KR20180030390A - Method for the manufacturing of blonanserin - Google Patents

Abstract

The present invention relates to an improved method to produce highly pure 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine, known as blonanserin by an INN name. The method includes four consecutive steps starting from C_(1-4) alkyl 4-fluorobenzoate. The present invention further relates to a method for producing an intermediate 3-(4-fluorophenyl)-3-oxopropanenitrile (BLON 1).

Description

METHOD FOR THE MANUFACTURING OF BLONANSERIN [0002]

The present invention relates to highly pure 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydro Cycloocta < / RTI > [b] pyridine. The method takes place in four successive steps, starting from a C _{1- 4} alkyl benzoate 4-fluoro. The present invention also relates to a process for the preparation of the intermediate 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON 1).

(4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b ] Pyridine is disclosed in EP0385237 and has the molecular structure shown below.

Bloonanserin

Bronan serine has been developed as an antipsychotic and has been approved in Japan and Korea for the treatment of schizophrenia. It belongs to the 4-phenyl-2- (1-piperazinyl) pyridine family and is dopamine D2, D3, and serotonin 5-HT _2A receptor antagonists.

Bronan serine can be obtained by a variety of synthetic routes, for example as disclosed in EP0385237, CN 102093289, JP2013216655, KR20150117123, CN101955459 and CN105315206.

There is a need in the art to improve the method of making highly pure < RTI ID = 0.0 > Bronzeneserin < / RTI > and / or to find an alternative method of producing Bronnan Serulin. In particular, there is a need for a method that can be performed under mild conditions, is efficient, cost-effective, and easily applicable to an industrial scale.

Also, by obtaining intermediate and final blownan serine with very high purity, it is desirable to exclude additional difficult purification steps.

The present invention relates to a process for the preparation of 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10- hexahydrocycloocta [b] Pyridine. ≪ / RTI >

The method under which reacts with a C _{1- 4} alkyl, the 4-benzoate in acetonitrile under the presence of an alkali metal HMDS provide intermediate 3- (4-fluoro-phenyl) -3-oxo-propanenitrile (BLON1) Lt; RTI ID = 0.0 > 1. ≪ / RTI >

Scheme 1:

R = C _1-4 alkyl

In a further embodiment, the method comprises the steps shown in Scheme 2 below.

Scheme 2:

All intermediates BLON1, BLON2, BLON3 and BLON4 as well as blownarcine were obtained in high purity without any crystalline byproducts / impurities.

The present invention also relates to a process for the preparation of intermediate 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON 1) by the reaction shown in Scheme 1.

Justice

Throughout the description, the term "blownarcerin" is intended to include any form of compound, such as a free base and a pharmaceutically acceptable salt. The free base and pharmaceutically acceptable salts include anhydrous forms and solvated forms such as hydrates. The anhydrous forms and solvates include both amorphous and crystalline forms. In certain embodiments, the blownarcine is in the hydrochloride form.

In this context, the term "alkali metal HMDS " refers to bases selected from LiHMDS, NaHMDS and KHMDS, in particular NaHMDS.

In this context, the term "strong acid" refers to an acid with a pKa value of less than zero. Especially polyphosphoric acid (PPA), para-toluenesulfonic acid (p-TsOH), sulfuric acid and phosphoric acid, and combinations thereof.

The term "C _{1 - 4} alkyl" includes linear and branched C _{1 - 4} alkyl such as methyl, ethyl, 1-propyl 2-propyl, 1-butyl, 2-butyl and 2-methyl-2-propyl of course, "C _l-4 alkyl 4-fluoro-benzoate," as used herein are methyl 4-fluoro-benzoate, into ethyl 4-fluoro-benzoate, 1-propyl-4-benzoate, 2-propyl-4-fluoro 4-fluorobenzoate, 2-butyl 4-fluorobenzoate, and 2-methyl-2-propyl 4-fluorobenzoate. Especially ethyl 4-fluorobenzoate and methyl 4-fluorobenzoate.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors _1- C ₄ alkyl is blown starting from 4-fluoro benzoate I-serine, 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7 , 8,9,10-hexahydrocycloocta [b] pyridine.

Step a) In, C _{1- 4} alkyl benzoate 4-fluoro is reacted with acetonitrile in the presence of an alkali metal HMDS provides 3- (4-fluorophenyl) -3-oxo-propanenitrile (BLON1).

R = C _1-4 alkyl

The inventors have a large impact on both the addition reaction (the alkaline metal HMDS a C _{1- 4} alkyl 4-fluoro-benzoate and added to mixture containing acetonitrile) method and the reaction temperature is in terms of conversion rate and purity And confirmed the immersion.

The use of either the base KOt-Bu or NaH in THF or toluene requires the reaction to be carried out at high temperature (above 60 DEG C) in order to obtain good conversion rates. In addition, when the present inventors reacted KOt-Bu or NaH in THF or toluene with acetonitrile and methyl 4-fluorobenzoate, the impurities were found to be present at about 1% level. The impurity was identified to be 4-methoxybenzoyl acetonitrile, which is formed by the nucleophilic attack of an aromatic cyclic methoxide replacing fluorine (released from the methyl ester). The impurities were found to be very deleterious in the process of blownan serine production in that impurities (or derivatives thereof) are delivered to the final product and the removal of the 4-methoxy analogue is difficult or even impossible.

4- Methoxybenzoyl acetonitrile

The use of more bulky 4-fluorobenzoic acid esters such as alkyl (e.g. n-butyl) or benzyl 4-fluorobenzoate as the starting material under the same conditions as above can be used to prepare 3- (4-fluorophenyl) Propanenitrile (BLON1), but also produces the corresponding 4-alkoxy- or benzyloxy-benzoyl acetonitrile impurity.

The formation of the 4-methoxybenzoyl acetonitrile impurity can be inhibited by using a base such as n-BuLi or LDA as described in WO 2010/056722 and at a temperature of -78 ° C. However, operation at these low temperatures requires special energy consumption techniques (cold reactors). As a comparative example, the present inventors have disclosed in WO 2010/056722 p. 350, but operating at 0 < 0 > C ( Example 1g) . Only 10% of the desired intermediate product 4-fluorobenzoyl acetonitrile was formed. The resulting reaction mixture contained mostly unreacted raw material, ethyl 4-fluorobenzoate (73%).

The present inventors are working in toluene from C _{1- 4} alkyl 4-fluoro-benzoate and was added and the temperature of about 0 ℃ HMDS alkali metal, especially sodium bis (trimethylsilyl) amide (NaHMDS) for the mixture comprising acetonitrile (Greater than 80%) and very good control of 4-methoxybenzoyl acetonitrile ( Examples 1a, 1b, 1c and 1d ) . Without further purification steps, the desired intermediate product BLON1 had a 4-methoxybenzoyl acetonitrile level of less than 0.03% (A% GC) and a high purity (at least 98.5%).

While maintaining the same reaction conditions, NaHMDS was replaced with n-butyllithium (as in Examples 1a-1d) to yield 4-fluorobenzoyl acetonitrile in moderate yield and high level impurities (Example 1f) .

A further advantage of using NaHMDS (40% solution in THF, for example) is that it is commercially available, not expensive, and easy to handle.

The case of operating at a temperature of about 0 ℃, to yield a high purity BLON1 needs to be added to the mixture of the alkali metal HMDS include benzoate and acetonitrile in a 4-C _{1- 4} alkyl. NaHMDS is provided a BLON1 of C ₁₄ reverse the order of addition is mixed with an alkyl 4-benzoate with a very low purity (14%) was added to the acetonitrile.

In step b) , BLONl is reacted with cyclooctanone in the presence of a strong acid or strong acid mixture to give the intermediate 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2).

EP0385237 discloses the use of polyphosphoric acid (PPA) as reagent and solvent. However, PPA is very viscous and is not very easy to handle (eg, charging on pilot scale). Further, at the time of heating, when the cyclooctanone begins to be melted, the reaction starts sharply. CN105315206 discloses the use of a combination of PPA and phosphoric acid. The use of para-toluenesulfonic acid (p-TsOH) in combination with sulfuric acid is disclosed, for example, in CN 102093289B, CN102030707A. The application of this combination has the disadvantage that during prolonged heating, sulfuric acid provides a black tar-oily by-product.

The present inventors have found that by using a mixture comprising para-toluenesulfonic acid (p-TsOH) and phosphoric acid it is possible to make the handling of the manufacturing process easier and to obtain the intermediate BLON2 with very high purity (99.8% A% And confirmed an excellent alternative.

In step c) , BLON2 is reacted with phenylphosphonic dichloride to give the intermediate 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] (BLON3).

The use of phenylphosphonic dichloride was described in EP0385237 at a high reaction temperature of 170 < 0 > C. The present inventors have found that reduction of the reaction temperature provides a complete and efficient conversion. Step c) involves the use of phenylphosphonic dichloride at a reaction temperature of 145 < 0 > C. The intermediate BLON3 is obtained in very high purity (99.9% A% HPLC) under the proposed reaction conditions.

In step d) , BLON3 is reacted with ethyl piperazine in the presence of a palladium catalyst, a ligand and a base to give 2- (4-ethyl-1-piperazinyl) -4- 7,8,9,10-hexahydrocycloocta [b] pyridine (Bronan serine). In a preferred embodiment, the palladium catalyst is bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ) or palladium (II) acetate. In a preferred embodiment the ligand is selected from the group consisting of 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or XPhos (2-dicyclohexylphosphino- '-Triisopropylbiphenyl). In a preferred embodiment, the base is sodium tert-butoxide.

In one embodiment of the invention, step d) is carried out at about 80 캜 (for example, in toluene). At this temperature, step d) proceeds very rapidly (complete conversion within 2 hours). Other reaction systems have been disclosed in EP0385237, KR20150117123 and CN101955459, but they require significantly higher reaction temperatures, a relatively high amount of potassium iodide or a longer reaction time. Bronan serine obtained by the present invention exhibits very high purity (99.9% A% HPLC) and is therefore suitable for commercial production methods and pharmaceutical uses.

It should be understood that, for all process steps, the intermediates BLON 1, BLON 2 and BLON 3 can be used for further processing in all purity and in isolated form or in isolation. In a preferred embodiment, one or more intermediates BLON 1, BLON 2 and BLON 3, for example, BLON 1 obtained in step a) were isolated prior to further processing to be isolated before being used for the reaction in step b). More preferably, the one or more intermediates BLON 1, BLON 2 and BLON 3 are isolated, for example, before further processing so that the BLON 1 obtained in step a) is isolated and purified before being used for the reaction in step b) . In a further preferred embodiment, the one or more intermediates BLON 1, BLON 2 and BLON 3 are at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% (A%) as measured by < / RTI >

In one embodiment, the invention relates to a process for the preparation of intermediate 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON 1) by the method of step a) above. The present invention further relates to the use of said BLON 1 in the production of blownan serine.

The present invention is also directed to each of the intermediates BLON 1, BLON 2 and BLON 3 by each of the steps of a), b) and c) obtained by the method of the present invention.

The present invention also relates to a pharmaceutical composition comprising a blownarcaine obtained by the method of the present invention. The pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient, carrier and / or diluent and may be in solid dosage form, for example, a tablet for oral administration.

Methods for the preparation of solid pharmaceutical preparations are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21 ^st ed., Lippincott Williams & Wilkins (2005). Solid form preparations, such as tablets, may be prepared by mixing the active ingredient with a conventional carrier, such as an adjuvant and / or diluent, and compressing the mixture in a tablet machine. Non-limiting examples of adjuvants and / or diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose, rubber and the like. Any other suitable adjuvants or additives, such as coloring agents, fragrances and preservatives, may also be employed, as long as they are compatible with the active ingredient. Thus, the pharmaceutical compositions of the present invention typically comprise an effective amount of a blownan serine and one or more pharmaceutically acceptable carriers.

Bronan serine obtained according to the present invention may be administered orally or parenterally, by any suitable route of administration, for example, and may be in any suitable form for administration such as tablets, capsules, powders, syrups, May be provided in the form of a dispersion. In one embodiment, the pharmaceutical composition will comprise a therapeutically effective amount of Bronan serine.

The term "therapeutically effective amount" means an amount sufficient to cure, ameliorate, or partially stop the clinical manifestation of a given disease and its complications in a therapeutic intervention involving administration of the compound. To achieve this, an appropriate amount is defined as the "therapeutically effective amount ". The effective amount for each purpose will depend on the severity of the disease or injury as well as the weight and general condition of the subject. Determination of the appropriate dose can be accomplished by using routine experimentation to construct a matrix of values and evaluating different time points in the matrix, all of which are within the general skill of the trained physician.

Preferably, the amount of blownarcerin in the pharmaceutical composition in unit dosage form is from 1 mg to 100 mg, such as from 1 mg to 50 mg, such as from 1 mg to 20 mg, such as 2, 4, 6, 8, 10 or 12 mg .

In particular, it is contemplated that the pharmaceutical compositions of the present invention may be used for the treatment of schizophrenia. In one embodiment, the Bronan serine obtained by the present method can be used in the manufacture of a medicament for the treatment of schizophrenia.

In another embodiment, the invention is directed to a method of treating schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a Bronan serine, or a pharmaceutical composition thereof, obtained by the method.

All references, including publications, patent applications, and patents, cited herein, are hereby incorporated by reference in their entirety for all purposes, irrespective of any separately provided introduction of specific documents performed elsewhere herein, (To the maximum extent permitted by law) and are hereby incorporated by reference to the same extent as if it were the full text of the present application.

The use of singular terms and similar references in the context of describing the present invention should be construed to cover both singular and plural unless otherwise indicated herein or clearly contraindicated in the context. For example, the phrase "compound" should be understood to denote a variety of "compounds" of the invention or particular embodiments of the present invention unless otherwise indicated.

Quot ;, " including, " " including, "or" containing, ", or " comprising, " (For example, it should be understood that the composition described herein including a particular element also describes a composition consisting of the elements unless otherwise indicated or specifically contraindicated in context), the particular element or elements Comprising substantially ", or " consisting essentially of, "or" consisting essentially of, "

It is to be understood that the various aspects, embodiments, implementations and features of the invention referred to herein may be claimed separately or in any combination.

According to the invention Example

Next, an embodiment of the present invention is disclosed. The first implementation is labeled E1, the second implementation is labeled E2, and so on.

E1. A method for producing Bronan serine, the method comprising the steps of:

a) _reacting a C _1-4 alkyl 4-fluorobenzoate with acetonitrile in the presence of an alkali metal HMDS to provide 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) Way.

E2. The method of embodiment 1, wherein the method comprises the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS with C _{1- 4} alkyl 4-fluoro.

E3. In Embodiment 1, step a)

C _{1- 4} alkyl benzoate 4-fluoro is reacted with acetonitrile in the presence of an alkali metal HMDS comprises providing a 3- (4-fluorophenyl) -3-oxo-propanenitrile (BLON1);

The method comprising the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS in the 4-C _{1- 4} alkyl; And

Wherein step a) takes place at a temperature in the range of from -20 to + 20 ° C, for example in the range of from -10 to + 10 ° C, for example in the range of from -5 to + 5 ° C.

E4. A method according to any one of embodiments 1-3, wherein the alkali metal HMDS which the C _{1- 4} alkyl 4-benzoate, at least 1.5 molar equivalents compared to, for example, at least 1.6 molar equivalents, for example at least 1.7 molar equivalents, for example at least 1.8 moles E. G. At least 1.9 molar equivalents, such as about 2 molar equivalents.

E5. The process as in any one of embodiments 1-4 wherein step a) occurs at a temperature in the range of -20 to + 20 ° C, such as in the range of -10 to + 10 ° C, such as in the range of -5 to + 5 ° C.

E6. The process of any one of embodiments 1-5 wherein step a) occurs in a solvent comprising toluene.

E7. In Embodiment 1, step a)

C _{1- 4} alkyl 4-fluoro-benzoate was reacted with acetonitrile in the presence of an alkali metal HMDS comprises providing a 3- (4-fluorophenyl) -3-oxo-propanenitrile (BLON1), the method wherein the alkaline metal HMDS C _{1- 4} alkyl 4-fluoro-benzoate and the range -20 to + 20 ℃ the mixture comprising acetonitrile, such as -10 to + 10 ℃ range, for example -5 to +5 Lt; RTI ID = 0.0 > C, < / RTI > And

Wherein step a) takes place in a solvent comprising toluene.

E8. The method of embodiment 7, wherein the method is the alkali metal HMDS C _{1- 4} alkyl 4-fluoro-benzoate and the acetonitrile to a mixture comprising the nitrile C _{1- 4,} at least 1.5 molar equivalent as compared to alkyl benzoate 4- , Such as at least 1.6 molar equivalents, such as at least 1.7 molar equivalents, such as at least 1.8 molar equivalents, such as at least 1.9 molar equivalents, such as about 2 molar equivalents.

E9. The process of any one of embodiments 1 to 8, wherein said alkali metal HMDS is selected from KHMDS, LiHMDS and NaHMDS, preferably NaHMDS.

E10. Embodiments 1 to 9. A method according to any one of the C _{1- 4} alkyl how the 4-fluoro benzoate is methyl benzoate with 4-fluoro.

E11. The process of any of embodiments 1 to 10 wherein at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8, or 100% of the 3- (4-fluorophenyl) -3-oxopropanenitrile 99.9% (A% GC).

E12. The process according to any one of embodiments 1-11, wherein 4-methoxybenzoyl acetonitrile is obtained in an amount (A% GC) of 0.3% or less, such as 0.2% or less, such as 0.1% or less, as compared to BLON1.

E13. The process of any one of embodiments 1-12, wherein the 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) is obtained with a purity of at least 98.5%, such as at least 99.0%, such as at least 99.5%; 4-methoxybenzoyl acetonitrile is obtained in an amount (A% GC) of not more than 0.3%, for example not more than 0.2%, for example not more than 0.1%, based on BLON1.

E14. The method of any one of embodiments 1-13, wherein in step a)

b) reacting the 3- (4-fluorophenyl) -3-oxopropanenitrile obtained in step a) with cyclooctanone in the presence of a strong acid or strong acid mixture to give 4- (4-fluorophenyl) -5,6 , 7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2).

E15. The method of embodiment 14 wherein said strong acid mixture is a mixture comprising para-toluene sulfonic acid (p-TsOH) and phosphoric acid.

E16. A method for producing Bronan serine, the method comprising the steps of:

b) reacting 3- (4-fluorophenyl) -3-oxopropanenitrile with cyclooctanone in the presence of a mixture comprising para-toluenesulfonic acid (p-TsOH) and phosphoric acid to give 4- (4-fluorophenyl) ) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2).

E17. The process as in any one of embodiments 14-16, wherein step b) occurs in a solvent comprising toluene.

E18. The process of any one of embodiments 14-17, wherein the 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin- BLON2) is obtained with a purity of at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% (A% HPLC (Method 1)).

E19. The process of any one of embodiments 14-18, wherein in step b)

b) Preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one obtained in step b) To give 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3) .

E20. The process of embodiment 19 wherein step c) occurs at a temperature in the range of from 130 to 160 캜, such as in the range of from 140 to 150 캜, such as about 145 캜.

E21. A method for producing Bronan serine, the method comprising the steps of:

c) Reaction of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one with phenylphosphonic dichloride to give 2- Chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3);

Step c) takes place at a temperature in the range of from 130 to 160 캜, such as from 140 to 150 캜, for example at a temperature of about 145 캜.

E22. The process of any one of embodiments 19-21, wherein the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3) Is obtained with a purity of at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% (A% HPLC (Method 2)).

E23. The process of any one of embodiments 19-22, wherein in step c)

d) By reacting the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine obtained in step c) with a palladium catalyst, a ligand and a base ≪ / RTI > to provide a blocking agent.

E24. A method for producing Bronan serine, the method comprising the steps of:

d) Treatment of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine with palladium catalyst, ligand and base afforded ethylpiperazine Lt; RTI ID = 0.0 > of Bronan serine. ≪ / RTI >

E25. The process of embodiment 23 or 24, wherein the palladium catalyst is bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ).

E26. The method of any one of embodiments 23-25, wherein the ligand is 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP).

E27. The process of any one of embodiments 23-26, wherein said base is sodium tert-butoxide.

E28. The process of any one of embodiments 23-27 wherein the palladium catalyst is bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ) and the ligand is 2,2'-bis (diphenylphosphino) 1'-binaphthyl (BINAP), and the base is sodium tert-butoxide.

E29. The process of any one of embodiments 23-28, wherein step d) occurs at a temperature in the range of 60 to 110 캜, such as in the range of 70 to 90 캜, such as in the range of 75 to 80 캜, such as about 80 캜.

E30. The process as in any one of embodiments 23-29, wherein step d) occurs in a solvent comprising toluene.

E31. The method as in any one of embodiments 1-30, wherein the method further comprises:

a) _reacting C _1-4 alkyl 4-fluorobenzoate with acetonitrile in the presence of an alkali metal HMDS to provide 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1); next

b) reacting the 3- (4-fluorophenyl) -3-oxopropanenitrile obtained in step a) with cyclooctanone in the presence of a strong acid or strong acid mixture to give 4- (4-fluorophenyl) -5,6 , 7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2)

b) Preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one obtained in step b) To give 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta [b] pyridine (BLON3)

d) By reacting the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine obtained in step c) with a palladium catalyst, a ligand and a base ≪ / RTI > and reacting it with ethyl piperazine to provide a blownan serine.

E32. A method for producing Bronan serine, the method comprising the steps of:

Performing step a) according to any one of embodiments 1 to 13, followed by

Performing step b) according to any one of embodiments 16 to 18, followed by

Performing step c) according to any one of embodiments < RTI ID = 0.0 > 21-22, <

Comprising the step of performing step d) according to any one of embodiments < RTI ID = 0.0 > 24-30. ≪ / RTI >

E33. The method of any one of embodiments 1-32, wherein the blend is obtained at a purity of at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8, or 99.9% How to do it.

E34. Bronan serine obtained by the method according to any one of embodiments 1-33.

E35. The blonanserin according to embodiment 34, wherein the blend is obtained at a purity of at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% (A% HPLC (method 2)).

E36. A pharmaceutical composition comprising a blownarsein obtained by the method according to any one of embodiments 1-33.

E37. 32. The use of Bronan serine obtained by the method according to any one of embodiments 1-33 for use in the treatment of schizophrenia.

E.38. 33. A method of treating schizophrenia comprising administering a therapeutically effective amount of a Bronan serine obtained by a method according to any one of embodiments 1-33.

E.39 Use of the blownancerin obtained by the process according to any one of the embodiments 1-33 for the manufacture of a medicament for the treatment of schizophrenia.

E40. A process for the preparation of 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1), said process comprising the following steps:

a) _reacting a C _1-4 alkyl 4-fluorobenzoate with acetonitrile in the presence of an alkali metal HMDS to provide 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) Way.

E41. The method of embodiment 40, wherein the method comprises the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS with C _{1- 4} alkyl 4-fluoro.

E42. In Embodiment 40, step a)

C _{1- 4} alkyl benzoate 4-fluoro is reacted with acetonitrile in the presence of an alkali metal HMDS comprises providing a 3- (4-fluorophenyl) -3-oxo-propanenitrile (BLON1);

The method comprising the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS in the 4-C _{1- 4} alkyl; And

Wherein step a) takes place at a temperature in the range of from -20 to + 20 ° C, for example in the range of from -10 to + 10 ° C, for example in the range of from -5 to + 5 ° C.

E43. In any one of embodiments 40 to 42, at least 1.5 molar equivalents, such as at least 1.6 molar equivalents, such as at least 1.7 molar equivalents, such as at least 1.8 molar equivalents, relative to the C _1-4 alkyl 4-fluorobenzoate, , Such as at least 1.9 molar equivalents, such as about 2 molar equivalents.

E44. The process of any one of embodiments 40 to 43, wherein step a) occurs at a temperature in the range of from -20 to + 20 ° C, such as in the range of -10 to + 10 ° C, such as in the range of -5 to + 5 ° C.

E45. The process as in any one of embodiments 40 to 44, wherein step a) occurs in a solvent comprising toluene.

E46. The process as in any one of embodiments 40-45, wherein step a)

Wherein C _{1- 4} alkyl benzoate 4-fluoro is reacted with acetonitrile in the presence of an alkali metal HMDS comprises providing a 3- (4-fluorophenyl) -3-oxo-propanenitrile (BLON1), the method wherein the alkaline metal HMDS C _{1- 4} alkyl 4-fluoro-benzoate and acetonitrile mixture from -20 to + 20 ℃ range in containing, for example, -10 to + 10 ℃ range, for example -5 to + Lt; RTI ID = 0.0 > 5 C; < / RTI > And

Wherein step a) takes place in a solvent comprising toluene.

E47. The method of embodiment 46, wherein the method is the alkali metal HMDS C _{1- 4} alkyl 4-fluoro-benzoate and the acetonitrile to a mixture comprising the nitrile C _{1- 4,} at least 1.5 molar equivalent as compared to alkyl benzoate 4- , Such as at least 1.6 molar equivalents, such as at least 1.7 molar equivalents, such as at least 1.8 molar equivalents, such as at least 1.9 molar equivalents, such as about 2 molar equivalents.

E48. The process of any one of embodiments 40 to 47, wherein said alkali metal HMDS is selected from KHMDS, LiHMDS and NaHMDS, preferably NaHMDS.

E49. A method according to any one of embodiments 40 to 48, in which the above C _{1- 4} alkyl 4-benzoate with methyl 4-benzoate.

E50. Use of 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) obtained by the process according to any one of embodiments 40 to 49, in the manufacture of Bronan serine.

E51. 3- (4-Fluorophenyl) -3-oxopropanenitrile (BLON1) obtained by the process according to any one of embodiments 40 to 49.

E52. The polymer of embodiment 51, wherein at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% (A%) of the 3- (4-fluorophenyl) -3-oxopropanenitrile GC), 3- (4-fluorophenyl) -3-oxopropanenitrile.

E53. The process according to embodiment 51 or 52, wherein 3- (4-fluorophenyl) -4-methoxybenzoyl acetonitrile is obtained in an amount of 0.3% or less, such as 0.2% or less, -3-oxopropanenitrile.

E54. The method of any one of embodiments 51-53, wherein at least 98.5%, such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8, or 99.9% of the 3- (4-fluorophenyl) A% GC); 3- (4-fluorophenyl) -3-oxopropanenitrile which is obtained in an amount of not more than 0.3%, for example not more than 0.2%, for example not more than 0.1% (A% GC) of 4-methoxybenzoyl acetonitrile as compared to BLON1.

E55. B) pyridin-2 (1H) -one as a starting material, the process described in Examples 40-49 To produce 3- (4-fluorophenyl) -3-oxopropanenitrile by the method according to any one of the preceding claims,

b) reacting said 3- (4-fluorophenyl) -3-oxopropanenitrile obtained by the process according to any of embodiments 40 to 49 with cyclooctanone in the presence of a strong acid or strong acid mixture to give 4- (4 -Fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2).

E56. The process of embodiment 55 wherein in step b) the strong acid mixture is a mixture comprising para-toluene sulfonic acid (p-TsOH) and phosphoric acid.

E57. A process for the preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H)

b) reacting 3- (4-fluorophenyl) -3-oxopropanenitrile with cyclooctanone in the presence of a mixture comprising para-toluenesulfonic acid (p-TsOH) and phosphoric acid to give 4- (4-fluorophenyl) ) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2).

E58. The process as in any one of embodiments 55-57, wherein step b) occurs in a solvent comprising toluene.

E59. (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta [b] thiophene obtained by the process according to any one of embodiments 55 to 57 in the manufacture of 4- Pyridin-2 (1H) -one (BLON2).

E60. B) pyridin-2 (1H) -quinolinone obtained by the process according to any one of < RTI ID = 0.0 & - ON (BLON2).

E61. B) pyridin-2 (1H) -one (BLON2) of Embodiment 60 is at least 98.5 4- (4-fluorophenyl) -5,6,7,8,8-tetramethylpiperidine obtained with a purity of at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% , 9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one.

E62. Method for the preparation of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta [b] pyridine, B] pyridin-2 (1H) -one by following the procedure according to the procedure described in Example 1, Step 1, followed by the subsequent step of preparing 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [ next stage

c) reacting the 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 obtained by the process according to any of embodiments 55-59 (1H) -one was reacted with phenylphosphonic dichloride to give 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine ). ≪ / RTI >

E63. The process of embodiment 62 wherein step c) occurs at a temperature in the range of from 130 to 160 캜, such as from 140 to 150 캜, for example, at a temperature of about 145 캜.

E64. Method for the preparation of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta [b] pyridine,

c) Reaction of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one with phenylphosphonic dichloride to give 2- Chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3);

Step c) takes place at a temperature in the range of from 130 to 160 캜, such as from 140 to 150 캜, for example at a temperature of about 145 캜.

E65. 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclohexane obtained by the process according to any of embodiments 62 to 64 in the manufacture of < Octa [b] pyridine (BLON3).

E66. 2-Chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine obtained by the process according to any one of embodiments 62 to 65 BLON3).

E67. The process of embodiment 66 wherein at least 98.5% of the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3) Chloro-4- (4-fluorophenyl) -5,6,7-tetrahydrocarbazole obtained with a purity of at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9% 8,9,10-hexahydrocycloocta [b] pyridine.

Example

The invention will be illustrated by the following non-limiting examples.

Gas Chromatography (GC) Method

(Analysis of BLON1 and by-product 4-methoxybenzoyl acetonitrile)

column: Capillary, HP-5 type; 30 m, 0.25 mm, ft 0.25 m or equivalent

Column temperature: Starting temperature 60 ° C

Heating gradient from 15 ° C / min to 300 ° C

Lt; RTI ID = 0.0 > 300 C <

Analysis period: 25 minutes

Injector temperature: 280 ℃ division method

Split ratio 10: 1

Carrier gas: Helium (1.0 ml / min)

Detection device: FID 300 ° C

gas Air (400 ml / min)

H2 (40 ml / min)

make up N2 (20 ml / min)

Injection volume: 1 μl

High Performance Liquid Chromatography ( HPLC ) Way

HPLC Method 1 (Analysis of BLON2)

Condition:

device: UPLC

column: Waters Acquity C18 CSH, 50 x 2.1 mm, 1.7 mu m particle size

Column temperature: 35 ℃

Injection volume: 2 μl

Mobile phase A: Water: acetonitrile: formic acid 98: 2: 0.1

Mobile phase B: Water: acetonitrile: formic acid 2: 98: 0.1

gradient:

Flow rate: 0.4 ml / min

Detection device: UV at 238 nm

Analysis time: 16 minutes

Sample dilution: Acetonitrile

HPLC Method 2 (Analysis of BLON3 and Bronan Serine)

Condition:

device: UPLC

column: Waters Acquity C18 CSH, 50 x 2.1 mm, 1.7 mu m particle size

Column temperature: 50 ℃

Injection volume: 2.0 μl

Mobile phase A: Buffer pH = 9: acetonitrile 95: 5

Mobile phase B: Buffer pH = 9: acetonitrile 5: 95

gradient:

Flow rate: 0.4 ml / min

Detection device: UV at 238 nm

Analysis time: 18 minutes

Sample dilution: Acetonitrile

Nuclear magnetic  Resonance (NMR)

≪ ¹ > H-NMR spectra were recorded at 20 [deg.] C on a Bruker Avance 300 operating at 300 MHz for ¹ H. Chemical shifts were reported against the remaining deuterated solvent peaks.

Example  One: methyl  4- From fluorobenzoate  3- (4- Fluorophenyl ) -3- Oxopropanenitrile  Produce (Step a))

Example  1a: NaHMDS  Used kg scale.

The reactor was charged with methyl 4-fluorobenzoate (29.44 kg), toluene (177 L) and acetonitrile (59 L; 5.9 molar equivalents relative to methyl 4-fluorobenzoate). The mixture was cooled to a temperature of -5 [deg.] C. A solution of sodium bis (trimethylsilyl) amide (NaHMDS 40% in THF) (192 L; 2 mol / mol relative to methyl 4-fluorobenzoate) was added while maintaining the temperature between -5 / + 5 C. The addition line was rinsed with toluene (9 L). The reaction mixture was quenched by the addition of dilute hydrochloric acid while maintaining the temperature at -5 / + 25 < 0 > C. The acid addition was continued until the pH was less than 5. The layers were separated and the lower aqueous layer was removed. Solvent was removed by distillation under vacuum until small volume. Toluene (59 L) was added and the mixture was heated to 85/90 ° C to obtain a solution. The mixture was cooled to T = 50/55 < 0 > C and n-heptane (29 L) was charged to give a precipitate. The mixture was further cooled to T = 20/25 < 0 > C and the solid product was isolated by filtration and washed with n-heptane (59 L). The wet product was dried under vacuum at T = 40/45 ° C to give 4-fluorobenzoyl acetonitrile (26 kg, 83% yield) with GC purity of 98.7% A%; The amount of impurity 4-methoxybenzoyl acetonitrile was 0.03% (A% GC).

Three laboratory scale experiments with NaHMDS (1b, 1c and 1d) yielded even higher yields and purity.

Example 1b: 30 g scale; 85% yield, purity 99.6%, 4-methoxybenzoyl acetonitrile was below the detection level.

Example 1c: 60 g scale; 88% yield, a purity of 99.9%, and 0.03% (A% GC) of 4-methoxybenzoyl acetonitrile.

Example 1d: 30 g scale; 84% yield, purity 99.9%, 4-methoxybenzoyl acetonitrile was below the detection level.

Example  1e: 50 g  Sodium on scale Hydride (2 equivalents)  Used Comparative Example :

Methyl 4-fluorobenzoate (50 g) was reacted with sodium hydride (2 eq.) In methyl tert-butyl ether (MTBE) at 90 <0>C; 4-Fluorobenzoyl acetonitrile was obtained in about 64% yield; ¹ H-NMR signal (300 MHz, DMSO) of 4-methoxybenzoyl acetonitrile impurity was estimated to be about 3% (estimated by NMR; 81% for purity and 17.5% for 4-fluorobenzoic acid and 4-methoxybenzoyl acetonitrile - d6, 293 K): δ = 3.91 (s, 3H, OC H 3), 4.04 (s, 2H, C H 2), 6.99 (m, 2H, aromatic), 7.91 (m, 2H, aromatic)).

The performance of the reaction in toluene or the use of the base potassium tert-butoxide did not improve the reaction.

Example  1f: n- Butyllithium  Used Comparative Example .

The reaction was carried out as described in Examples 1a-d, but substituting the base NaHMDS with n-butyllithium. The work-up was modified as follows: after quenching the reaction mixture, the solvent was removed and an oil was obtained. The GC analysis showed the following composition (area% GC): 4-fluorobenzoyl acetonitrile (49%), raw ester methyl 4-fluorobenzoate (17%); Sum of impurities (34%).

Example  1g: using the method of WO 2010/053722 operating at 0 ° C Comparative Example .

The experiment was carried out on a 3.8 g scale of ethyl 4-fluorobenzoate. The reaction was carried out as described in WO 2010/053722, but operating at 0 ° C instead of applying low temperature conditions (-78 ° C / -60 ° C). After evaporation of the work-up solvent (EtOAc), the moderator reaction mixture was obtained as an oil. No recrystallization was performed. GC analysis of the oil showed the following composition (area% GC): 4-fluorobenzoyl acetonitrile (10%), raw ester ethyl 4-fluorobenzoate (73%); The sum of the impurities (17%).

Example 2:  3 -(4- Fluorophenyl ) -3- From oxopropanenitrile  4- (4- Fluorophenyl ) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one. (Step b))

Example  2a: kg Scale

The reactor was charged with 12.0 kg of 3- (4-fluorophenyl) -3-oxopropanenitrile, 14.0 kg of p-toluenesulfonic acid monohydrate, 60 L of toluene, 12 kg of cyclooctanone, Part of phosphoric acid 85% (4.2 kg). The mixture was heated to reflux and water (both from reagent and condensation) was removed via the reaction by means of a Dean-Stark apparatus. The mixture was kept under reflux and the mixture was kept under reflux and additional phosphoric acid (2 x 6.4 kg and 4.2 kg) was added in portions while water was being removed.

The mixture was adjusted to T = 80-85 C and water (48 L) was added. The layers were separated and the lower aqueous layer was removed. The organic layer was washed with water (48 L). The organic layer was cooled to T = 70-75 C and a 5% solution of sodium hydroxide (21.1 L) was added to give a pH of greater than 8. The product began to settle. Toluene (36 L) was added and the mixture was cooled to T = 20-25 ° C. The solid was isolated by filtration and washed with water and toluene.

The wet product was dried under vacuum at T = 50-55 ° C to give 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin- (10.7 kg, 54% yield) was obtained with 99.8% A% HPLC purity (Method 1).

Example  2b: Laboratory scale

Starting from 25 g of 4-fluorobenzoyl acetonitrile, 29.3 g of 4- (4-fluorophenyl) -5,6,7,8,9, 10-hexa (70% yield) was provided in 99.8% A% HPLC purity (Method 1).

Example 3:  4 -(4- Fluorophenyl ) -5,6,7,8,9,10- Hexahydrocycloocta [b] pyridine -2 (lH) -one to 2- Chloro -4- (4- Fluorophenyl ) -5,6,7,8,9,10- Hexahydrocycloocta [b] pyridine  Produce (Step c))

Example  3a: kg scale

To the reactor was added 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (20 kg), dichloromethane , And phenylphosphonic dichloride (28.7 kg). The solvent dichloromethane was removed by distillation under atmospheric pressure. The temperature was gradually increased to T = 140 ~ 148 ° C and maintained for 8 ~ 9 hours.

The reaction mixture was cooled to T = 105-108 ° C and toluene (100 L) was added slowly while maintaining T = 80-110 ° C. The mixture was cooled to T = 50-55 [deg.] C and water (40 L) was slowly added while maintaining the temperature at T = 50-85 [deg.] C. The temperature was adjusted to T = 70-75 占 폚, the layers were separated, and the lower aqueous layer was removed. A brine solution (36 L) was added and the pH of the aqueous layer was adjusted to above 8 by the addition of 5% NaOH. The layers were separated and the lower aqueous layer was removed. The organic layer was filtered through a cartridge and the solvent was removed by distillation under vacuum until small volume. Removal of residual toluene was carried out by stripping using isopropanol (40 L). Isopropanol (90 L) was added and the suspension was heated to T = 80-85 ° C. Melting occurred and the mixture was cooled to T = 20-25 占 폚. The product was isolated by filtration and washed with isopropanol.

The wet product was dried under vacuum at T = 45-50 ° C to give 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine kg, molar yield 78%) was obtained with 99.95% A% HPLC purity (Method 2).

Example 4:  2 - Chloro -4- (4- Fluorophenyl ) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine was prepared 2- (4-ethyl-1- Piperazinyl ) -4- (4- Fluorophenyl ) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (Bronan Serine) (Step d))

Example  4a: Circle position  One-port procedure with acid-base purification.

To the reactor were added 7.4 kg of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine, 95 g of BINAP, Benzylidene acetone) palladium (44 g), sodium tert-butoxide (3.7 kg), toluene (37 L) and ethyl piperazine (8.7 kg). The temperature was increased to T = 75-80 ° C and maintained at T = 80-85 ° C for 3 hours. (Note: the reaction is exothermic, typically complete conversion is achieved after 2 hours at 80 ° C). The mixture was cooled to 60-65 &lt; 0 &gt; C and water (37 L) was added maintaining the temperature at T = 60-65 &lt; 0 &gt; C. The temperature was adjusted to T = 70-75 DEG C and the layers were separated. The lower aqueous layer was removed. The organic layer was washed with brine solution (36 L). The temperature was lowered to below &lt; RTI ID = 0.0 &gt; 25 C &lt; / RTI &gt; and the organic layer was filtered through a charcoal cartridge.

The organic layer was treated with water (22 L) and hydrochloric acid (4.5 L). The layers were separated and the organic layer was removed. The aqueous layer (containing the product) was treated with toluene (37 L) and sodium hydroxide (5.2 L). The temperature was adjusted to T = 70-75 DEG C and the layers were separated. The lower aqueous layer was removed.

The solvent was removed by distillation under vacuum until small volume. Acetone (22 L) was added and the mixture was heated to reflux. Dissolution occurred and the mixture was cooled to T = 0-5 ° C. The product was isolated by filtration and washed with cold acetone. The wet product was dried under vacuum at T = 48-53 ° C to yield 7.8 kg of blownan serine (85% molar yield) in 99.92% A% HPLC purity (Method 2).

Recrystallization

(7.6 kg) obtained by the above procedure was recrystallized from isopropanol (range: Blank filtration of Bronan serine) (6.7 kg; 88% yield; 99.94% A% HPLC purity (Method 2)).

Example  4b: Laboratory scale, acid-base not refined.

BINAP (137 mg), bis (dibenzylideneacetone) palladium (60 g), sodium tert-butoxide (5 g) and toluene (50 ml) were charged to the reactor. The mixture was stirred for 1 hour; B) pyridine (G029-003, BLON3) (10 g), ethyl piperazine (10 g), and the like were added to a solution of 2-chloro-4- (4- fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [ 11.8 g).

The temperature was increased to T = 100 ° C and held at T = 100 ° C for 1 hour. The in-process sample showed 96.6% A% HPLC purity (Method 2). The additional time and heating did not change the purity.

The mixture was cooled to 20-25 &lt; 0 &gt; C and water (50 ml) was added. The temperature was adjusted to T = 65-70 ° C and the layers were separated. The lower aqueous layer was removed. The organic layer was washed with water (50 mL). The solvent was removed by distillation under vacuum until small volume. Acetone (30 mL) was added and the mixture was heated to reflux. The mixture was cooled to T = 25 占 폚. The product was isolated by filtration and washed with acetone. The wet product was dried under vacuum at T = 55-60 ° C to obtain blownan serine (10.1 g, molar yield 80%) in 99.87% A% HPLC purity (Method 2).

Claims (18)

A method for producing Bronan serine, the method comprising the steps of:
a) _reacting C _1-4 alkyl 4-fluorobenzoate with acetonitrile in the presence of an alkali metal HMDS to provide 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) ;
The method comprising the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS in the 4-C _{1- 4} alkyl; And
Wherein step a) takes place at a temperature in the range of from -20 to +20 &lt; 0 &gt; C. The method according to claim 1,
The alkaline metal HMDS which the C _{1- 4} alkyl 4-benzoate, at least 1.5 molar equivalents compared to fluoro, for example at least 1.6 molar equivalents, for example at least 1.7 molar equivalents, for example at least 1.8 molar equivalents, for example at least 1.9 molar equivalent, such as about 2 Molar equivalent. 3. The method according to claim 1 or 2,
Wherein step a) takes place at a temperature in the range of from -10 to + 10 ° C, for example in the range of from -5 to + 5 ° C. 4. The method according to any one of claims 1 to 3,
Wherein step a) takes place in a solvent comprising toluene. 5. The method according to any one of claims 1 to 4,
_Wherein said C _1-4 alkyl 4-fluorobenzoate is methyl 4-fluorobenzoate. 6. The method according to any one of claims 1 to 5,
Wherein the alkali metal HMDS is NaHMDS. 7. The method according to any one of claims 1 to 6,
Following step a):
b) reacting the 3- (4-fluorophenyl) -3-oxopropanenitrile obtained in step a) with cyclooctanone in the presence of a strong acid or strong acid mixture to give 4- (4-fluorophenyl) -5,6 , 7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one (BLON2). 8. The method of claim 7,
Wherein the strong acid mixture is a mixture comprising para-toluene sulfonic acid (p-TsOH) and phosphoric acid. 9. The method according to claim 7 or 8,
Following step b):
b) Preparation of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one obtained in step b) To give 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (BLON3) . 10. The method of claim 9,
Following step c):
d) By reacting the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine obtained in step c) with a palladium catalyst, a ligand and a base &Lt; / RTI &gt; to provide a blocking agent. 11. The method of claim 10,
Wherein the palladium catalyst is bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ), the ligand is 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) Wherein said base is sodium tert-butoxide. A process for the preparation of 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1), said process comprising the following steps:
a) _reacting C _1-4 alkyl 4-fluorobenzoate with acetonitrile in the presence of an alkali metal HMDS to provide 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) ;
The method comprising the step of adding a mixture containing acetonitrile, benzoate and the alkali metal HMDS in the 4-C _{1- 4} alkyl; And
Wherein step a) takes place at a temperature in the range of from -20 to +20 &lt; 0 &gt; C. 13. The method of claim 12,
The alkaline metal HMDS which the C _{1- 4} alkyl 4-benzoate, at least 1.5 molar equivalents compared to fluoro, for example at least 1.6 molar equivalents, for example at least 1.7 molar equivalents, for example at least 1.8 molar equivalents, for example at least 1.9 molar equivalent, such as about 2 Molar equivalent. The method according to claim 12 or 13,
Wherein step a) takes place at a temperature in the range of from -10 to + 10 ° C, for example in the range of from -5 to + 5 ° C. 15. The method according to any one of claims 12 to 14,
Wherein step a) takes place in a solvent comprising toluene. 16. The method according to any one of claims 12 to 15,
_Wherein said C _1-4 alkyl 4-fluorobenzoate is methyl 4-fluorobenzoate. 17. The method according to any one of claims 12 to 16,
Wherein the alkali metal HMDS is NaHMDS. Use of 3- (4-fluorophenyl) -3-oxopropanenitrile (BLON1) obtained by the process of any one of claims 12 to 17 in the production of blownan serine.