) 0.11 kg of n-butyllithium in hexane 23% (1.75 mol) was added and stirred.

3) 0.27 kg of chlorotriethylsilane (1.8 mol) was added and stirred.

4) Added 0.10 kg of n-butyllithium in hexane 23% (1.55 mol) at -75 to -68°C and stirred.

5) Loaded into another reactor 1 mol of ketone (I) and at least 2 liters of tetrahydrofuran.

6) Stirred and heated until complete dissolution of ketone (I).

7) Cooled and added the solution to the reaction mixture in step 4, maintaining the temperature in the range from -75 to -68°C, and stirred.

8) Water was added and mixed.

9) Glacial acetic acid was added and mixed.

10) Allow the layers to settle. The layers were separated. The aqueous layer was removed.

11) Add water and sodium hydroxide 29% to the organic layer and mix.

12) Allow the layers to settle. The layers were separated. The aqueous layer was removed.

13) The organic layer was evaporated.

14) Add 2-propanone and evaporate.

15) Step 14 was repeated twice.

16) Add at least 4 L of 2-propanone to the evaporated residue, mix and cool.

17) Hydrochloric acid was added and stirred.

18) Centrifuge the pellet and wash the product with 2-propanone.

19) Dry the product in a suitable dryer.

The method described above was adapted for 549-822 mol of ketone (I). The method gave 45-69% alcohol (IIa). Example A2.

Synthesis of (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl2(1H)-quinolinone (IV) .

As shown in Scheme 2, the conversion from (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl1H-imidazol-5-yl)methyl]-1-methyl-2(1H )-quinolinone monohydrochloride (IIa) in (±)-6-[amino(4chlorophenyl)(1-methyl-1 H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2( 1 H)-quinolinone (IV) consists of two consecutive steps.

The first step was the chlorination of the alcohol (IIa) with thionyl chloride in 1,3 dimethyl-2-imidazolidinone as a solvent.

The second step was the in situ amination of the intermediate chloride (III) (not shown in Scheme 2) to the amine (IV) using a solution of ammonia in methanol. The product was crystallized by adding water. The precipitate was separated, washed with water and dried.

In particular, the amine (IV) was obtained as follows.

1) 2 L of 1,3-dimethyl-2-imidazolidinone and 1 mol of hydrochloride (IIa) were loaded into the reactor and

- 8 042764 sewed.

2) Added a minimum of 0.26 kg of thionyl chloride (2.2 mol) while maintaining the temperature below 45°C.

3) Stirred at 20-45°C for at least 3 hours.

4) A minimum of 1.71 L of ammonia in methanol (12 mol) was charged to another reactor, stirred and cooled.

5) The reaction mixture from step 3 was added keeping the temperature below 45°C.

6) Stirred at 12-45°C for at least 15 hours.

7) Add a maximum of 5 liters of water and mix.

8) The product was centrifuged and washed each load of the centrifuge with water.

9) Dry the product in a suitable dryer.

The method described above was adapted for 480-720 moles of alcohol (IIa). The method gave 65-85% of the amine (IV).

Example A3.

Synthesis of (R)-6-[amino(4-chlorophenyl)(1-methyl-1 H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl2(1H)-quinolinone [R- (R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3) (VIa).

As shown in Scheme 2, the conversion from (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H )-quinolinone (IV) in (R)-6-[amino(4-chlorophenyl)(1-methyl-1Nimidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1 H )-quinolinone [R-(R*,R*)]-2,3bis(benzoyloxy)butanedioate (2:3) (VIa) consisted of the formation of an amine salt (IV) [R-(R*,R*)]- 2,3bis(benzoyloxy)-butanedioic acid with [R-(R*,R*)]-2,3-bis(benzoyloxy)-butanedioic acid monohydrate using 2-propanone as solvent. The product was separated, washed with 2-propanone, and dried.

In particular, salt (VIa) was prepared as follows.

1) A minimum of 3.6 L of 2-propanone, 1 mol of amine (IV) and a minimum of 2.8 mol of [R-(R*,R*)]-2,3-bis(benzoyloxy)butanedioic acid monohydrate and stirred at a maximum temperature of 25°C.

2) The product was centrifuged and washed with 2-propanone on each centrifuge load.

3) The filtrate was collected as mother liquor (VIb).

4) Dry the product in a suitable dryer.

The method described above was adapted for 460-1255 mol of amine (IV). The method gave 27-37% salt (VIa).

Example A4.

Synthesis of crude (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3chlorophenyl)-1-methyl-2(1H)-quinolinone (V ).

As shown in Scheme 2, the conversion from (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H )-quinolinone [R-(R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3) (VIa) to crude (R)-6-[amino(4-chlorophenyl)(1- methyl-1H-imidazol-5-yl)methyl]-4-(3chlorophenyl)-1-methyl-2(1H)-quinolinone (V) consisted of releasing the base of the salt (VIa) with ammonium hydroxide using a mixture of water and ethanol as solvent. The product crystallized on cooling. The precipitate was separated, washed with water and dried.

Specifically, crude (R)-(+)-tipifarnib (V) was prepared as follows.

1) The reactor was loaded with denatured anhydrous ethanol and 1 mol of salt (VIa) and stirred.

2) Added ammonium hydroxide.

3) Water was added, heated to reflux and refluxed for a maximum of 150 minutes.

4) Cooled and stirred.

5) The product was centrifuged and washed with water for each batch of centrifuge.

6) Dry the product in a suitable dryer.

The method described above was adapted for 147-706 mol salt (VIa). The method gave 70-95% crude material (V).

Example A5.

Synthesis of unmilled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3chlorophenyl)-1-methyl-2(1H)-quinolinone (V ).

As shown in Scheme 2, crude (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H) -quinolinone (V) was dissolved in ethanol and treated with activated charcoal. After filtration through diatomaceous earth, the reaction mixture was partially evaporated. The product crystallized on cooling. The precipitate was separated and washed with ethanol. The wet product was redissolved in ethanol and treated with activated charcoal. After filtration through diatomaceous earth, the reaction mixture was partially evaporated. The product crystallized on cooling. The precipitate was separated, washed with ethanol and dried.

Specifically, unmilled (R)-(+)-tipifarnib (V) was prepared as follows.

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1) The reactor was charged with denatured anhydrous ethanol, 1 mol of crude substance (V), at least 12.5 g of activated carbon type Norit A Supra, diatomaceous earth and mixed.

2) Heated to reflux and refluxed with stirring.

3) Filter the reaction mixture into another reactor, wash the filter with anhydrous denatured ethanol, stir and evaporate a maximum of 5.72 L of solvent over a maximum of 24 hours.

4) Cooled and stirred.

5) The product was centrifuged and washed with each centrifuge load with denatured anhydrous ethanol.

6) The reactor was charged with denatured anhydrous ethanol, wet product from step 5, at least 12.5 g of activated carbon type Norit A Supra, diatomaceous earth and mixed.

7) Heated to reflux and refluxed with stirring.

8) Filter the reaction mixture into another reactor, wash the filter with anhydrous denatured ethanol, stir and evaporate a maximum of 5.43 L of solvent over a maximum of 24 hours.

9) Steps 4 and 5 were repeated.

10) Dry the product in a suitable dryer until the loss on drying reaches <0.20% w/w.

The method described above was adapted for 392-588 mol of the crude substance (V). The method gave 69-84% unground substance (V).

Example A6.

Synthesis of (R)-(+)-tipifarnib (V).

As shown in Scheme 2, unmilled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H) β-quinolinone (V) was crushed and optionally sieved and homogenized.

Since grinding is a continuous flow semi-batch process, there was no typical batch size. The method gave a yield of 90% or higher (V).

Example B1.

Study of the feasibility of extracting the mother liquor.

In order to recover the undesired enantiomer as the dibenzoyl tartrate salt (VIb) in the mother liquor and effect the conversion from the undesired enantiomer salt (VIb) to the alcohol (IIa) (see Scheme 2), several experiments were carried out to investigate the feasibility of the proposed recovery and conversion process. The details of the experiments are shown in Tables 1, 2 and 3. Experiments were first carried out using the salt (VIa) of the desired enantiomer.

Table 1. Racemization of VIa without _NaNO2

batch number materials IPC (IV/II)%* T1-1 Via H ₂ O Meon Acid a 19 h at 40°С 4 hours at 75°C 1.5 g 1.0 X solids about 4.5ml 3V 15 ml 10V 64.22/18.43 3.24/50.55 Via n ₂ o Aceto n Acid a 2 h at 50°С 18 hours at 50°C 24 h at 50°C T1-2 1.0 g 1.0 X solids about 20 ml 20V 96.32/2.99 86.15/13.01 71.66/27.07 T1-3 20 ml 20V 0.1 ml 37% HC1 97.57/1.96 86.39/12.81 69.28/29.53 T1-4 1 ml 1V 20 ml 20V 90.55/5.62 68.51/19.64 44.28/36.51

* determined by integrating the peak area of the HPLC graph.

In experiment T1-1, 10 volumes of methanol and 3 volumes of water were used as the solvent, and the reaction was carried out at 40 and 75°C. In experiment T1-2, 20 volumes of water were used as the solvent. In experiment T1-3, 0.1 ml of concentrated hydrochloric acid was used as an additive. In experiment T1-4, 1 volume of water and 20 volumes of acetone were used as a solvent. The last three experiments T1-2/3/4 were carried out at 50°C.

The data from experiment T1-1 indicate that the conversion from salt (VIa) to alcohol (II) is feasible. In addition, the analysis of alcohol (II) using chiral chromatography showed complete racemization of the chiral center. However, the reaction conditions lead to the formation of significant amounts of impurities.

The data of experiments T1-2/3/4 indicate that racemization without sodium nitrite has

- 10 042764 low conversion rate even with acid at 50°C. For example, in experiment T1-3, only about 30% alcohol (II) was observed after stirring at 50°C for 24 hours.

In further experiments, sodium nitrite was used as the oxidizing agent in an attempt to improve the reaction conversion and purity profile. The details of the experiments are given in Table. 2.

Table 2. Racemization of VIa with _NaNO2

batch number materials IPC (IV/II)%* Via NaNO 2 Solvent Acid a 39 h at 20°С T2-1 1.5 g 1.0 X solid 0.3 g 15 ml MeOH 4.5 ml H ₂ O 80.32/16.1 0 Via NaNO 2 Solvent Acid a 2 hours at 20°C 18 hours at 20°C 24 hours at 20°C T2-2 1.0 g 1.0 X solid 0.1 g 1.5 eq. 20 ml t-AshOH 1 ml H ₂ O 42.38/48.6 9 49.24/41.7 6 29.57/57.8 9 T2-3 20 ml acetone 1 ml H ₂ O 16.65/72.7 7 24.17/64.7 5 20.23/69.2 3 T2-4 20 ml MeCN 1 ml H ₂ O 36.53/60.7 2 38.40/59.0 36.10/61.1 5 T2-5 20 ml MeCN 1 ml H ₂ O H ₂ SO ₄ 2.0 equiv. 1.67/92.55 0.11/97.41

* determined by integrating the peak area of the HPLC graph.

Five experiments were carried out using salt (VIa), and 1.5 eq. sodium nitrite was used as the reaction reagent. In experiment T2-2, 20 volumes of tert-amyl alcohol and 1 volume of water were used as the solvent. In experiment T2-3, 20 volumes of acetone and 1 volume of water were used as a solvent. In experiment T2-4, 20 volumes of acetonitrile and 1 volume of water were used as the solvent. In experiment T2-5, 20 volumes of acetonitrile and 1 volume of water were used as a solvent, and 2.0 eq. sulfuric acid was used as an additional additive. Experiments T2-2/3/4/5 were carried out at 20°C.

As shown in Table 2, sodium nitrite can convert the desired enantiomeric salt (VIa) to alcohol (II) at a moderate temperature of 20°C. In particular, almost all of the starting material in experiment T2-5 was converted to alcohol (II) after stirring at 20°C for 2 hours. In addition, analysis of alcohol (II) using chiral chromatography showed complete racemization of the chiral center.

In further experiments, a mother liquor containing salt (VIb) was used to directly investigate the extraction process. The details of these experiments are given in table. 3.

Table 3. Racemization of the mother liquor with NaNO ₂

No. part pi materials IPC (IV/II)%* VIb NaN O2 50% H ₂ S O4 Dissolve spruce Outgoing purity Solution after solvent change 2h at 20°C 18 hours at 20°C TZ-1 1.0 X Master solution 0.16 g 1.5 equiv. 20 ml acetone 1 ml H ₂ O 89.93/1.16 15.60/74 0.54/87.86 TZ-2 2.0 eq. 20 ml MeCN 1 ml H ₂ O 85.55/4.34 0.51/89.61 0.48/90.02

* determined by integrating the peak area of the HPLC graph.

In experiment T3-1, 20 ml of acetone and 1 ml of water were used as a solvent. In experiment T3-2, 20 ml of acetonitrile and 1 ml of water were used as a solvent, and 2.0 eq. sulfuric acid was used as an additive. Both of these experiments were carried out at 20°C.

As shown in Table. 3, almost all of the starting material was converted to alcohol (II) after stirring at 20° C. for 18 hours in both experiments. Chiral HPLC confirmed that the resulting alcohol (II) was racemic in both experiments. The use of acetone or acetonitrile as a solvent gave similar control results in the manufacturing process.

Example B2.

Investigation of technological parameters for carrying out the racemization reaction.

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To find a suitable way to carry out the reaction, several experiments were carried out using a solution of T2-5. The details of these experiments are given in table. 4, where DBTA means dibenzoyltartaric acid.

Table 4. Technological parameters for the racemization reaction

batch number and Materials for processing Purity (DBTA/II)%* II Solvent Founded not R n Solution before processing (including DBTA) Solution after treatment and phase separation Organic layer water layer T4-1 1 ml T2-5 2 ml iPrOAc 1 ml H ₂ O 10% NaOH 5 35.20/63.22 16.70/79.60 85.24/13.92 T4-2 7 0.31/95.48 89.70/7.6 3 T4-3 10 0.14/95.66 80.92/15.89 Т4-4 NH ₃ H ₂ O 0.15/95.57 90.59/8.0 2 T4-5 2 ml 2MeTHF 1 ml H ₂ O 10% NaOH 3.77/93.23 89.05/3.2 3

* determined by integrating the peak area of the HPLC graph.

In experiments T4-1/2/3, the reaction mixture was diluted with 2 volumes of isopropyl acetate and 1 volume of water, and then treated with 10% sodium hydroxide to adjust the pH of the mixture. In experiment T4-4, the reaction mixture was diluted with 2 volumes of isopropyl acetate and 1 volume of water, and then treated with ammonium hydroxide to adjust the pH of the mixture to about 10. In experiment T4-5, the reaction mixture was diluted with 2 volumes of 2-methyltetrahydrofuran and 1 volume of water, and then treated with 10% sodium hydroxide to adjust the pH of the mixture to about 10.

Several remarks can be made based on the experimental data in Table 1. 4. First, pH 5 is not a suitable pH for processing, as up to 16.70% DBTA remains in the organic layer. Good separation is achieved at pH values from about 7 to about 10 when the amount of residual DBTA in the organic layer is less than 1% using isopropyl acetate. Secondly, any residual alcohol (II) in the aqueous layer can be recovered by back extraction of the aqueous layer. Finally, the use of 2-methyltetrahydrofuran resulted in 3.77% residual DBTA in the organic layer.

As a result of these experiments, it was determined that isopropyl acetate and 10% sodium hydroxide are optimal materials for the treatment procedure, and adjusting the pH to about 10 can ensure effective removal of DBTA.

Example B3.

Optimization of the extraction process.

To further optimize the reaction conditions, six experiments were carried out at different temperatures and with different solvents. The details of these experiments are shown in tables 5 and 6, where DBTA means dibenzoyltartaric acid.

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Table 5. Study of reaction conditions

AI part number materials Observation during the reaction VIb Solvent Wow yes NaNθ2 50% H ₂ S θ4 ur reaction temperature Before adding NaNO ₂ After completed IA reaction T5-1 1.0 X VIb (Stock solution) 40 ml acetone (20 V) 2 ml (1V) 0.2 g 1.5 equiv. 20°C Clear solution after adding water A lot of solids settled (DBTA) and the mixture could still be stirred. T5-2 28 ml acetone (14 V) 2 ml (1V) 20°C A lot of solid precipitated (DBTA) and the mixture was difficult to stir. T5-3 14 ml acetone (7V) 2 ml (1V) 20°С A lot of solids settled (DBTA) and the mixture could still be stirred. (Analogies but Sing reactions) T5-4 14 ml acetone (7V) 2 ml (1V) 40°С A lot of solids settled (DBTA) and the mixture could still be stirred. (Analogies but Sing reactions) T5-5 14 ml acetone (7V) 4 ml (2V) 20°C Clear solution T5-6 10 ml MeCN (5V) 4 ml (2V) 2.0 eq. 20°С Clear solution after stirring for 0.5 h Clear solution

All six experiments were carried out using the mother liquor (VIb) obtained from large scale production. The mother liquor was concentrated, and then water was charged to the reaction mixture. The course of the reactions was observed and recorded in the table. 5. Then sodium nitrite and sulfuric acid (if necessary) were added to the reaction mixture and the reactions were monitored by HPLC.

In experiment T5-1, the volume of the reaction mixture was close to the full capacity of the reactor. The reaction mixture was a clear solution after adding water. However, during the reaction

- 13 042764 a large amount of solid precipitated out. After completion of the reaction, the reaction mixture could still be stirred, but some solids adhered to the inner wall of the reactor.

To increase the productivity of the reactor in the next two experiments, smaller volumes of solvent were used. In experiment T5-2, 14 volumes of acetone were used. In experiment T5-3, 7 volumes of acetone were used. In both experiments, a large amount of solid precipitated. In particular, in experiment T5-2, which used 14 volumes of solvent, the reaction mixture showed much worse mixing characteristics. Experiments show that water promotes the dissolution of DBTA.

Experiment T5-4 was an attempt to improve the stirring behavior by increasing the reaction temperature to 40°C. However, this did not lead to the desired result.

In experiment T5-5, 2 volumes of water were used. The reaction mixture remained a clear solution even after the completion of the reaction, which could make the process reliable.

In experiment T5-6, the reaction solvent was changed to acetonitrile with 2 volumes of water. However, the reaction mixture required stirring for about half an hour to obtain a clear solution. After completion of the reaction, the reaction mixture was also a clear solution.

The results of control in the production process for six experiments are given in table. 6.

Table 6. Study of reaction conditions

batch number and materials IPC (IV/II)%* Solvent water Reaction temperature Solution after concentration or solvent change 2h 18 h T5-1 40 ml acetone (20 V) 2 ml (1V) 20°С 72.07/11.39 17.69/65.2 9 2.49/79.3 5 T5-2 28 ml acetone (14 V) 2 ml (1V) 20°C 73.21/10.94 31.63/52.1 9 2.59/78.7 8 T5-3 14 ml acetone (7V) 2 ml (1V) 20°С 72.60/11.12 10.83/70.6 8 2.29/79.6 4 T5-4 14 ml acetone (7V) 2 ml (1V) 40°C 72.14/11.23 4.06/77.49 2.00/75.26 T5-5 14 ml acetone (7V) 4 ml (2V) 20°С 71.15/11.77 6.73/76.18 1.65/81.7 0 T5-6 10 ml MeCN (5V) 4 ml (2V) 20°С 71.50/11.64 1.40/82.40 1.22/82.3 2

* determined by integrating the peak area of the HPLC graph.

Several remarks can be made based on the experimental results in Table 1. 6. First, reactions at 20° C. give similar results after stirring for 18 hours, but increasing the reaction temperature to 40° C. results in a decrease in product purity. Secondly, the use of a smaller volume of solvent (and hence a high concentration of reactants) resulted in a higher reaction rate. For example, only about 7% of salt (VIb) remained after stirring for 2 hours in experiment T5-5. Finally, the use of acetone or acetonitrile as solvent gives similar results.

Example B4.

Further exploration of the extraction process.

To further study the reaction conditions, three experiments per 20 g amount were performed. The details of the experiments are shown in tables 7, 8 and 9.

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Table 7. Study of reaction conditions

AI part number materials Observation during the reaction VIb Solvent Wow yes NaNθ2 50% H ₂ S about ₄ Reaction temperature Before adding NaNO ₂ After completion of the reaction T7-1 1.0 X VIb (Mother solution) 249 ml acetone (12.5 V, no concentration) 20 ml (1V) 2.44 g 1.8 eq. 20°С Clear solution after adding water. A lot of solids settled out (DBTA) and the mixture was difficult to stir. T7-2 100 ml MeCN (5V) 40 ml (2V) 2.0 eq. Clear solution after stirring for 0.5 h. No solid (DBTA) precipitated. The mixture was transparent. T7-3 120 ml acetone (6V) 40 ml (2V) Clear solution after adding water. No solid (DBTA) precipitated. Mixture was transparent.

All three experiments were carried out using stock solution (VIb) obtained from large scale production. The mother liquor was concentrated, and then water was charged to the reaction mixture. The course of the reactions was observed and recorded in the table. 7. Sodium nitrite and sulfuric acid (if necessary) were then added to the reaction mixture and the reactions monitored by HPLC.

In experiment T7-1, the reaction was carried out using the mother liquor directly without concentration. The reaction mixture was a clear solution after adding water. However, during the course of the reaction, a large amount of solid was released, which made it difficult to stir the reaction mixture.

In experiment T7-2, the solvent was first changed to obtain a solution in acetonitrile. The reaction mixture was initially a viscous solution but became a clear solution after adding water and stirring for half an hour. During the course of the reaction, the DBTA solid did not precipitate and the reaction mixture remained clear.

In experiment T7-3, the reaction mixture was concentrated to 6 volumes. The reaction mixture became a clear solution upon addition of water. The DBTA solid did not precipitate during the course of the reaction, and the reaction mixture was also a clear solution after completion of the reaction.

The results of control in the production process for these three experiments are shown in table. 8.

Table 8. Study of reaction conditions

batch number and materials IPC (IV/II)%* Solvent Water Initial purity Solution after concentration or solvent change 2h 18 h T7-1 249 ml acetone (12.5 V, no concentration) 20 ml (IV) 78.19/7.1 3 7.65/77.5 1 0.48/82.7 2 T7-2 100 ml MeCN (5V) 40 ml (2V) 77.46/7.50 0.75/85.1 0 0.34/85.2 1 T7-3 120 ml acetone (6V) 40 ml (2V) 77.00/8.22 1.15/83.7 1 0.86/83.0 4

* determined by integrating the peak area of the HPLC graph.

- 15 042764

The purity of alcohol (II) obtained in three experiments was almost the same. Chiral HPLC confirmed that alcohol (II) was obtained as a racemic mixture in all three experiments. However, the reaction without concentration (experiment T7-1) required a longer period of time to convert all of the starting material into the product.

The use of smaller solvent volumes (and hence higher concentrations) resulted in a higher reaction rate in the T7-2/3 experiments. After stirring for 2 hours, only about 1% of starting material (VIb) remained.

All three experiments were continued further using processing and crystallization procedures. In experiments T7-1/2, the reaction mixture was diluted with 100 ml of isopropyl acetate and 100 ml of water, then treated with 10% aqueous sodium hydroxide to adjust the pH of the mixture to about 10. In experiment T7-3, the reaction mixture was diluted with 100 ml of isopropyl acetate, then treated with about 80 ml 10% aqueous sodium hydroxide to adjust the pH of the mixture to about 10. To achieve a high degree of extraction, the aqueous layer was again extracted with 100 ml of isopropyl acetate. The combined organic layer was used to crystallize the salt (IIa), first by changing the solvent with 10 volumes of acetone, and then acidifying with 1.5 eq. 37% HCl.

The final results for the dry filtrate salt (IIa) are shown in table. 9. RT is HPLC retention time. The main impurity at RT 7.5 min was identified and fully characterized. The chemical structure is designated as VII in the table. 9.

Table 9. Results of crystallization studies

Experiment # T7-1 T7-2 T7-3 RT 5.4 min mesityl oxide 0.02 0.02 0.33 RT 6.7 min (V) GT ¹ { МН _a GHj 0.30 o,n 0.10 RT 7.5 min (VII) S' Z Q A Account Q 0.15 1.12 0.90 RT 8.1 min (II) .Ct (G Cl · -' 0¾ GH ₃ 98.93 97.77 97.75 RT 8.5 min jOiOTi. CH, 0.04 0.10 0.13 RT 9.0 min o ( OM T jOiTXl CI -' N -O gh ₅ 0.06 0.18 0.28 RT 9.2 min 0.02 0.08 o,n RT 11.3 min 0.09 0.12 0.08 RT 11.5 min 0.20 0.17 0.10 RT 11.9 min (I) ct ( J o T GHj 0.10 0.16 0.23

After crystallization with acetone, the purity of the alcohol (IIa) was almost 98% in the final product.

Example B5.

Impurity study (VII).

Eight experiments were carried out to study the formation of impurity (VII). The details of these experiments are given in table. 10.

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Table 10. Impurity study (VII)

AI part number materials IPC for 18h Observation during the reaction VIb Acetone water Impurity VII Before adding NaNO ₂ After the completion of the reaction T10-1 1.0 X VIb (Stock solution) 12.5 V (without concentration) 0V 0.12% Clear solution A lot of solid (DBTA) precipitated and the mixture could not be stirred. T10-2 0.5V 0.15% A lot of solid (DBTA) precipitated and the mixture was difficult to stir. T10-3 1V 0.30% A lot of solid (DBTA) settled out and the mixture was still stirrable. T10-4 2V 0.52% No solid (DBTA) precipitated. The mixture was clear. Т10-5 6V 0.5V 0.17% A lot of solid (DBTA) settled out and the mixture was still stirrable. T10-6 1V 0.40% A lot of solid precipitated (DBTA) and the mixture it was difficult to mix. T10-7 2V 0.61% No solid (DBTA) precipitated. The mixture was clear. T10-8 6V 1.04% A lot of solid precipitated (B) A lot of solid (DBTA) settled out and the mixture was still stirrable.

Experimental data in table. 10 show that more water in the reaction mixture leads to a higher content of impurity (VII). This is especially true in experiment T10-8 where 6 volumes of water resulted in a 1.04% impurity. However, it should be noted that while low water volume may give better results in terms of purity profile, at the same time, low water volume can cause mixing problems. This was the case in experiment T10 1 where the reaction mixture was practically unstirred because there was no water in the reaction mixture.

Experiment T10-5 (6 volumes of acetone solution with 0.5 volumes of water) gave only 0.17% of impurity (VII) in the reaction with 3 g amount. To further validate the method, the same procedure of Experiment T10-5 was repeated with larger amounts in three additional experiments. The details of these three experiments are shown in Tables 11 and 12.

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Table 11. Further study of the extraction process

AI part number materials Observation during the reaction VIb Acetone water NaN about ₂ Temperature Cheers Reactions Before adding NaNO ₂ After the completion of the reaction T11-1 20 g 6 V (Concentrated solution up to 6 V) 0.5V 1.8 equiv. 20°C Clear solution A lot of solid (DBTA) settled out and the mixture was still stirrable. T11-2 40 g A lot of solid precipitated (DBTA) Reaction mixture on top was too viscous to stir tp-z 100 g and almost gelatinous.

f is the calculated mass of salt (VIb) contained in the mother liquor.

Table 12. Further study of the extraction process

Experiment # Τ11-1 ΤΙ 1-2 Τ11-3 RT 5.4 min Mesitylox id 1° 0.07 0.05 0.02 RT 6.7 min (V) and Λ - ζ Λ—<. Λ T -Z y. V Η.Ο. 0.16 0.02 RT 7.5 min (VII) <-j p \ /—\ Z \_/ Z £ 0.18 0.44 0.43 RT 8.1 min (II) n |G 7 OH - SK '- · · - 'N' Ό CH ₅ 98.20 97.47 98.33 RT 8.5 min .CI n ^:: _m -ch _s (i ~ /7'7 Ί' 7 Cl- 'N' Ό CH, 0.15 0.19 0.15 RT 9.0 min ,.-4.Cl N™ ii7 ΟΜί' % Cl- ···· ’Ν' Ό CH, 0.33 0.37 0.17 RT 9.2 min 0.10 0.16 0.06 RT 11.3 min 0.16 0.24 0.12 RT 11.5 min 0.24 0.27 0.05 RT 11.9 min (I) .CI || 7 ... Λ .... ..4 j 7' ϊ 7 7 CI- ··.···· -·.:· -Ν' Ό CH, Η.Ο. 0.25 0.16

In the 20 g experiment (experiment T11-1), although a lot of solid (DBTA) precipitated at the completion of the reaction, the reaction mixture could still be stirred. However, when the quantities were increased to 40 g or 100 g in this process, mixing problems arose. The reaction mixture was too viscous to stir after completion of the reaction. This was especially noticeable at the top of the reaction mixture, where it was almost jelly-like.

In addition, the content of impurities (VII) was also higher than usual (about 0.2%) in reactions with a large amount.

- 18 042764

In an attempt to further optimize the method, three more experiments were carried out with different amounts of acetone and water per 60 g amount. The details of these experiments are given in table. 13.

Table 13. Further study of the extraction process

batch number and materials Observation during reaction (VIb/VII/II)* VI b Acet he Water IPC for 2 h IPC for 18h T13-1 60 g 9V 0.75V Clear solution 3.66/0.20/86.47 A lot of solid settled (DBTA) The reaction mixture on top was too viscous to stir and almost gelatinous. 0.14/0.27/90.17 T13-2 6V 1V Clear solution 0.13/0.55/89.04 0.13/0.58/89.26 T13-3 6V 1.5V Clear solution 0.03/0.82/89.22 Clear solution 0.10/0.77/90.28

* determined by integrating the peak area of the HPLC graph;

f is the calculated mass of salt (VIb) contained in the mother liquor.

The results in the table. 13 show that reactions with small volumes of water (0.75 and 1 volume) have mixing problems, especially after mixing for a long time. Reaction with 1.5 volumes of water always gives a clear solution, even after the reaction is complete, but this results in a higher level of impurities.

Two experiments were carried out with the procedure as in T13-1, at different temperatures (30 and 40°C). The details of these experiments are given in table. 14.

Table 14. Further study of the extraction process

AI part number materials Observation during reaction (VIb/VII/II)* VI S Acet he Water Temperature IPC for 1 h IPC for 18h Treatment T14-1 60 g 9V 0.75V zo°s Clear solution 2.47/0.18/8 7.78 A lot of solid settled (DBTA) The reaction mixture on top was too viscous to stir and almost gelatinous. 0.11/0.51/8 7.91 T14-2 40°C Clear solution 0.13/1.13/8 9.47 0.09/0.38/8 8.38

* determined by integrating the peak area of the HPLC graph;

f is the calculated mass of salt (VIb) contained in the mother liquor.

As the experimental results in Table. 14, when reacting at high temperatures (30 and 40°C), mixing problems still occur, especially after mixing for a long time. Moreover, the content of impurity (VII) was also higher than at 20°C (20°C, RT 7.5 min about 0.2%).

Based on the experimental results presented here, the use of 6 volumes of acetone and 1.5 volumes of water has been found to minimize mixing problems and provide optimum results in the final recovery process.

Example B6.

Demonstration batch in the kilogram laboratory.

A demonstration batch of the mother liquor recovery process was processed at 1.445 kg in a 1 kg laboratory with a 30 L reactor. Details for the demonstration batch are given in Tables 15 and 16. In this experiment, several batches of mother liquor from large scale production were combined and their total volume was about 20 liters.

The mother liquor was concentrated to 6 volumes and 1.5 volumes of water was added. Then the reactor was slowly loaded with 1.8 eq. sodium nitrite, maintaining the temperature of the reaction mixture below 40°C. After completion of the reaction, 5 volumes of isopropyl acetate were added and 10% aqueous sodium hydroxide solution was charged to adjust the pH of the mixture to 10. Then, the aqueous layer after phase separation was re-extracted with 5 volumes of isopropyl acetate. Finally, 1.5 eq. concentrated hydrochloric acid to crystallize the product after changing the solvent.

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Table 15. Demonstration batch in the kilogram laboratory

No. part pi materials Reaction Treatment Crystallization VIb t Acetone water NaN about ₂ Temperature 'PrO As 10% NaO H HC1 concentration T15 1.44 5 kg The mother liquor was concentrated to 6 V 1.5V 2.16L 1.8 eq. 175 g 20°C 10 V 14.44 l 9 l pH=1 0 1.5 eq. 208.4 g

f total weight of salt (VIa) and (VIb) contained in the mother liquor.

Table 16. Results for a demonstration batch in a kilogram laboratory

Experiment # T15 Scheme Mother liquor before reaction IPC Solution before crystallization mother liquor Dry filter RT 5.4 min Mesitylo xid 0.96 0.2 5 oh and 30.86 0.05 RT 6.7 min (V) mn _g T ΓΎιΓιΓι GHj 74.79 0.1 5 0.05 oh and 0.05 RT 7.4 min DBTA / / 0.09 0.23 But. RT 7.5 min (VII) HE ] CHj But. 0.6 1 0.99 0.55 0.73 RT 8.1 min (P) o O \ \ W o 4 Gn ^g ί 7 16.55 90, 72 94.18 29.25 97.10 RT 8.5 min .Ct JT Cl CHj 0.24 o,z 6 0.21 1.09 0.24 RT 9.0 min o 0 \ /—λ (tP ^r ί 7 o 2.71 2.5 8 1.12 12.75 0.43 RT 9.2 min 0.85 0.8 7 0.40 4.47 0.17 RT 11.3 min oh and o,z 5 0.19 0.68 0.24 RT And,5 min 0.01 o,z 9 0.36 0.78 0.28 RT I,9 min (I) r^< ^{CC 0} T dG'TCH Cl - - ¹ GHj 0.61 0.8 7 0.72 5.70 0.26 Exit or 5% 97% loss ya exit yes

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In this experiment, the reaction mixture was a clear solution even after stirring overnight. The whole process showed good progress at various stages for the demonstration batch, including reaction, processing and crystallization. In the final isolated product, the purity of the salt (IIa) was 97.10% and the impurity content (VII) was 0.73%. In addition, the resulting salt (IIa) isolated after this recycling process was racemic.

The yield loss on crystallization was 5% and the overall recovery yield was 97%, based on the amount of (S)-(-) tipifarnib in the mother liquor (VIb).

Example C1.

Recirculation process without sodium nitrite.

Four experiments were carried out with various solvents at elevated temperatures to further study the extraction process without the use of sodium nitrite. These experiments are detailed in Tables 17 and 18. Dry solid salt (VIa) was used in all experiments. The progress of the reactions was observed and recorded after the addition of the solvent, after the addition of water, and after stirring the reaction mixture for 48 h.

Table 17 Reaction Solvent Study: Reaction Conditions

batch number and materials Observation Via n ₂ O 1.0 V Solvent 6.0 V After adding solvent After adding water After stirring for 48 hours T17-1 1.0 g 1.0 X solids about 1 ml 6 ml MeCN undissolved Some solid settled (RT) Some solid settled (RT) T17-2 6 ml MEK undissolved Some solid settled (RT) Some solid settled (RT) T17-3 6 ml Acetone undissolved Some solid settled (RT) Some solid settled (RT) T17-4 6 ml DMF Dissolved Clear solution Clear solution

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Table 18. Study of the reaction solvent: experimental results

Lot No. Temperature (solvent) Time to stir ya results Enantiomeric composition II RT=1, 26 min Benzoic acid IV DBT A II Them. Via But. But. 64.8 9 34.07 1.04 Т17-1 80°С (MeCN/H ₂ O) 3 h 3.46 4.97 14.7 7 17.45 55.62 6 h 4.12 7.70 7.70 10.19 64.96 24 hours But. 15.45 4.91 0.74 75.21 48 h 1.78 16.26 4.01 0.41 70.64 48.69/51.31 Т17-2 80°С (MEK/Н ₂ О) 3 h 3.88 4.58 37.0 4 20.73 32.49 6 h 5.58 7.80 22.4 12.89 47.06 24 hours 4.95 16.80 2.04 0.98 69.67 48.09/51.91 T17-3 reflux at 60°C (acetone/H ₂ O) 3 h 2.40 2.47 44.4 3 25.65 22.41 6 h 4.17 4.34 36.6 3 22.25 31.33 24 hours 5.90 10.10 I,5 0 7.99 59.67 48 h 4.52 13.86 4.98 2.39 67.48 47.87/52.13 Т17-4 80°С (DMF/H ₂ O) 3 h 3.16 4.50 39.5 4 19.24 27.59 6 h 3.87 7.00 29.9 1 12.18 37.92 24 hours 3.13 13.39 I,8 7 1.32 58.44 48 h 1.01 17.12 5.01 oh and 65.11 48.38/51.62

In experiment T17-1, where MeCN was used as the reaction solvent, only 7.70% of unconverted amine (IV) remained after stirring for 6 hours at 80°C. However, the reaction subsequently slowed down and 4.01% of the unconverted amine (IV) still remained after stirring for 24 hours. °C, 22.43% of unconverted amine (IV) remained. The amount of unconverted amine (IV) was further reduced to about 2% after stirring for 24 h. .

The enantiomeric composition of the alcohol (II) in the product solution was tested and was racemic within the measurement error.

Example C2.

Study of the volume of water.

Six more experiments were carried out to study the effects of different volumes of water. These experiments are detailed in Tables 19 and 20. Dry solid salt (VIa) was used in all experiments. The progress of the reactions was observed and recorded after the addition of the solvent, after the addition of various volumes of water, and after stirring the reaction mixture for 48 h.

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Table 19. Water Volume Study: Reaction Conditions

batch number and materials Observation Via O I Solvent After adding solvent After adding water After stirring for 48 hours at 80°C T19-1 1.0 g 1.0 X solids about 1 ml 6 ml MeCN undissolved Some solid has settled (RT) Some solid settled (RT) T19-2 2 ml undissolved Some solid has settled (RT) Some solid settled (RT) T19-3 ml undissolved Some solid has settled (RT) Clear solution T19-4 1 ml 6 ml MEK undissolved Some solid has settled (RT) Some solid settled (RT) T19-5 2 ml undissolved Some solid has settled (RT) Clear solution with two phases T19-6 3 ml undissolved Some solid Clear solution with two phases substances precipitated (RT)

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Table 20. Water Volume Study: Experimental Results

batch number Stirring time Results (%) RT 1.2 6 min benzoin i acid IV DBT A II IV/(IV+I I) Them. Via But. But. 64.8 9 34.07 1.04 98.4 T19-1 (MeCN/H ₂ O=6V/l V) 3 h 3.4 6 4.97 14.7 7 17.45 55.6 2 21.0 6 h 4.1 2 7.70 7.70 10.19 64.9 6 10.6 24 hours But. 15.45 4.91 0.74 75.2 1 6.1 48 h 1.7 8 16.26 4.01 0.41 70.6 4 5.4 ΤΙ 9-2 (MeCN/H ₂ O=6V/2 V) 3 h 3.3 4 4.06 10.3 6 21.34 58.4 6 15.1 6 h 4.2 7 5.86 5.85 16.34 64.5 7 8.3 24 hours 4.9 0 12.33 3.79 3.85 70.6 9 5.1 48 h 4.1 1 15.08 3.56 1.07 71.6 1 4.7 ΤΙ 9-3 (MeCN/H ₂ O=6V/3 V) 3 h 3.2 2 3.23 7.03 24.51 59.8 6 10.5 6 h 4.2 3 4.65 3.64 20.48 64.5 0 5.3 24 hours 6.7 6 9.65 2.42 8.89 68.9 0 3.4 48 h 6.9 0 12.070 2.42 3.85 70.6 1 3.3 ΤΙ 9-4 (MEK/H ₂ O= 6V/1V) 3 h 3.8 8 4.58 37.0 4 20.73 32.4 9 53.3 6 h 5.5 8 7.80 22.4 12.89 47.0 6 32.3 24 hours 4.9 5 16.80 2.04 0.98 69.6 7 2.8 T19-5 (MEK/H ₂ O= 6V/2V) 3 h h, h 0 4.44 34.7 2 21.48 34.5 1 50.2 6 h 4.4 2 6.78 24.6 4 16.17 46.1 3 34.8 24 hours 6.6 2 15.50 2.62 2.68 70.8 6 3.6 48 h 5.1 9 18.68 1.16 0.74 72.5 4 1.6 T19-6 (MEK/H ₂ O= 6V/3V) 3 h 2.6 4 4.14 35.1 6 22.30 34.4 8 50.5 b h 3.8 0 6.83 22.6 2 16.57 48.6 2 31.8 24 hours 8.4 8 13.08 4.61 5.29 67.6 0 6.4 48 h 6.6 7 17.79 0.95 1.35 72.2 8 1.3

From the experimental results shown in Tables 19 and 20, it can be concluded that increasing the amount of water from 1.0 to 3.0 volumes resulted in a modest increase in the reaction rate, since the increased amount of water could dissolve any solid precipitated during the reaction. However, approximately 3-6% unreacted amine (IV) still remained after stirring for 24 hours.

It can also be concluded from the experimental results in Tables 19 and 20 that MeCN proved to be a more effective solvent than MEK, especially when considering the results after 6 hours.

Example C3.

Study of acid additives.

Four more experiments were carried out to investigate the accelerating effect of an acid additive, 5% by weight, sulfuric acid, on the reaction rate. Experiments were carried out using stock solution (VIb) with the same solvent/water ratio (6.0 V/3.0 V) at 80°C. The results of the experiments are shown in tables 21 and 22.

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Table 21 Acid Additive Study: Reaction Conditions

No. part pi materials Observation VIb 1.0 X (stock solution) AND ABOUT Solvent 6.0 V Doba in k a After adding the solvent After adding water After heating up to 80°С After stirring for 24 h at 80°С T21- 1 45 g 3.0V MeCN No Undissolved Undissolved Clear solution Clear solution (RT) T21- 2 5 g 5% _H2SO4 T21- 3 45 g MEK No Undissolved Undissolved Clear solution Clear solution with two phases T21- 4 5 g 5% _H2SO4

t is the calculated mass of salt (VIb) contained in the mother liquor.

Table 22 Acid Additive Study: Experimental Results

batch number Mixing time Results (%) RT=1.2 6 min benzoin i acid IV DBT A II IV/(IV+II) I m. VIb (Mother liquor) 0.16 0.24 61.0 4 35.86 0.41 99.3 T21-1 (MeCN) 2h 3.98 3.05 1.95 53.05 36.0 7 5.1 4h 7.05 5.87 0.13 45.13 38.8 8 oh, s 6 h 10.26 9.40 But. 36.80 39.4 8 But. 8h 10.65 9.88 But. 35.84 39.4 7 But. T21-2 (5% H ₂ SO ₄ in MeCN) 2h 3.05 2.21 1.47 55.72 36.1 3 3.9 4 h 5.42 4.04 oh and 50.65 37.9 8 oh, s 6 h 8.48 6.64 But. 43.41 39.2 9 But. 8h 8.57 6.78 But. 43.68 38.6 8 But. T21-3 (MEK) 2h 3.31 2.26 13.9 4 54.89 24.3 2 36.4 4 h 5.93 4.31 5.68 49.18 33.1 7 14.6 6 h 9.05 7.16 1.67 41.58 38.1 6 4.2 8h 9.45 7.55 1.24 41.57 38.1 2 3.2 16 h 12.88 12.83 0.05 30.68 40.4 9 0.1 T21-4 (5% H ₂ SO ₄ in MEK) 2 h 2.96 1.75 12.1 9 55.37 26.5 6 31.5 4h 13.33 4.18 6.21 42.10 32.9 4 15.9 6 h 8.54 5.48 1.04 46.00 37.4 4 2.7 8h 7.67 5.66 0.84 46.58 37.9 9 2.2

When using the mother liquor (VIb) directly in the racemization reaction, the reaction rate was significantly higher when using MeCN as a solvent than when using MEK. Almost all of the starting material (IV) was converted to alcohol (II) within 4 hours in MeCN, while in MEK it took about 16 hours under similar conditions.

The acid addition (5 wt %, sulfuric acid) appears to have had a limited accelerating effect on the reaction rate. The experimental results in the presence of an acid additive and in its absence are similar in many respects.

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Example C4.

Manufacturing procedure.

The conversion of the mother liquor (VIb) to the alcohol hydrochloride (IIa) can be carried out using the following procedure.

1) The mother liquor (VIb) containing 1.64 kg (1.6 mol) of salts (VIa) and (VIb) was loaded into the reactor.

2) Concentrated to 5 L (3.0 V), then charged with 7.3 kg (4.5 X) methyl ethyl ketone and 4.5 kg (2.7 X) process water.

3) The resulting biphasic mixture was stirred at 76°C for 14 hours.

4) The reaction was monitored by UPLC until the ratio IV/(IV+II) was 2% or less.

5) Added 3.8 kg (2.3 X) process water.

6) 2.4 kg of 30% w/w NaOH solution was added so that the reaction mixture had a pH > 8.

7) The layers were separated.

8) The aqueous layer was extracted with IPAc (6.0 kg, 3.7X).

9) Add 4.5 kg (2.7 X) process water to the combined organic layers.

10) The resulting mixture was kept at 20°C for 12 hours.

11) The mixture was concentrated at 50° C. under reduced pressure until its volume was approximately 9 L (5.5 V).

12) Added 3.3 kg (2.0 X) IPAc.

13) The resulting suspension was kept at 20°C for 12 hours.

14) Filter the suspension and wash the wet filter cake with 1.3 kg (0.8 X) of acetone.

15) Wash the wet cake with acetone (4.7 X, 6 V).

16) 35% HCl solution (224 g, 2.1 mol, 0.14 X) was added at 20°C over 5 hours and held for 14 hours.

17) Filtered, washed with acetone (3.3 kg, 2.0 X) and dried at 80° C. for 72 h under vacuum.

The method described above gives a typical yield of approximately 80-90%.

Claims (55)

1. The method of obtaining (R)-(+)-tipifarnib, including the steps: (i) obtaining starting material containing an enantiomeric excess of (S)-(-)-tipifarnib; (ii) converting the starting material from step (i) into a racemic mixture of tipifarnib, wherein step (ii) comprises the steps of: (ii)(a) reacting the starting material with sodium nitrite in a reaction solvent to obtain a mixture of products containing a racemic alcohol of formula (II), ^SN Formula (II) (ii)(b) isolating said racemic alcohol of formula (II) from a mixture of products from step (ii)(a); and (ii)(c) converting the racemic alcohol from step (ii)(b) to a racemic mixture of tipifarnib; and (iii) isolating (R)-(+)-tipifarnib from the tipifarnib racemic mixture from step (ii), wherein step (iii) comprises the steps of: (iii)(a) crystallizing (R)-(+)-tipifarnib from the tipifarnib racemic mixture from step (ii)(c) in the presence of a chiral resolving agent; and (iii)(b) isolating the crystals of (R)-(+)-tynifarnib from the mother liquor from step (iii)(a). 2. The method of claim 1, wherein the starting material from step (i) contains an acid salt of tipifarnib. 3. The method of claim 2 wherein the acid is an enantiomerically pure chiral organic acid. 4. The method of claim 3 wherein the acid is a chiral resolving agent. 5. The method of claim 2 wherein the acid is (-)-dibenzoyl-L-tartaric acid. 6. The method of claim 1, wherein the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof. 7. The method of claim 1, wherein the reaction solvent of step (ii)(a) is a mixture of an organic solvent and water. - 26 042764 8. The method of claim 7 wherein the mixture has a volume ratio of organic solvent to water in the range of 20:1 to 3.5:1. 9. The method of claim 8 wherein the volume ratio of organic solvent to water is 4:1. 10. The method according to any one of claims 6 to 9, wherein the organic solvent is miscible with water. 11. The method according to any one of claims 6 to 9, wherein the organic solvent is acetone, acetonitrile, methanol, t-amyl alcohol, or a mixture thereof. 12. The method according to any one of claims 6 to 9, wherein the organic solvent is acetone. 13. The method according to any one of claims 6 to 9, wherein the organic solvent is acetonitrile. 14. The method according to claim 1, in which stage (ii)(a) takes place at a temperature in the range from 20 to 75°C. 15. The method according to claim 1, in which stage (ii)(a) takes place at a temperature of 20°C. 16. The method of claim 1, wherein step (ii)(a) is carried out in the presence of an additive. 17. The method of claim 16 wherein the additive is an acid. 18. The method of claim 17 wherein the acid is sulfuric acid. 19. The method of claim 17 wherein the acid is hydrochloric acid. 20. The method of claim 1, wherein step (ii)(b) comprises: adjusting the pH of the product mixture with a base; extracting the product mixture with an extraction solvent; and crystallization of the racemic alcohol of formula (II). 21. The method of claim 20 wherein the pH of the product mixture is adjusted to a range of 5 to 10. 22. The method of claim 20, wherein the product mixture is adjusted to pH 10. 23. The method of claim 20 wherein the base is sodium hydroxide or ammonium hydroxide. 24. The method of claim 20 wherein the base is sodium hydroxide. 25. The method of claim 20 wherein the extraction solvent is isopropyl acetate or 2-methyltetrahydrofuran. 26. The method of claim 20 wherein the extraction solvent is isopropyl acetate. 27. The method of claim 20 wherein the racemic alcohol crystallizes as the hydrochloride salt. 28. The method of claim 1 wherein the chiral resolving agent of step (iii)(a) is (-)-dibenzoyl-L-tartaric acid. 29. The method of claim 1, wherein the mother liquor of step (sh)(a) contains an enantiomeric excess of (S)-(-)-tipifarnib. 30. The method of claim 1, wherein the method further comprises: (iv) recycling the mother liquor of step (iii)(b) for use as starting material in step (i). 31. The method of claim 30, wherein steps (i)-(iv) can be performed in multiple cycles. 32. The method of obtaining (R)-(+)-tinifarnib, including the steps: (i) obtaining a starting material containing an enantiomeric excess of (S)-(-)-typifarnib; (ii) converting the starting material from step (i) into a racemic mixture of tipifarnib, wherein step (ii) comprises the steps of: (ii)(a) heating the starting material in the reaction solvent to obtain a mixture of products containing racemic alcohol of formula (II), ^SN Formula (II) (ii)(b) isolating said racemic alcohol of formula (II) from a mixture of products from step (ii)(a); and (ii)(c) converting the racemic alcohol from step (ii)(b) to a racemic mixture of tipifarnib; and (iii) isolating (R)-(+)-tipifarnib from the tipifarnib racemic mixture from step (ii), wherein step (iii) comprises the steps of: (iii)(a) crystallizing (R)-(+)-tipifarnib from the tipifarnib racemic mixture from step (ii)(c) in the presence of a chiral resolving agent; and (iii)(b) isolating the (I)-(+)-tipifarnib crystals from the mother liquor from step (iii)(a). 33. The method of claim 32, wherein the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof. 34. The method of claim 33, wherein the reaction solvent of step (ii)(a) is a mixture of an organic solvent and water. - 27 042764 35. The method of claim 34 wherein the mixture has a volume ratio of organic solvent to water in the range of 6:1 to 2:1. 36. The method of claim 35, wherein the volume ratio of organic solvent to water is 2:1. 37. The method according to any one of claims 33-36, wherein the organic solvent is mixed with water. 38. The method according to any one of claims 33-36, wherein the organic solvent is acetonitrile, methyl ethyl ketone, acetone, dimethylformamide, or a mixture thereof. 39. The method according to any one of claims 33-36, wherein the organic solvent is methyl ethyl ketone. 40. The method according to any one of claims 33-36, wherein the organic solvent is acetonitrile. 41. The method according to claim 32, wherein step (ii)(a) takes place at a temperature in the range of 60 to 80°C. 42. The method according to claim 41, wherein step (ii)(a) takes place at a temperature of 80°C. 43. The method of claim 41, wherein step (ii)(a) takes place at a temperature of 76°C. 44. The method of claim 32, wherein step (ii)(a) takes place in the presence of an additive. 45. The method of claim 44 wherein the additive is an acid. 46. The method of claim 45, wherein the acid is sulfuric acid. 47. The method of claim 32, wherein step (ii)(b) comprises: adjusting the pH of the product mixture with a base; extracting the product mixture with an extraction solvent; and crystallization of the racemic alcohol of formula (II). 48. The method of claim 47 wherein the product mixture is adjusted to pH 8. 49. The method of claim 47 wherein the base is sodium hydroxide. 50. The method of claim 47 wherein the extraction solvent is isopropyl acetate. 51. The method of claim 47 wherein the racemic alcohol crystallizes as the hydrochloride salt. 52. The method of obtaining (R)-(+)-tipifarnib, including the steps: (i) obtaining starting material containing an enantiomeric excess of (S)-(-)-tipifarnib; (ii)(a) reacting the starting material with sodium nitrite to obtain a mixture of products containing racemic alcohol of formula (II), N CH ₃ Formula (II) (ii)(b) isolating said racemic alcohol of formula (II) from a mixture of products from step (ii)(a); (ii)(c) converting the racemic alcohol from step (ii)(b) to a racemic mixture of tipifarnib; (iii)(a) crystallizing (R)-(+)-tipifarnib from the tipifarnib racemic mixture of step (ii)(c) in the presence of a chiral resolving agent; (iii)(b) isolating (R)-(+)-tipifarnib crystals from the mother liquor of step (iii)(a); and (iv) recycling the mother liquor of step (iii)(b) for use as the starting material in step (i). 53. The method of obtaining (R)-(+)-tipifarnib, including the steps: (i) obtaining a racemic mixture of tipifarnib; (ii) crystallizing (R)-(+)-tipifarnib from the tipifarnib racemic mixture of step (i) in the presence of a chiral resolving agent; (iii) isolating (R)-(+)-tipifarnib crystals from the mother liquor; (iv) converting any remaining tipifarnib in the mother liquor from step (iii) to racemic alcohol of formula (II), N CH ₃ Formula (II) (v) converting the racemic alcohol from step (iv) to the racemic mixture of tipifarnib; and (vi) recycling the racemic mixture of tipifarnib from step (v) back to step (i). 54. A process for converting (8)-(-)-tipifarnib to racemic alcohol of formula (IIa), comprising: - 28 042764 (i) reaction of (8)-(-)-tipifarnib or its salt with sodium nitrite in a mixture of acetone and water 4:1 at 20°C to obtain a mixture of products; (j) adjusting the pH of the product mixture to 10 with sodium hydroxide; (iii) extracting the product mixture with isopropyl acetate; (iv) adding 1.5 eq. concentrated hydrochloric acid; and (y) isolating the racemic alcohol of formula (Pa) by crystallization, (±) HO N O OH3 Formula (Pa) 55. A method for converting (8)-(-)-tipifarnib to racemic alcohol of formula (Pa), including: (i) heating (8)-(-)-tipifarnib or a salt thereof in a 2:1 mixture of methyl ethyl ketone and water at 76° C. to obtain a mixture of products; (j) adjusting the pH of the product mixture to 8 with sodium hydroxide; (iii) extracting the product mixture with isopropyl acetate; (iv) adding concentrated hydrochloric acid; and (v) isolating the racemic alcohol of formula (Pa) by crystallization, (±)-HCl N CH _a Formula (Pa)