Process for preparation of trirasilil or salt thereof

Abstract

A process for the preparation of trirasilil having the formula (I) or a salt thereof, wherein the use of an intermediate of the formula (VIII) is contemplated: wherein PG is a protecting group which predominantly has the effect of avoiding the formation of impurities of the formulae (XII) and (XIII). In addition, due to the electron withdrawing effect of the amide carbonyl group, the reactivity of the compound (VIII) is stronger due to the existence of the protecting group.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for the preparation of the active ingredient trilaciclib or salts thereof. The present invention also relates to intermediates useful for the synthesis of trilaciclib. BACKGROUND

[0002] Trilaciclib is an active ingredient having the formula (I):

[0003]

[0004] The active ingredient is able to transiently arrest normal cells to prevent chemotherapy-induced myelosuppression and thereby improve antitumor efficacy. For example, it can be used in small cell lung cancer (SCLC) patients receiving topotecan-based chemotherapy.

[0005] International patent application WO 2016 / 040858 reports a synthesis route for trilaciclib (see in particular page 96, scheme 9) in which the separation of the key intermediate is carried out using chromatographic techniques (on silica gel) which makes the process unsuitable for industrial scale.

[0006] The synthesis process according to WO'858 is shown in the following scheme 1 :

[0007] Scheme 1

[0008]

[0009] In the final step, the above process involves the reaction of a compound (Villa) corresponding to intermediate VIII but having a free amide nitrogen, with compound (IX), wherein the amide nitrogen in said compound (Villa) is free.

[0010] However, the Applicant has found that the free amide nitrogen can act as a nucleophile and cause side reactions between the free nitrogen of the formed trilaciclib and the chlorine of the above intermediate (Villa).

[0011] These side reactions specifically lead to the formation of the following impurities:

[0012]

[0013] International application WO 2018 / 005865 describes a further synthesis route for trilaciclib, as outlined in the following scheme 2:

[0014] Scheme 2

[0015]

[0016] The yield of the final step leading to the formation of Trazepil is about 64% (see WO'865, page 88, example for the preparation of compound 19) while the overall process yield for the synthesis of Trazepil is only 15.7%.

[0017] Moreover, the free amide of intermediate 11 is quantitatively deprotonated in the presence of strong bases such as lithium bis(trimethylsilyl)amide (LiHMDS) used in step 1.

[0018] Applicants believe that the use of a strong base in this step of the above process is the reason for the low yields previously reported, in addition to the consequent formation of undesirable side products, which are far from the standards suitable for an industrial process. A further drawback of the above process is the use of a large excess of compound (IX) equal to 3 equivalents, which makes the process also disadvantageous from an economic point of view.

[0019] Therefore, there is a need to find a process for the synthesis of Trazepil which is easier to industrialize and allows a favorable control of the spectrum of impurities that can be formed, in particular avoiding the formation of impurities of formula (XII) and (XIII). SUMMARY

[0021] Applicants have now found that the above objectives and others are possible, which will be better illustrated by the process for the preparation of Trazepil or salts thereof. The presence of a protecting group on the nitrogen atom of the -NH- group in the intermediate of formula (Villa) is provided therein, which allows avoiding the formation of impurities of formula (XII) and (XIII). Moreover, due to the electron-withdrawing effect of the amide carbonyl, the presence of the protecting group makes the compound (VIII) more reactive. This allows the coupling reaction with compound (IX) to be carried out at lower temperatures than in WO'858, with consequent further reduction of the formation of impurities and increase of the yield of Trazepil.

[0022] Moreover, the process according to the present application preferably provides the isolation of the intermediate of the reaction by crystallization: this makes the process advantageously industrialized, unlike the chromatographic techniques used in the prior art.

[0023] Therefore, according to a first aspect, the present application relates to a process for the preparation of Trazepil or salts thereof having formula (I):

[0024]

[0025] The process comprises:

[0026] a) reacting a compound of formula (II) or salts thereof:

[0027]

[0028] with a compound of formula (III) or salts thereof:

[0029]

[0030] wherein PG is a protecting group,

[0031] to obtain a compound of formula (IV):

[0032]

[0033] b) isolating said compound of formula (IV);

[0034] c) reacting said compound of formula (IV) with a compound of formula (V):

[0035]

[0036] in a molar ratio comprised between 1 :1 and 1 :1.50 and in the presence of a catalyst,

[0037] to obtain a compound of formula (VII):

[0038]

[0039] d) isolating said compound of formula (VII);

[0040] e) reacting said compound of formula (VII) with an acid, followed by an oxidizing agent and followed by a nucleophilic base, to obtain a compound of formula (VIII):

[0041]

[0042] f) reacting said compound of formula (VIII) with a compound of formula (IX):

[0043]

[0044] in the presence of a phosphine ligand, a metal catalyst and a base, in an organic solvent, to obtain a compound of formula (X):

[0045]

[0046] g) isolating said compound of formula (X);

[0047] h) converting said compound of formula (X) into a compound of formula (I) or a salt thereof.

[0048] In a preferred embodiment, said protecting group PG is a protecting group unstable under acidic conditions, preferably a tert-butyloxycarbonyl derivative group, more preferably a BOC (tert-butyloxycarbonyl).

[0049] In another preferred embodiment, said PG protecting group is a hydrogenolytically labile protecting group, preferably a benzyloxycarbonyl derived group, more preferably CBZ (benzyloxycarbonyl).

[0050] In a preferred embodiment, step e) is carried out in a single reaction environment without isolation of intermediates (one-pot reaction).

[0051] According to another aspect, the present application relates to a compound of formula (X):

[0052]

[0053] wherein PG is a protecting group, preferably a protecting group as defined above.

[0054] Further aspects, features and advantages of the present application will become apparent from the following detailed description. BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1 NMR spectra are shown in relation to the compound of formula (X1).

[0057] Figure 2 IR spectra are shown in relation to the compound of formula (X1);

[0058] Figure 3 NMR spectra are shown in relation to the compound of formula (VIIc).

[0059] Figure 4 NMR spectra are shown in relation to the compound of formula (VIId).

[0060] Figure 5 A schematic representation of the present process according to the present application is shown. DETAILED DESCRIPTION

[0062] For the purposes of the present application, in the following specification and claims, the definition of a numerical interval includes each value within the interval and its end points, unless otherwise stated.

[0063] For the purposes of the present application, in the specification and in the following claims, the term "comprising" also includes the term "essentially consisting of" or "consisting of".

[0064] According to a preferred aspect, said compound of formula (III) or a salt thereof, which is reacted with said compound of formula (II) in step a), is an acetate salt.

[0065] Preferably, step a) is carried out in a solvent selected from:

[0066] (a) an aprotic polar solvent, preferably an ether, an ester, a ketone, a carbonate, acetonitrile;

[0067] (b) water;

[0068] (c) an apolar solvent selected from toluene and dichloromethane;

[0069] or mixtures thereof.

[0070] According to a preferred aspect, the solvent used in step a) is a mixture of water and an aprotic polar solvent, preferably an ether, more preferably methyltetrahydrofuran (Me-THF).

[0071] According to a preferred aspect, the compound of formula (IV) is isolated in step b) by crystallization, preferably by addition of a mixture containing water and a water-soluble solvent selected from a Ci-C4alcohol and acetonitrile. The Ci-C4alcohol is preferably selected from the group consisting of ethanol (EtOH), isopropanol (IP A), butanol (BuOH) and mixtures thereof, more preferably t-butanol (t-BuOH).

[0072] After isolation in step b), the compound of formula (IV) typically has a purity of > 95%.

[0073] With regard to step c), the catalyst used is preferably a catalyst based on divalent copper or monovalent copper, more preferably CuCI2.

[0074] According to a preferred aspect, step c) is carried out in an anhydrous environment, preferably wherein the water content determined according to the Karl-Fisher method does not exceed 2 wt.-%.

[0075] The use of an anhydrous environment allows to operate with reduced amounts of compound (V) (with reference to the specific molar ratio as reported) making the isolation of compound (VII) in subsequent step d) more easily achievable at industrial level.

[0076] According to a further preferred aspect, step c) is carried out in a high-boiling solvent, preferably a high-boiling aprotic polar solvent, more preferably dimethyl sulfoxide (DMSO) or a mixture of DMSO with another solvent, more preferably a mixture of DMSO with toluene. By "high-boiling solvent" is meant a solvent having a boiling point higher than 100 °C.

[0077] Preferably, step d) is carried out by extraction from the reaction mixture (preferably with a volume of the organic phase less than 40 times the volume of the loaded compound of formula (IV)) and subsequent crystallization.

[0078] Preferably, as regards the extraction of compound (VII), the operation starts from an organic solvent selected from ethers or esters, more preferably Me-THF, and is treated with an aqueous solution containing water and a salt. Said salt is preferably selected from inorganic salts, more preferably NH4CI.

[0079] According to a preferred aspect, step e) comprises the following steps, which are preferably carried out in a single reactor, without isolation of intermediates (one-pot reaction):

[0080] i) reacting said compound of formula (VII) with an acid, preferably with acetic acid, to obtain a compound of formula (Vila), (VIIb) or a mixture thereof;

[0081] ii) converting said compound of formula (Vila), (VIIb) or a mixture thereof into a compound of formula (VIIc) by adding an oxidizing agent, preferably a hydrogen peroxide-based oxidizing agent, more preferably tert-butyl hydroperoxide, and subjecting the mixture to distillation, preferably sequential distillation;

[0082] iii) converting said compound of formula (VIIc) into said compound of formula (VIII) by treatment with a nucleophilic base, preferably selected from DMAP (4-dimethylaminopyridine), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), TBD (triazabicyclodecene), DBU (1,5-diazabicyclo(5.4.0)undec-7-ene), preferably DBN and DBU, more preferably DBU; and isolating said compound of formula (VIII), preferably by crystallization.

[0083] According to an alternative embodiment, step ii) can be carried out using peroxoacetic acid as oxidizing agent, to obtain said compound of formula (VIII). In the latter case, without being bound by any theory, it is believed that said compound of formula (VIII) is formed from a spontaneous rearrangement of the intermediate of formula (VIIe):

[0084]

[0085] In step f) (coupling reaction), said phosphine ligand is preferably a bidentate phosphine ligand. Said bidentate phosphine ligand is preferably selected from BINAP (1,1’-binaphthalene-2,2’-diyl-bis(diphenylphosphane)), DPEPhos (bis[(2-diphenylphosphino)phenyl]ether) and DPPF (1,1’-ferrocenediyl-bis(diphenylphosphane).

[0086] As regards the metal compound used in step f), said metal compound is preferably a palladium-containing compound, more preferably palladium acetate. Said metal compound is used as a catalyst.

[0087] In step f) the catalyst is preferably a palladium (Pd) compound, more preferably palladium acetate. Preferably, the catalyst has a Pd content of not more than 0.05 molar equivalents. No reactions operating with such low amounts of palladium have been reported in the prior art.

[0088] In step f) the base is preferably selected from amines and inorganic carbonates, more preferably it is an inorganic carbonate, in particular cesium carbonate.

[0089] In step f) the organic solvent is preferably selected from the group consisting of amides, esters, ethers, ureas and mixtures thereof. More preferably, the organic solvent is selected from the group consisting of dioxane, dimethyl isosorbide, dimethyl carbonate, N-butyl-pyrrolidone, N-methyl-pyrrolidone (NMP), DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone), DMI (1,3-dimethyl-2-imidazolidinone), tetramethyl urea. Particularly preferred is dimethyl carbonate.

[0090] In step g) the isolation of the compound (X) is preferably carried out by crystallization. Preferably, the crystallization can be carried out in a solvent selected from the group consisting of esters, ethers, ureas, alcohols, optionally mixed with water.

[0091] In particular, the isolation of the compound of formula (X) carried out using an alcohol or a mixture of an alcohol and water allows to obtain a product (X) having a reduced palladium content.

[0092] Preferably, the compound (X) has a palladium content lower than or equal to 30 ppm, more preferably lower than or equal to 20 ppm, even more preferably lower than or equal to 10 ppm, even more preferably lower than or equal to 5 ppm. Preferably, the palladium content ranges from 0.01 ppm to 6 ppm, more preferably from 0.01 ppm to 5 ppm.

[0093] In step h) the compound of formula (X) is converted into crizotinib or a salt thereof, preferably into crizotinib bistrifluoroacetate. In this preferred aspect, the conversion is carried out by acid hydrolysis with trifluoroacetic acid. Subsequently, the crizotinib salt thus obtained can be converted into another salt (in particular into crizotinib bis-hydrochloride) or into crizotinib base according to known techniques.

[0094] In a preferred embodiment, the process of the present application is carried out according to the scheme shown in Figure 5 In particular, in the scheme step e) is a one-pot reaction. Examples

[0095] The following working examples are merely illustrative of the present application and should not be construed as limiting the scope of the protection as defined by the appended claims.

[0096] Example 1. Preparation of intermediate (IV)

[0097] 100 g of the compound of formula (II), 120 g of the compound of formula (III) (wherein the PG protecting group is Boc (tert-butyloxycarbonyl)), 90 g of K CO , 350 mL of demineralized water, and 200 mL of Me-THF (methyltetrahydrofuran) were added at room temperature. The reaction mixture was heated to 60-65° C. and the reaction was continued until completion. When the reaction was complete, the reaction mixture was cooled to room temperature and then 800 mL of Me-THF was added.

[0098] The organic phase is recovered, 500 mL of water are added to the latter and the mixture is brought to pH 4.8 using acetic acid.

[0099] The organic phase was recovered and an aqueous solution of KCO was added thereto until the pH reached 7.5. The organic phase was recovered and 500 mL of water was added thereto. The organic phase was recovered again and the solvent was changed to tert-butyl alcohol. The product was then crystallized by adding water, which served as an anti-solvent.

[0100] The product of formula (IV) is obtained in a purity of about 95% and a molar yield of about 75%.

[0101] Example 2. Preparation of intermediate (VII)

[0102] 100 g of the compound of formula (IV), 35 g of sodium iodide, 6.52 g of 6-methylpicolinic acid, 98.6 g of potassium carbonate, and 700 mL of DMSO (dimethyl sulfoxide) were added at room temperature. 200 mL was distilled from the above materials under vacuum, and then the system was inertized with nitrogen.

[0103] The reaction mixture was heated to 110-115°C, to which 3.2 g of CuCl and 33.5 g of propargylaldehyde diethyl acetal were then added, followed by a final wash of the mixture with 100 mL of DMSO. The reaction was allowed to continue until completion. Once the reaction was complete, the reaction mixture was cooled to room temperature, and then 1 L of Me-THF and 1.3 L of a 20 wt% aqueous solution of ammonium chloride were added.

[0104] Reclaim the organic phase and add 500mL of 10% aqueous sodium sulfite solution thereto. Reclaim the organic phase and add 500mL of water thereto. Reclaim the organic phase again and add 100mL of MeTHF and 500mL of water. Reclaim the organic phase then and use isopropyl alcohol to carry out solvent exchange. Make product crystallization then by adding water, wherein water is as antisolvent.

[0105] The compound of formula (VII) is obtained with a purity greater than 90% and a molar yield of about 75%.

[0106] Example 3. Preparation of intermediate (VIII)

[0107] At room temperature, 40 g of compound of formula (VII), 400 mL of ACN (acetonitrile) and 6.5 mL of TFA (trifluoroacetic acid) are introduced and the mixture is left to react for one hour. Then 13.2 g of 70% aqueous solution of tert-butyl hydroperoxide are added thereto.

[0108] Subsequently, the water is removed by subsequent distillation under vacuum, obtaining a solution having a volume of about 200 mL.

[0109] The solution thus obtained is added at 10-15°C to a solution of 40 mL of ACN and 25.5 mL of DBU. When the addition is complete, the reaction is brought to 15-20°C until completion; the precipitated product is recovered by filtration. The compound of formula (VIII) is obtained with a purity greater than 97% and a molar yield of about 75%.

[0110] Example 4. Preparation of intermediate (X)

[0111] In an inert system of nitrogen, 25 g of compound of formula (VIII), 15.4 g of compound of formula (IX), 31.25 g of cesium carbonate, 140 mg of palladium acetate, 895 mg of DPPF (1,1'-bis(diphenylphosphino)ferrocene) are introduced. Subsequently, 240 mL of degassed dimethyl carbonate are added and the reaction mass is heated to 80°C and left to react for 30 min. Next, 358 mg of DPPF are added and the reaction is continued until completion. The product precipitates as it forms.

[0112] When the reaction is complete, the reaction mixture is concentrated under vacuum to a volume of 125 mL, then 162 mL of methanol and 162 mL of water are added dropwise. The product is recovered by filtration.

[0113] The product of formula (X) is obtained with a purity greater than 97% and a molar yield of about 85% and a palladium content lower than 20 ppm.

[0114] Example 5. Preparation of Tralaxibine bis-trifluoroacetate salt

[0115] At room temperature, 23 g of compound of formula (X), 115 mL of acetic acid and 9.7 mL of TFA are introduced. The reaction mixture is heated to 65°C and the reaction is continued until completion. When the reaction is complete, the mixture is cooled to 40°C, then 70 mL of isopropanol and 230 mL of toluene are added dropwise. The product is then observed to precipitate. The mixture is cooled to room temperature and left to stir for about one hour. The product is recovered by filtration. Crizotinib bis-trifluoroacetate is obtained with a purity greater than 99% and a molar yield of about 90%.

[0116] Example 6. Preparation of Tralaxibine bis-hydrochloride salt

[0117] Charge 10 g of tradipitant bistrifluoroacetate, 80 mL of methanol and 20 mL of water. Heat the material to 50 °C and then add dropwise 3.6 mL of 37% aqueous HC1, then cool the mixture to room temperature. The product is observed to precipitate. After about an hour, 80 mL of acetone are added dropwise. The product is recovered by filtration. Tradipitant bis hydrochloride is obtained with a purity greater than 99% and a molar yield of about 95%.

[0118] Notably, on the basis of the reported data above, the process according to the present application is more efficient in terms of yield, both with respect to the coupling step of intermediate (VIII) (85% yield vs 63.7%) and for the entire process, compared to that described in WO 2018 / 005865. In fact, the process according to the present application allows an increase in the overall yield of tradipitant of at least 10 percentage points compared to WO '865.

Claims

1. A method for preparing triclasiclib or a salt thereof having formula (I), The method comprises: a) making a compound of formula (II) or a salt thereof: Reaction with a compound of formula (III) or a salt thereof: Where PG is a protecting group, To obtain the compound of formula (IV): b) isolating the compound of formula (IV); c) reacting the compound of formula (IV) with a compound of formula (V): with a molar ratio between 1:1 and 1:1.50 and in the presence of a catalyst to obtain a compound of formula (VII): d) isolating the compound of formula (VII); e) reacting the compound of formula (VII) with an acid, followed by an oxidizing agent and then a nucleophilic base to obtain a compound of formula (VIII): f) reacting the compound of formula (VIII) with a compound of formula (IX): In the presence of a phosphine ligand, a metal catalyst and a base, the reaction is carried out in an organic solvent to obtain a compound of formula (X): g) isolating the compound of formula (X); h) converting the compound of formula (X) into triclasiclib or a salt thereof of formula (I).

2. The method according to claim 1, wherein the protecting group PG is a protecting group that is unstable under acidic conditions, preferably a group derived from tert-butyloxycarbonyl, more preferably BOC (tert-butyloxycarbonyl).

3. The method according to claim 1, wherein the PG protecting group is a hydrogenation-labile protecting group, preferably a group derived from benzyloxycarbonyl, more preferably CBZ (benzyloxycarbonyl).

4. The process according to any one of the preceding claims, wherein step e) is carried out in a single reaction environment without isolation of intermediates (one-pot reaction).

5. A method according to any one of the preceding claims, wherein the compound of formula (III) is in the form of an acetate salt.

6. The process according to any one of the preceding claims, wherein step a) is carried out in a solvent selected from: (a) aprotic polar solvents, preferably ethers, esters, ketones, carbonates, acetonitrile; (b) water; (c) a non-polar solvent selected from toluene and dichloromethane; or a mixture thereof.

7. The method according to claim 6, wherein the solvent used in step a) is a mixture of water and an aprotic polar solvent, and the aprotic polar solvent is preferably an ether, more preferably methyltetrahydrofuran (Me-THF).

8. The process according to any one of the preceding claims, wherein in step b) the compound of formula (IV) is isolated by crystallization, preferably by adding a mixture containing water and a water-miscible solvent selected from C1-C4 alcohols and acetonitrile, preferably tert-butanol (t-BuOH).

9. The process according to any one of the preceding claims, wherein after the isolation in step b), the compound of formula (IV) has a purity of ≥95%.

10. The process according to any one of the preceding claims, wherein the catalyst in step c) is a copper- or copper-based catalyst, preferably CuCl2.

11. The process according to any one of the preceding claims, wherein step c) is carried out in anhydrous environment, preferably wherein the water content, determined according to Karl-Fisher method, is not more than 2% by weight.

12. The process according to any one of the preceding claims, wherein step c) is carried out in a high-boiling solvent, preferably a high-boiling aprotic polar solvent, more preferably dimethyl sulfoxide (DMSO) or a mixture of DMSO with another solvent, more preferably a mixture of DMSO with toluene.

13. The process according to any one of the preceding claims, wherein step e) comprises the following steps: i) reacting the compound of formula (VII) with an acid, preferably with acetic acid, to obtain a compound of formula (Vila), (Vllb) or a mixture thereof; ii) converting the compound of formula (Vila), (Vllb) or a mixture thereof into a compound of formula (VIIc) by adding an oxidizing agent, preferably a hydrogen peroxide-based oxidizing agent, more preferably tert-butyl hydroperoxide, and subjecting the mixture to distillation, preferably to sequential distillation; iii) converting the compound of formula (VIIc) into the compound of formula (VIII) by treatment with a nucleophilic base, preferably selected from DMAP (4-dimethylaminopyridine), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), TBD (triazabicyclodecene), DBU (1,5-diazabicyclo(5.4.0)undec-7-ene), preferably DBN and DBU, more preferably DBU; and isolating the compound of formula (VIII), preferably by crystallization.

14. The process according to any one of the preceding claims, wherein in step f) (coupling reaction) the phosphine ligand is a bidentate phosphine ligand, preferably selected from BINAP (1,1 ’-binaphthalene-2,2’-diyl-bis(diphenylphosphane)), DPEPhos (bis[(2-diphenylphosphino)phenyl]ether) and DPPF (1,1 ’-ferrocenediyl-bis(diphenylphosphane).

15. The process according to any one of the preceding claims, wherein in step f) the catalyst is a palladium compound (Pd), preferably palladium acetate.

16. The process according to claim 15, wherein the catalyst has a Pd content not higher than 0.05 molar equivalents.

17. The process according to any one of the preceding claims, wherein in step f) the base is selected from amines and inorganic carbonates, preferably an inorganic carbonate, in particular cesium carbonate.

18. The process according to any one of the preceding claims, wherein in step f) the organic solvent is selected from: amides, esters, ethers, ureas or mixtures thereof, preferably selected from: dioxane, dimethyl isosorbide, dimethyl carbonate, N-butyl-pyrrolidone, N-methyl-pyrrolidone (NMP), DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone), DMI (1,3-dimethyl-2-imidazolidinone), tetramethylurea.

19. The process according to any one of the preceding claims, wherein the isolation of the compound (X) in step g) is carried out by crystallization, preferably in a solvent selected from the group consisting of esters, ethers, ureas, alcohols, optionally mixed with water.

20. Compound of formula (X): ###0002### wherein PG is a protecting group.

21. Compound according to claim 20, wherein the protecting group PG is a protecting group unstable under acidic conditions, preferably a t-butoxycarbonyl derivative group, more preferably BOC (t-butoxycarbonyl).

22. Compound according to claim 20, wherein the PG protecting group is a hydrogenation-labile protecting group, preferably a benzyloxycarbonyl derivative group, more preferably CBZ (benzyloxycarbonyl).

23. Compound according to any one of claims 20 to 22, having a Pd content lower than or equal to 30 ppm, preferably lower than or equal to 20 ppm, more preferably lower than or equal to 10 ppm, even more preferably lower than or equal to 5 ppm. ​

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