Method for the synthesis of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester

Abstract

The present invention relates to a method for synthesizing 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester or its hydrochloride salt; and a crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride salt. [Formula 1] JPEG2024524658000027.jpg61155

Description

[Technical field]

[0001] The present invention relates to 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester. to a process for the synthesis of 4-((R)-2-{[6-((S)-3-Methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (hereinafter also referred to as "Compound"·HCl), and to a crystalline form of "Compound"·HCl for use as a medicament or for use in the manufacture of a medicament.

[0002] [ka] [Background technology]

[0003] The manufacture and medical uses of the Compound are described in WO2009 / 069100; WO2018 / 167139; Baldoni D et al., Clin Drug Investig (2014), 34(11), 807-818; Caroff E et al., J. Med. Chem. (2015), 58, 9133-9153; Storey RF et al., European Heart Journal, ehz807, doi:10.1093 / eurheartj / ehz807; and Sinnaeve PR et al., J Am Coll Cardiol (2020), 75(20), 2588-97 (doi.org / 10.1016 / j.jacc.2020.03.059). For example, "Compound"·HCl can be prepared according to the procedure shown in Scheme 1: Compound 3 can be obtained by amide coupling of piperazine-1-carboxylic acid butyl ester or its hydrochloride with (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid (Compound 2) in the presence of a coupling reagent such as T3P or EDC, HOBt, etc. The amino protecting group in Compound 3 can be converted by amide coupling of piperazine-1-carboxylic acid butyl ester or its hydrochloride with (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid (Compound 2) in the presence of a coupling reagent such as T3P, EDC, HOBt, etc. The reaction can be removed under suitable acidic conditions, such as HCl in dioxane, to give 4-[(R)-2-amino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid butyl ester (compound 4). Compound 4 can be coupled with (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid sodium salt (compound 6) in the presence of a coupling reagent, such as EDC or HOBt, to give compound 7. Compound 6 can be obtained, for example, by saponifying (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonitrile (compound 5) with a base, such as aqueous sodium hydroxide, in a solvent, such as 2-propanol.

[0004] [ka]

[0005] The "compound" can be prepared, for example, from 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (compound 7) by treating with TMSBr in acetonitrile and purifying by reversed-phase column chromatography (Caroff E et al., J. Med. Chem. (2015), 58, 9133-9153). This method is disadvantageous for large-scale synthesis because it requires a large amount of expensive TMSBr for deprotection and a purification step by column chromatography. These disadvantages can be solved by treating with concentrated hydrochloric acid in a DCM / THF mixture with 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy- This problem can be overcome by deprotecting (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carboxamide)-3-phosphonopropanoic acid (hereinafter also referred to as the "hydrolysis product"), followed by deprotection of (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carboxamide)-3-phosphonopropanoic acid. For example, a solution of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester in DCM (4 vol) and 32% w / w aqueous HCl (3.6 vol) after stirring at RT for 4 h gives a mixture of 2.8% a / a of "hydrolysis product" and 93.5% a / a of "compound"·HCl when analyzed by HPLC. After 20 h, the amount of "hydrolysis product" in the above mixture further increases to 15.2% a / a. Thus, deprotection in concentrated HCl has the disadvantage of rapid decomposition of the desired product, necessitating more extensive purification and causing a loss in yield.

[0006] Surprisingly, it has been found that carrying out this reaction using the hydrochloride salt in certain organic solvents containing only catalytic amounts of water significantly reduces the amount of by-product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid and gives "compound"·HCl in higher yield and better reaction rate. While the reaction is very slow and / or gives large amounts of by-products (e.g., using HCl in solvents such as heptane, acetonitrile, 2-methyl-tetrahydrofuran or ethanol), it gives surprisingly good results using HCl in toluene, acetone, carboxylic acid esters, especially carboxylic acids (e.g., acetic acid). [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows the powder X-ray diffraction diagram of crystalline form (I) of "Compound"·HCl, measured using the XRPD method described in the experimental section and shown for Cu Kα radiation. The X-ray diffraction diagram shows peaks with the following percentage relative intensities (relative peak intensities are given in brackets) compared to the most intense peak in the diagram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of more than 10% from the range 3-28° 2-theta are reported): 3.7° (12%), 5.1° (50%), 5.7° (93%), 5.9° (100%), 10.2° (17%), 10.4° ( 16%), 10.7°(25%), 11.0°(20%), 12.9°(28%), 14.7°(13%), 15.2°(32%), 15.4°(26%), 18.0°(26%), 18.3°(23%), 18.8°(26%), 19.4°(21%), 19.6°(31%), 20.2°(58%), 21.0°(54%), 21.3°(49%), 22.2°(45%), 22.6°(33%), 25.2°(40%) and 26.4°(18%).

[0008] In the X-ray diffraction diagram of FIG. 1, the refraction angle 2 theta (2θ) is plotted on the horizontal axis and the counts on the vertical axis.

[0009] For the avoidance of any doubt, the above peaks describe the experimental results of the powder X-ray diffraction shown in Figure 1. In contrast to the above list of peaks, it should be understood that only selected characteristic peaks are necessary to completely and unambiguously characterize each crystalline form of "Compound"·HCl of the present invention. Summary of the Invention

[0010] Description of the invention The invention will now be described and various aspects of the invention will be illustrated. 1) In a first aspect, the present invention relates to a method for preparing 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester ("Compound") or its hydrochloride salt ("Compound"·HCl),

[0011] [ka]

[0012] The method comprises reacting a compound of formula (I)

[0013] [ka]

[0014] (In the formula, R 1 and R 2 are, independently of each other, (C 1-4 ) represents alkyl. with a hydrochloride salt in a mixture comprising an organic solvent and water; The organic solvents are acetone, toluene, R 3 C(O)OR 4 or any mixture thereof, R 3is hydrogen or (C 1-2 ) alkyl, R 4 is hydrogen or (C 1-3 ) alkyl; The amount of water is less than 12 equivalents relative to the amount of the compound of formula (I).

[0015] The definitions set forth herein are intended to be comprehensive unless a broader or narrower definition is given by a specific definition. Unless otherwise stated, all definitions and preferred definitions of any term apply uniformly throughout the specification and claims. It is to be understood that any definition or preferred definition of a term may define and replace each respective term independently (and in conjunction with) any or all other terms or preferred definitions defined herein.

[0016] The hydrochloride required in the reaction may be from any suitable source of hydrochloride, which does not increase the amount of water in the reaction mixture by 12 equivalents or more relative to the amount of the compound of formula (I). For example, the hydrochloride may be added to the reaction mixture as hydrochloride gas or as a solution in a solvent, which may be an organic solvent (e.g., dioxane, ethanol and isopropanol, especially dioxane) or water (especially an aqueous solution, especially a concentrated aqueous solution); or may be generated in-situ by reaction of an electrophilic chloride source (i.e., a compound that releases chloride upon reaction with a nucleophile) with a protic nucleophile (i.e., a compound having a functional group that has a heteroatom bonded to a hydrogen atom, the heteroatom having one or more free electron pairs). Examples of electrophilic chloride sources are carboxylic acid chlorides, especially (C 1-3 ) alkyl-C(O)Cl, especially CH3C(O)Cl), SOCl2, POCl3, PCl3 and PCl5; preferably carboxylic acid chlorides, especially (C 1-3 ) alkyl-C(O)Cl, especially CHC(O)Cl. Examples of protic nucleophiles are water, alkanols (especially (C 1-4 ) alkanols, especially ethanol), amines (especially (C1-3 ) alkyl-NH2 and ((C 1-3 )alkyl)2-NH) and thiols (especially (C 1-4 ) alkyl-SH); preferably water and alkanols (especially (C 1-4 ) alkanols, especially ethanol); most preferably ethanol. A preferred combination of electrophilic chloride source and protic nucleophile is a carboxylic acid chloride and an alkanol, especially (C 1-3 ) alkyl-C(O)Cl and (C 1-4 ) alkanols, especially CH3C(O)Cl and ethanol). In addition, carboxylic acid anhydrides, especially ((C 1-3 It should be understood that the reaction of (CHC(O))O, particularly (CHC(O))O), with aqueous hydrochloride can be used to generate the hydrochloride salt in the reaction mixture at low water content (e.g., less than 12 equivalents of water). In the context of "generated in situ by reaction of an electrophilic chloride source with a protic nucleophile," the term "in situ" means that the hydrochloride salt is generated in the reaction mixture by either adding an electrophilic chloride source to the reaction mixture with a protic nucleophile, or by adding a protic nucleophile to the reaction mixture with an electrophilic chloride source.

[0017] The organic solvents are acetone, toluene, R 3 C(O)OR 4 or any mixture thereof” is intended to include the organic solvent, such as acetone, toluene, R 3 C(O)OR 4 , more than one (particularly two or three, especially two) different R 3 C(O)OR 4 (R 3 C(O)OR 4 is R 3 , R 4 Either or R 3 and R 4 or a mixture of acetone, toluene and one or more (particularly one, two or three, especially one or two) R 3 C(O)OR4 (R 3 C(O)OR 4 R, if applicable 3 , R 4 Either or R 3 and R 4 (wherein both R and R are different). When the organic solvent is a mixture, the organic solvent may be any mixture of more than one (particularly two or three, more particularly two) different R 3 C(O)OR 4 (R 3 C(O)OR 4 is R 3 , R 4 Either or R 3 and R 4 The preferred organic solvent is a mixture of R 3 C(O)OR 4 and two different R 3 C(O)OR 4 (R 3 C(O)OR 4 is R 3 , R 4 Either or R 3 and R 4 ) more preferably CH3C(O)OH and a mixture of CH3C(O)OH and CH3C(O)OEt; and most preferably CH3C(O)OH (acetic acid).

[0018] The term "equivalents" in the context of "The amount of the first compound is 'X' equivalents relative to the amount of the second compound" means that a mixture contains 'X' times the amount (in any units related to the number of molecules) of the first compound relative to the amount of the second compound (expressed in the same units). For example, the term "equivalents" in the context of "The amount of water is less than 12 equivalents (or between a value 'x' equivalents and a value 'y' equivalents) relative to the amount of the compound of formula (I)" means that the reaction mixture contains an amount of water (in any units related to the number of molecules) in the stated range of equivalents relative to the amount of the compound of formula (I) (expressed in the same units). For example, when the amount of water in the reaction mixture is defined as being less than 12 equivalents relative to the amount of the compound of formula (I), this means that the molar ratio of water to the compound of formula (I) in the reaction mixture is less than 12 to 1; when the amount of water in the reaction mixture is defined as being between 0.5 and 3.0 equivalents relative to the amount of the compound of formula (I), this means that the molar ratio of water to the compound of formula (I) in the reaction mixture is 1 to 2, 3 to 1, or any value in between.

[0019] Preferably, the amount of water is between 0.2 and 9.5 equivalents (more preferably between 0.5 and 3.0 equivalents, most preferably between 0.5 and 2.0 equivalents) relative to the amount of compound of formula (I). The amount of water is intended to mean the total amount of water present in the reaction mixture, i.e. the amount of water added plus the amount of water present in the reagents, solvents, reaction vessel and other sources of water. When not used in relation to temperature, the term "about" placed before a numerical value "X" means in this application between 10% of XX and 10% of X+X, in particular between 5% of XX and 5% of X+X, and especially between 2% of XX and 2% of X+X. In the specific case of temperature, the term "about" placed before a temperature "Y" means in this application between a temperature Y-10°C and Y+10°C, in particular between Y-5°C and Y+5°C, and especially between Y-3°C and Y+3°C. Room temperature means a temperature of about 25°C.

[0020] Whenever the words "between" or "to" are used to describe a numerical range, the endpoints of the stated range are expressly intended to be included in that range. For example: when a temperature range is described as being between 40° C. and 80° C. (or 40° C. to 80° C.), it is meant that the endpoints 40° C. and 80° C. are included in the range; or when a variable is defined as an integer between 1 and 4 (or 1 to 4), it is meant that the variable is the integer 1, 2, 3, or 4.

[0021] The expression % w / w means the percentage by weight relative to the total weight of the composition under consideration. Similarly, the expression v / v means the volume ratio of two components under consideration.

[0022] The term "alkyl", used alone or in combination, means a straight or branched saturated hydrocarbon chain having 1 to 4 carbon atoms. x-y The term "alkyl" (x and y are each integers) refers to an alkyl group as defined above having x to y carbon atoms. For example, (C 1-4 ) The alkyl group has 1 to 4 carbon atoms. 1-4 ) Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 1-3 ) Examples of alkyl groups are methyl, ethyl, n-propyl and iso-propyl. 1-2 Examples of alkyl groups are methyl and ethyl. 1 " is "(C 1-4 When expressing an "alkyl" group, "(C 1-4 The term "R alkyl" means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, preferably methyl, ethyl, n-propyl and isopropyl, most preferably ethyl. 2 " is "(C 1-4 When expressing an "alkyl" group, "(C 1-4 The term "alkyl" includes methyl, ethyl, n-propyl, , isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, preferably methyl, ethyl, n-propyl and isopropyl, most preferably ethyl. 3 " is "(C 1-2 When expressing an "alkyl" group, "(C 1-2 The term "alkyl" means methyl and ethyl, preferably methyl. 4 " is "(C 1-3 When expressing an "alkyl" group, "(C 1-3 The term "alkyl" refers to methyl, ethyl, n-propyl and isopropyl, preferably methyl and ethyl, most preferably ethyl.

[0023] "(C 1-3 The term "alkyl-C(O)Cl", used alone or in combination, refers to an alkyl group as defined above having 1 to 3 carbon atoms, attached to a -C(O)Cl group via a carbon atom. Examples of such groups are acetyl chloride (CHC(O)Cl), propionyl chloride (CHCHC(O)Cl), butyryl chloride (CHCHCHC(O)Cl) and isobutyryl chloride (CH)CHC(O)Cl). Preferred are acetyl chloride (CHC(O)Cl) and propionyl chloride (CHCHC(O)Cl), most preferred is acetyl chloride (CHC(O)Cl).

[0024] "((C 1-3 The term "alkyl-C(O))O", whether used alone or in combination, means that both hydrogen atoms are independently selected from (C 1-3 ) alkyl-carbonyl-group ((C 1-3 ) alkyl-C(O)-) is substituted with water (HO), and the above (C 1-3 ) alkyl-groups are as defined above. 1-3 Examples of alkyl-C(O)O groups are acetic anhydride, propionic anhydride, butyric anhydride and isobutyric anhydride. Preferred is acetic anhydride.

[0025] "(C 1-4 The term "(2-hydroxy)alkanol", used alone or in combination, means a straight or branched alkane having 1 to 4 carbon atoms and in which one hydrogen atom is replaced by hydroxy. Examples of said group are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol. Preferred are methanol, ethanol and isopropanol, most preferred is ethanol.

[0026] "(C 1-4 The term "alkyl-SH", used alone or in combination, means a straight or branched alkane having 1 to 4 carbon atoms and in which one hydrogen atom is replaced by a sulfanyl group (-SH). Examples of such groups are methanethiol, ethanethiol, propanethiol, isopropanethiol, butanethiol, isobutanethiol, sec.-butanethiol and tert.-butanethiol.

[0027] "(C 1-3 The term "alkyl-NH" whether used alone or in combination means a radical in which one hydrogen atom is replaced by an alkyl radical as defined above (C 1-3 ) alkyl group substituted ammonia (NH3). Examples of such groups are methylamino, ethylamino, n-propylamino, and isopropylamino.

[0028] "((C 1-3 The term "alkyl)-NH" whether used alone or in combination means that the two hydrogen atoms are independently selected from the group consisting of (C 1-3) alkyl group (NH3), where the two alkyl groups may be the same or different. Examples of such groups are dimethylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, diethylamino, ethyl-n-propylamino, ethyl-isopropylamino, di-n-propylamino, n-propyl-isopropylamino and di-isopropylamino.

[0029] 2) A further embodiment relates to a process according to embodiment 1), which is a process for the preparation of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride ("compound"·HCl).

[0030] 3) A further aspect is R 1 represents methyl, ethyl, n-propyl or isopropyl.

[0031] 4) A further aspect is R 2 represents methyl, ethyl, n-propyl or isopropyl.

[0032] 5) A further aspect is R 1 and R 2 are the same and represent methyl, ethyl, n-propyl or isopropyl.

[0033] 6) A further aspect is R 1 and R 2 In one embodiment,

[0034] 7) A further embodiment relates to the process according to any one of embodiments 1) to 6), wherein the hydrochloride salt is added to the reaction mixture as a hydrochloride salt gas or the hydrochloride salt is generated in-situ by reaction of an electrophilic chloride source with a protic nucleophile.

[0035] 8) A further embodiment relates to the process according to any one of embodiments 1) to 6), wherein said hydrochloride salt is generated in-situ by reaction of an electrophilic chloride source with a protic nucleophile.

[0036] 9) A further embodiment is where the electrophilic chloride source is a carboxylic acid chloride, particularly (C 1-3 ) alkyl-C(O)Cl), SOCl2, POCl3, PCl3 and PCl5.

[0037] 10) A further embodiment is wherein the electrophilic chloride source is (C 1-3 ) alkyl-C(O)Cl.

[0038] 11) A further embodiment relates to a process according to any one of embodiments 7) or 8), wherein the electrophilic chloride source is acetyl chloride (CH3C(O)Cl).

[0039] 12) A further embodiment is where the protic nucleophile is selected from the group consisting of water, alkanols (especially (C 1-4 ) alkanols), amines (especially (C 1-3 ) alkyl-NH2) and thiols (especially (C 1-4 ) alkyl-SH).

[0040] 13) A further embodiment is a method for preparing a protic nucleophile comprising the steps of: 1-4 ) alkanols (in particular ethanol).

[0041] 14) A further embodiment is wherein the protic nucleophile is (C 1-4 ) alkanols (in particular ethanol).

[0042] 15) A further embodiment is the hydrochloride salt of 1-3 of an electrophilic chloride source selected from water and (C 1-4 ) alkanols (especially (C 1-4 ) Al The process according to any one of embodiments 7) or 8), wherein the compound is generated in situ by reaction with a protic nucleophile selected from the group consisting of cyclohexyl ether, ...

[0043] 16) A further embodiment relates to a process according to any one of embodiments 7) or 8), wherein the hydrochloride salt is generated in-situ by reaction of acetyl chloride (CH3C(O)Cl) with ethanol.

[0044] 17) A further embodiment is a method for producing the electrophilic chloride source (particularly (C 1-3 The method according to any one of the embodiments 7) to 16), wherein the amount of alkyl-C(O)Cl, especially CHC(O)Cl, is between 0.5 and 20 equivalents relative to the amount of the compound of formula (I). The lower limits of the electrophilic chloride source are 0.5, 0.8, 0.9 and 1.0 equivalents, and the upper limits are 20, 10, 5.0, 3.0 and 2.0 equivalents. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0045] 18) A further embodiment is a method for producing the electrophilic chloride source (particularly (C 1-3 ) the amount of alkyl-C(O)Cl, in particular CHC(O)Cl) is between 0.9 and 5.0 equivalents (in particular between 1.0 and 3.0 equivalents) relative to the amount of compound of formula (I).

[0046] 19) A further embodiment is a method for producing the electrophilic chloride source (particularly (C 1-3) the amount of alkyl-C(O)Cl, especially CHC(O)Cl) is between 1.0 and 2.0 equivalents (in particular about 1.5 equivalents) relative to the amount of compound of formula (I).

[0047] 20) A further embodiment is a method for preparing a protic nucleophile (particularly water and (C 1-4 The method according to any one of the embodiments 7) to 19), wherein the amount of the protic nucleophile is between 1.0 and 10 equivalents relative to the amount of the electrophilic chloride source. The lower limits of the protic nucleophile are 1.0, 1.2, 1.4 and 1.5 equivalents, and the upper limits are 10, 5.0, 2.5 and 2.0 equivalents. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0048] 21) A further embodiment is a method for preparing a protic nucleophile (particularly water and (C 1-4 The method according to any one of embodiments 7) to 19), wherein the amount of the alkanol, especially ethanol, is between 1.2 and 5.0 equivalents (especially between 1.4 and 2.5 equivalents) relative to the amount of the electrophilic chloride source.

[0049] 22) A further embodiment is a protic nucleophile (particularly water and (C 1-4 The method according to any one of embodiments 7) to 19), wherein the amount of the alkanol, especially ethanol, is between 1.5 and 2.0 equivalents (in particular about 1.67 equivalents) relative to the amount of the electrophilic chloride source.

[0050] 23) A further embodiment is the hydrochloride salt of ((C 1-3 It relates to a process according to any one of embodiments 1) to 6), in which the compound is generated in situ by reaction with an aqueous solution of a hydrochloride salt of an alkyl-C(O))O (in particular acetic anhydride).

[0051] 24) A further embodiment relates to the process according to embodiment 7), wherein the hydrochloride is added to the reaction mixture as hydrochloride gas.

[0052] 25) In a further embodiment, hydrochloride gas is added to the reaction mixture; or generated in situ by reaction of a protic nucleophile with a child chloride source; or ((C 1-3 ) alkyl-C(O))O in an aqueous solution of hydrochloride; the amount of said hydrochloride is between 0.5 and 20 equivalents relative to the amount of the compound of formula (I). The lower limits of the amount of said hydrochloride are 0.5, 0.8, 0.9 and 1.0 equivalents, and the upper limits are 20, 10, 5.0, 3.0 and 2.0 equivalents. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are disclosed herein.

[0053] 26) A further embodiment relates to the process according to any one of embodiments 1) to 16) or 24), wherein the amount of hydrochloride is added to the reaction mixture as a hydrochloride gas; or is generated in situ by reaction of an electrophilic chloride source with a protic nucleophile; relative to the amount of compound of formula (I), the amount of hydrochloride is between 0.9 and 5.0 equivalents (in particular between 1.0 and 3.0 equivalents).

[0054] 27) A further embodiment relates to the process according to any one of embodiments 1) to 16) or 24), wherein the amount of hydrochloride is added to the reaction mixture as a hydrochloride gas; or is generated in situ by reaction of an electrophilic chloride source with a protic nucleophile; relative to the amount of compound of formula (I), the amount of hydrochloride is between 1.0 and 2.0 equivalents (in particular about 1.5 equivalents).

[0055] 28) A further embodiment is wherein the organic solvent is toluene, R 3 C(O)OR 4 or any mixture thereof, R 3 is hydrogen or (C 1-2 ) alkyl, R 4 is hydrogen or (C 1-3 ) alkyl.

[0056] 29) In a further embodiment, the organic solvent is 3 C(O)OR 4 or any mixture thereof, R 3 is hydrogen or (C 1-2 ) alkyl, R 4 is hydrogen or (C 1-3 ) alkyl.

[0057] 30) A further aspect is R 3 represents hydrogen or methyl (in particular methyl).

[0058] 31) A further aspect is R 4 represents hydrogen, methyl or ethyl (in particular hydrogen).

[0059] 32) A further embodiment relates to the process according to any one of embodiments 1) to 27), wherein the organic solvent is acetic acid (CH3C(O)OH), methyl acetate (CH3C(O)OMe) or ethyl acetate (CH3C(O)OEt) or any mixture thereof.

[0060] 33) A further embodiment relates to the process according to any one of embodiments 1) to 27), wherein the organic solvent is acetic acid (CH3C(O)OH).

[0061] 34) A further embodiment relates to the process according to any one of embodiments 1) to 33), wherein the volume of the organic solvent is between 1.5 and 20 liters per kilogram of the compound of formula (I). The lower limits of the volume of the organic solvent are 1.5, 2.0, 2.5 and 2.8 liters per kilogram of the compound of formula (I), and the upper limits are 20, 10, 5.0 and 3.3 liters per kilogram of the compound of formula (I). It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0062] 35) A further embodiment is a process for preparing a solvent comprising the steps of: and between 2.0 and 10 liters (particularly between 2.5 and 5.0 liters).

[0063] 36) A further embodiment relates to the process according to any one of embodiments 1) to 33), wherein the volume of the organic solvent is from 2.5 to 3.3 liters (in particular about 2.9 liters) per kilogram of compound of formula (I).

[0064] 37) A further embodiment relates to the process according to any one of embodiments 1) to 33), wherein the concentration of the compound of formula (I) in the organic solvent is between 20 and 30% w / w (in particular about 25% w / w).

[0065] 38) A further embodiment relates to the process according to any one of embodiments 1) to 37), wherein the amount of water is between 0.2 and 9.5 equivalents relative to the amount of the compound of formula (I). The lower limits of the amount of water are 0.2, 0.3, 0.5 and 0.8 equivalents, and the upper limits are 9.5, 5.0, 3.0 and 2.0 equivalents. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0066] 39) A further embodiment relates to the process according to any one of embodiments 1) to 37), wherein the amount of water is between 0.3 and 5.0 equivalents (in particular between 0.5 and 3.0 equivalents) relative to the amount of compound of formula (I).

[0067] 40) A further embodiment relates to the process according to any one of embodiments 1) to 37), in which the amount of water is between 0.5 and 2.0 equivalents (in particular between 0.8 and 2.0 equivalents) relative to the amount of compound of formula (I).

[0068] 41) A further embodiment is a compound of formula (I)

[0069] [ka]

[0070] (In the formula, R 1 and R 2 are the same and represent methyl or ethyl. with a hydrochloride salt in a mixture having an organic solvent and water; the hydrochloride is added to the reaction mixture as hydrochloride gas in an amount between 1.0 and 3.0 equivalents (particularly between 1.0 and 2.0 equivalents) relative to the amount of compound of formula (I); The organic solvent is acetic acid, methyl acetate (CH3C(O)OMe) or ethyl acetate (CH3C (O)OEt) or any mixture thereof (especially acetic acid), the concentration of the compound of formula (I) in said organic solvent being between 10 and 40% w / w (especially between 20 and 30% w / w); the amount of water is between 0.3 and 5.0 equivalents (particularly between 0.5 and 3.0 equivalents) relative to the amount of compound of formula (I); It relates to a method according to any one of embodiments 1) or 2).

[0071] 42) A further embodiment is a compound of formula (I)

[0072] [ka]

[0073] (In the formula, R 1 and R 2 are the same and represent methyl or ethyl. with a hydrochloride salt in a mixture having an organic solvent and water; The hydrochloride salt is (C 1-3 ) alkyl-C(O)Cl (especially CH3C(O)Cl) and (C 1-4 ) produced in situ by reaction of alkanols (especially ethanol), the amount of said hydrochloride salt generated in-situ is between 1.0 and 3.0 equivalents (particularly between 1.0 and 2.0 equivalents) relative to the amount of the compound of formula (I); the organic solvent is acetic acid, methyl acetate (CHC(O)OMe) or ethyl acetate (CHC(O)OEt) or any mixture thereof (in particular acetic acid) and the concentration of the compound of formula (I) in the organic solvent is between 10 and 40% w / w (in particular between 20 and 30% w / w); the amount of water is between 0.3 and 5.0 equivalents (particularly between 0.5 and 3.0 equivalents) relative to the amount of compound of formula (I); It relates to a method according to any one of embodiments 1) or 2).

[0074] 43) A further aspect is R 1 and R 2 are the same and represent ethyl.

[0075] 44) A further embodiment relates to the process according to any one of embodiments 41) to 43), wherein the organic solvent is acetic acid and the concentration of the compound of formula (I) in the organic solvent is between 20 and 30% w / w.

[0076] 45) A further embodiment relates to the process according to any one of embodiments 41) to 44), wherein the concentration of the compound of formula (I) in the organic solvent is about 25% w / w.

[0077] 46) A further embodiment relates to the process according to any one of embodiments 41) to 45), wherein the amount of water is between 0.8 and 2.0 equivalents relative to the amount of the compound of formula (I).

[0078] 47) A further embodiment relates to the process according to any one of embodiments 1) to 46), wherein the reaction is carried out at a temperature between 20° C. and 40° C. The lower limits of the reaction temperature are 20° C., 23° C., 25° C. and 27° C., and the upper limits are 40° C., 37° C., 35° C. and 33° C. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0079] 48) A further embodiment relates to the process according to any one of embodiments 1) to 46), in which the reaction is carried out at a temperature between 25° C. and 35° C. (in particular between 27° C. and 33° C.).

[0080] 49) A further embodiment relates to the process according to any one of embodiments 1) to 48), wherein the reaction mixture is stirred for a stirring time of at least 3 hours (particularly about 4 hours) before being treated with seeding crystals of "compound"·HCl.

[0081] The term "mixing time" refers to the time from the addition of the last reagent / reactant to the reaction mixture until the addition of the seed crystals. Preferably, the mixing time is between 3 and 8 hours, more preferably between 3.5 and 5 hours, and most preferably about 4 hours.

[0082] Preferably, the seed crystals of Compound·HCl are crystalline form 2 as described in WO2018 / 055016 or crystalline form (I) as described herein.

[0083] 50) A further embodiment relates to the process according to embodiment 49), wherein the seed crystals of "Compound"·HCl are in crystalline form 2 as described in WO2018 / 055016.

[0084] Seed crystals of crystalline form 2 may be obtained, for example, from the methods described in WO2018 / 055016 or from the methods described herein.

[0085] Seed crystals may be obtained by internal seeding, i.e., removing the sample from the reaction mixture, adding an anti-solvent (especially ethyl acetate) to the sample, and re-adding the resulting suspension to the reaction mixture. Preferably, 2.0-4.0 mL (most preferably about 2.5 mL) of ethyl acetate per gram of sample is added to the sample.

[0086] 51) A further embodiment relates to the process according to any one of embodiments 49) or 50), wherein the amount of seed crystals is between 0.1% w / w and 2.0% w / w, relative to the amount of compound of formula (I). The lower limits of the amount of seed crystals are 0.1, 0.2 and 0.3% w / w, and the upper limits are 2.0, 1.0 and 0.6% w / w. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are disclosed herein.

[0087] 52) A further embodiment relates to the process according to any one of embodiments 49) or 50), wherein the amount of seed crystals is between 0.1% w / w and 1.0% w / w (in particular between 0.1% w / w and 0.6% w / w) relative to the amount of compound of formula (I).

[0088] 53) A further embodiment is any one of embodiments 49) or 50), wherein the amount of seed crystals is between 0.2% w / w and 0.6% w / w relative to the amount of compound of formula (I). This article relates to a method for following one of the methods.

[0089] 54) A further embodiment relates to the process according to any one of embodiments 1) to 53), wherein an anti-solvent is added to the reaction mixture, the anti-solvent being selected from toluene, acetone, ethyl acetate (in particular acetone or ethyl acetate) or any mixture thereof.

[0090] 55) A further embodiment relates to the process according to embodiment 54), wherein the anti-solvent is ethyl acetate.

[0091] 56) A further embodiment relates to the process according to any one of embodiments 54) or 55), in which the volume of anti-solvent (in particular ethyl acetate) added is between 3.0 and 15 liters per kilogram of compound of formula (I). The lower limits of the volume of said anti-solvent are 3.0, 3.5, 4.0 and 4.5 liters per kilogram of compound of formula (I), and the upper limits are 15, 10, 7.0 and 6.0 liters per kilogram of compound of formula (I). It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0092] 57) A further embodiment relates to a process according to any one of embodiments 54) or 55), wherein the volume of anti-solvent (in particular ethyl acetate) added is between 3.5 and 7.0 liters per kilogram of compound of formula (I).

[0093] 58) A further embodiment relates to the process according to any one of embodiments 54) or 55), wherein the volume of ethyl acetate (anti-solvent) added is between 4.0 and 6.0 liters (in particular about 5.0 liters) per kilogram of compound of formula (I).

[0094] 59) A further embodiment relates to the process according to any one of embodiments 1) to 58), wherein the anti-solvent is added to the reaction mixture within 1 hour to 5 hours (in particular within 1.5 hours to 3 hours).

[0095] 60) A further embodiment relates to the process according to any one of embodiments 1) to 59), wherein the obtained precipitate is filtered and dried (or filtered, washed with a poor solvent (in particular ethyl acetate) and dried) to obtain "Compound"·HCl in solid form (hereinafter also referred to as precipitated "Compound"·HCl).

[0096] Reaction of compound of formula (I) with acetyl chloride (CHC(O)Cl, about 1.5 equivalents) and ethanol (about 2.5 equivalents) in acetic acid (about 3 vol) in the presence of water (about 2 equivalents) at about 30°C gives, after stirring, seeding with Compound·HCl in crystalline form 2 (as described in WO2018 / 055016), treatment with ethyl acetate (about 5 vol), filtration, washing with ethyl acetate and drying, Compound·HCl in crystalline form (I).

[0097] 61) A further embodiment relates to the method according to any one of embodiments 1) to 60), further comprising the step of recrystallizing the precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)) from a mixture of acetone and water.

[0098] 62) A further embodiment relates to the process according to embodiment 61), wherein the precipitated "Compound"·HCl (in particular "Compound"·HCl in crystalline form (I)) is dissolved in said mixture of acetone and water in a volume of between 3.0 and 25 liters per kilogram of precipitated "Compound"·HCl at a temperature between 35° C. and 65° C., the lower limits of the volume of said acetone / water mixture being 3.0, 3.2, 3.4 and 3.5 liters per kilogram of precipitated "Compound"·HCl; The upper limits are 25, 10, 7.0 and 5.0 liters per kilogram of precipitating "compound"·HCl. Each lower limit may be combined with each upper limit, such that all combinations are disclosed herein. The lower temperature limits are 35° C., 40° C. and 45° C., and the upper limits are 65° C., 60° C. and 55° C. Each lower limit may be combined with each upper limit, such that all combinations are disclosed herein.

[0099] Preferably, the precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)) is added to a mixture of acetone and water that has been pre-warmed to a temperature (e.g., between 35° C. and 65° C.).

[0100] 63) A further embodiment relates to the process according to embodiment 62), wherein the volume of said mixture of acetone and water is between 3.2 and 7.0 liters per kilogram of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)).

[0101] 64) A further embodiment relates to the process according to embodiment 62), wherein the volume of said mixture of acetone and water is between 3.4 and 5.0 liters (particularly 3.5±0.1 liters) per kilogram of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)).

[0102] 65) A further embodiment relates to the method according to any one of embodiments 62) to 64), wherein the temperature is between 40° C. and 60° C.

[0103] 66) A further embodiment relates to the method according to any one of embodiments 62) to 64), in which the temperature is between 45° C. and 55° C. (in particular 50° C.±2° C.).

[0104] 67) A further embodiment relates to the method according to any one of embodiments 61) to 66), wherein the ratio of acetone to water is between 2:1 v / v and 20:1 v / v. The lower limits of said ratio of acetone to water are 2:1 v / v, 5:2 v / v, 3:1 v / v and 7:2 v / v, and the upper limits are 20:1 v / v, 10:1 v / v, 7:1 v / v and 5:1 v / v. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0105] 67) A further embodiment relates to the method according to any one of embodiments 61) to 66), wherein the ratio of acetone to water is between 3:1 v / v and 7:1 v / v.

[0106] 68) A further embodiment relates to the method according to any one of embodiments 61) to 66), in which the ratio of acetone to water is between 7:2 v / v and 7:1 v / v (in particular between 7:2 v / v and 5:1 v / v).

[0107] 69) A further embodiment relates to the process according to any one of embodiments 61) to 68), wherein said solution of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)) in a mixture of acetone and water is diluted with acetone and / or treated with seed crystals of Compound·HCl at a temperature between 25° C. and 55° C. The lower limits of said temperatures are 25° C. and 30° C., and the upper limits are 55° C., 45° C. and 35° C. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0108] If the solution is diluted with acetone and treated with seed crystals, the seed crystals may be added before diluting the solution with acetone, or the solution may be diluted with acetone before adding the seed crystals. Add seed crystals before distilling.

[0109] 70) A further embodiment relates to the process according to embodiment 69), wherein the temperature of said solution of precipitated "Compound"·HCl (in particular "Compound"·HCl in crystalline form (I)) during dilution with acetone and / or treatment with seed crystals of "Compound"·HCl is between 25° C. and 35° C. (in particular 30° C.±2° C.).

[0110] 71) A further embodiment relates to a process according to any one of embodiments 69) or 70), wherein said solution of precipitated Compound·HCl (in particular of crystalline form (I) of Compound·HCl) in a mixture of acetone and water is diluted with acetone and treated with seed crystals of Compound·HCl.

[0111] 72) A further embodiment relates to the process according to any one of embodiments 69) to 71), wherein said solution of precipitated "Compound"·HCl (in particular "Compound"·HCl in crystalline form (I)) in a mixture of acetone and water is first diluted with acetone and then treated with seed crystals of "Compound"·HCl.

[0112] 73) A further embodiment relates to the process according to any one of embodiments 69) to 71), wherein said solution of precipitated "Compound"·HCl (in particular "Compound"·HCl in crystalline form (I)) in a mixture of acetone and water is first treated with seed crystals of "Compound"·HCl and then diluted with acetone.

[0113] 74) A further embodiment relates to the process according to any one of embodiments 69) to 73), wherein said solution of precipitated "Compound"·HCl (particularly "Compound"·HCl in crystalline form (I)) in a mixture of acetone and water is diluted with an amount of acetone between 6.0 and 20 liters per kilogram of precipitated "Compound"·HCl. Lower limits for the amount of acetone are 6.0, 8.0 and 10 liters per kilogram of precipitated "Compound"·HCl, and upper limits are 20, 17 and 14 liters per kilogram of precipitated "Compound"·HCl. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0114] 75) A further embodiment relates to the process according to any one of embodiments 69) to 73), wherein said solution of precipitated "Compound"·HCl (particularly "Compound"·HCl in crystalline form (I)) in a mixture of acetone and water is diluted with an amount of between 8.0 and 17 liters (particularly between 10 and 14 liters) of acetone per kilogram of precipitated "Compound"·HCl.

[0115] 76) A further embodiment relates to the process according to any one of embodiments 69) to 75), wherein the total volume of acetone (i.e. the volume of acetone in the acetone / water mixture used to dissolve the precipitated "compound"·HCl plus the volume of acetone used to dilute said solution of precipitated "compound"·HCl in a mixture of acetone and water) is between 12 and 35 liters per kilogram of precipitated "compound"·HCl (particularly "compound"·HCl in crystalline form (I)). The lower limits of the total volume of acetone are 12, 13.5 and 15 liters per kilogram of precipitated "compound"·HCl, and the upper limits are 35, 25, 20 and 17 liters per kilogram of precipitated "compound"·HCl. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are disclosed herein.

[0116] 77) A further embodiment is the method according to any one of embodiments 69) to 75), wherein the total volume of acetone is between 13.5 and 20 liters (particularly between 15 and 20 liters) per kilogram of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)). Regarding the law.

[0117] 78) A further embodiment relates to the process according to any one of embodiments 69) to 75), wherein the total volume of acetone is between 15 and 17 liters per kilogram of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)).

[0118] 79) A further embodiment relates to a process according to any one of embodiments 69) to 78), wherein said dilution of the solution of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)) in a mixture of acetone and water is carried out within 1 hour to 10 hours (particularly within 3 hours to 6 hours, especially between 3 hours and 4 hours).

[0119] 80) A further embodiment relates to the method according to any one of embodiments 69) to 79), in which the seed crystals of "Compound"·HCl are crystalline form 2 of "Compound"·HCl as described in WO2018 / 055016.

[0120] 81) A further embodiment relates to the process according to any one of embodiments 69) to 80), wherein the amount of said seed crystals of "Compound"·HCl (in particular of "Compound"·HCl in crystalline form 2 as described in WO2018 / 055016) is between 0.05% w / w and 5.0% w / w relative to the amount of precipitated "Compound"·HCl (in particular of "Compound"·HCl in crystalline form (I)). The lower limits for the amount of seed crystals are 0.05, 0.1, 0.2 and 0.4% w / w, and the upper limits are 5.0, 2.0, 1.0 and 0.6% w / w. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0121] Seed crystals of crystalline form 2 may be obtained, for example, from the methods described in WO2018 / 055016 or from the methods described herein. Seeding may be obtained by removing the sample from a solution of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)) in a mixture of acetone and water, adding this solution to acetone, and re-adding the resulting suspension to a solution of precipitated Compound·HCl in a mixture of acetone and water. Preferably, 5-40 mL (more preferably 10-20 mL, most preferably about 15 mL) of acetone per milliliter of sample is used for internal seeding at RT.

[0122] 82) A further embodiment relates to the process according to embodiment 81), wherein the amount of seed crystals is between 0.1% w / w and 2.0% w / w (particularly between 0.4% w / w and 2.0% w / w) relative to the amount of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)).

[0123] 83) A further embodiment relates to the process according to embodiment 81), wherein the amount of seed crystals is between 0.2% w / w and 1.0% w / w (particularly between 0.4% w / w and 0.6% w / w) relative to the amount of precipitated Compound·HCl (particularly Compound·HCl in crystalline form (I)).

[0124] 84) A further embodiment relates to the process according to any one of embodiments 61) to 83), wherein said mixture (in particular said suspension obtained from said solution of precipitated "Compound"·HCl (in particular "Compound"·HCl in crystalline form (I)) in a mixture of acetone and water after dilution with acetone and / or treatment with seed crystals of "Compound"·HCl) is cooled to a temperature between 0° C. and 20° C. (in particular between 0° C. and 10° C.) and the precipitate is isolated and optionally washed with acetone. Isolation of the precipitate from the mother liquor may be carried out by any means suitable for separating solids from liquids, such as filtration (preferred) or centrifugation. "Isolating the precipitate and optionally washing with acetone" The term "optionally" used in the context of "washing with acetone" means that the step of washing the precipitate with acetone may or may not be present in the process.

[0125] 85) A further embodiment relates to the process according to embodiment 84), wherein the isolated precipitate is dried under vacuum until the water content in the isolated precipitate is between 4.0% w / w and 8.2% w / w (preferably between 5.0% w / w and 7.0% w / w). The water content may be measured by Karl Fischer titration. The obtained product is "Compound"·HCl in crystalline form 2 as described in WO2018 / 055016.

[0126] 86) A further embodiment is a compound of formula (II)

[0127] [ka]

[0128] (In the formula, R 1 and R 2 are, independently of each other, (C1-4 ) represents alkyl. with a compound of formula (III)

[0129] [ka]

[0130] (In the formula, R 5 represents hydrogen, sodium or potassium (especially sodium). to obtain a compound of formula (I).

[0131] 87) A further aspect is R 1 and R 2 and each represents ethyl.

[0132] 88) A further aspect is R 5 represents sodium.

[0133] Preferably, the compound of formula (III) is a sodium salt (R 5 represents sodium.) is used as a

[0134] 89) A further embodiment relates to the process according to any one of embodiments 86) to 88), wherein the reaction is carried out in the presence of a mixture of EDC and HOBt.

[0135] 90) A further embodiment relates to the process according to any one of embodiments 86) to 89), wherein the reaction is carried out in a mixture of solvents selected from two or three of THF, toluene and water, in particular THF and water.

[0136] 91) A further embodiment relates to the process according to any one of embodiments 86) to 90), in which the reaction is carried out at a pH value between 4.5 and 6.0 (in particular between 4.8 and 5.5).

[0137] Compounds of formula (III) may be obtained by reaction of compounds of formula (IV) with aqueous sodium hydroxide in 2-propanol.

[0138] [ka]

[0139] The reaction may be carried out at an elevated temperature (e.g., at about 80° C.) and the compound of formula (III) may be isolated by crystallization (e.g., by cooling from about 80° C. to about 20° C.). Preferably, the reaction mixture is cooled slowly (at least 4 h) from about 80° C. to about 20° C. to improve the filterability of the resulting crystals. For example, the reaction mixture is cooled from about 80° C. to about 50° C. in 2 h, held at about 50° C. for an additional 30 min, and further cooled to about 20° C. within 4 h. The resulting crystals may be washed with toluene and dried.

[0140] 91) A further embodiment is a compound of formula (V)

[0141] [ka]

[0142] (In the formula, R 1 and R 2 are, independently of each other, (C 1-4 ) represents alkyl. with TFA to obtain a compound of formula (II).

[0143] 92) A further aspect is R 1 and R 2 and each represents ethyl.

[0144] 93) A further embodiment relates to a process according to any one of embodiments 91) or 92), wherein a solution of compound of formula (V) in toluene is added to TFA at a temperature between 30° C. and 60° C. The lower limits of said temperatures are 30° C., 35° C. and 40° C., and the upper limits are 60° C., 55° C. and 50° C. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0145] 94) A further embodiment relates to a process according to any one of embodiments 91) or 92), wherein a solution of a compound of formula (V) in toluene is added to TFA at a temperature between 40° C. and 50° C. (particularly about 45° C.).

[0146] 95) A further embodiment relates to the process according to any one of embodiments 93) or 94), wherein the amount of compound of formula (V) in said solution in toluene is between 50% w / w and 85% w / w. The lower limits for the amount of compound of formula (V) in said solution in toluene are 50% w / w, 60% w / w and 70% w / w, and the upper limits are 85% w / w and 80% w / w. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0147] 96) A further embodiment relates to a process according to any one of embodiments 93) or 94), wherein the amount of compound of formula (V) in said solution in toluene is between 60% w / w and 85% w / w (in particular about 70% w / w).

[0148] 97) A further embodiment relates to the process according to any one of embodiments 91) to 96), wherein the volume of TFA is between 0.5 and 1.5 liters per kilogram of compound of formula (V). The lower limits of the volume of TFA are 0.5, 0.7 and 0.9 liters per kilogram of compound of formula (V), and the upper limits are 1.5, 1.3 and 1.1 liters per kilogram of compound of formula (V). It is understood that each lower limit can be combined with each upper limit. Thus, all combinations are intended to be disclosed herein.

[0149] 98) A further embodiment relates to the process according to any one of embodiments 91) to 96), wherein the volume of TFA is between 0.7 and 1.3 liters (in particular about 1.0 liter) per kilogram of compound of formula (V).

[0150] 99) A further embodiment is a compound of formula (VI)

[0151] [ka]

[0152] (In the formula, R 1 and R 2 are, independently of each other, (C 1-4 ) is alkyl. with a compound of formula (VII)

[0153] [ka]

[0154] to obtain a compound of formula (V).

[0155] 100) A further aspect is R 1 and R 2 and each represents ethyl.

[0156] 101) A further embodiment is the reaction of 2,4,6-tripropyl-1,3,5,2 λ5 ,4 λ5 ,6 λ5 -trioxatriphosphinane 2,4,6-trioxide (T3P) or a mixture of EDC and HOBt, according to any one of embodiments 99) or 100).

[0157] 102) A further embodiment relates to the process according to any one of embodiments 99) to 101), wherein the reaction is carried out in a solvent selected from ethyl acetate, toluene, and a mixture of THF and water.

[0158] 103) A further embodiment is the reaction of 2,4,6-tripropyl-1,3,5,2 λ5 ,4 λ5 ,6 λ5 -trioxatriphosphinane 2,4,6-trioxide (T3P) and in a solvent selected from ethyl acetate and toluene, in particular toluene.

[0159] 104) A further embodiment is the method of claim 1, wherein the volume of the solvent is and the volume is between 3.5 liters and 7.5 liters (in particular about 3.9 liters).

[0160] 105) A further embodiment relates to the process according to any one of embodiments 99) to 104), wherein a solution of T3P (particularly T3P in an amount of about 1.03 equivalents relative to the amount of the compound of formula (VI)) in toluene is added to a mixture of a compound of formula (VI), a compound of formula (VII) (particularly a compound of formula (VII) in an amount of about 1.03 equivalents relative to the amount of the compound of formula (VI)) and triethylamine (particularly triethylamine in an amount of about 3.5 equivalents relative to the amount of the compound of formula (VI)) in toluene.

[0161] 106) A further embodiment relates to the process according to any one of embodiments 99) to 105), in which the reaction is carried out at a temperature between -5°C and 25°C (in particular between 10°C and 20°C).

[0162] 107) A further aspect of the present invention relates to a crystalline form (I) of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride ("Compound"·HCl), characterized by the presence of peaks at the following refraction angles 2θ: 5.7°, 5.9° and 12.9° in an X-ray powder diffraction diagram.

[0163] The crystalline form according to embodiment 107) is intended to include the "compound"·HCl in the form of hydrochloric acid salt (hydrochloride). Furthermore, the crystalline form may contain non-coordinating and / or coordinating solvents (particularly non-coordinating and / or coordinating water). Coordinating solvents (particularly coordinating water) are used herein as a term for crystalline solvates (particularly crystalline hydrates). For the avoidance of doubt, in this application the term "crystalline hydrate" includes non-stoichiometric hydrates. Similarly, non-coordinating solvents are used herein as a term for physically adsorbed or physically trapped solvents (as defined by Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates).

[0164] 108) Another embodiment relates to a crystalline form of the "Compound"·HCl according to embodiment 107), characterized by the presence of peaks at the following refraction angles 2θ: 5.1°, 5.7°, 5.9°, 11.0°, and 12.9° in a powder X-ray diffraction diagram.

[0165] 109) Another embodiment relates to a crystalline form of the "Compound"·HCl according to embodiment 107), characterized by the presence of peaks at the following refraction angles 2θ: 3.7°, 5.1°, 5.7°, 5.9°, 11.0°, 12.9°, 15.2°, 18.3°, 20.2° and 21.0° in a powder X-ray diffraction diagram.

[0166] 110) Another embodiment relates to a crystalline form of the "compound"·HCl according to embodiment 107), exhibiting an X-ray powder diffraction pattern essentially as shown in FIG. 1.

[0167] Abbreviations and Terms Used herein Abbreviation: The following abbreviations are used throughout the specification and examples: Ac Acetyl AcCl Acetyl chloride AcOH Acetic acid AcOEt Ethyl acetate AcOMe Methyl acetate Aq Water-based Boc tert.-Butyloxycarbonyl dba Dibenzylideneacetone DCM Dichloromethane EDC N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride eq. equivalent amount Et Ethyl h time HOBt Hydroxybenzotriazole HPLC High Performance Liquid Chromatography IPA 2-Propanol IPAc Isopropyl acetate IPC In-Process Control JT Jacket temperature M Molar concentration Me Methyl min NMP 1-Methyl-2-pyrrolidone NMR nuclear magnetic resonance org.organic ot theoretical RT room temperature %a / a Percentage determined by area ratio T3P 2,4,6-tripropyl-1,3,5,2 λ5 ,4 λ5 ,6 λ5 -Trioxatriphosphinane 2,4,6-trioxide THF Tetrahydrofuran TFA Trifluoroacetic acid TMSBr Trimethylsilyl bromide Vol 1 vol means 1 L of solvent per kg of relevant starting material

[0168] Experimental section X-ray powder diffraction analysis (XRPD) Powder X-ray diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operating in reflection mode (coupled 2 theta / theta). Typically, a Cu-X-ray tube was scanned at 40 kV / 40 mA. A step size of 0.02° (2θ) and a step time of 76.8 seconds were applied over a scan range of 3-50° 2θ. The divergence slit was set to fixed sample illumination (variable slit size) and the antiscatter slit was set to 0.3°. The powder was lightly pressed into a silicon single crystal sample holder with a depth of 0.5 mm and the sample was rotated in its own plane during the measurement. Diffraction data are reported using Cu Kα (λ=1.5418 Å) radiation. As is typical for previously recorded powder X-ray diffraction patterns, the accuracy of the 2θ values ​​provided herein is within the range of + / - 0.1-0.2°.

[0169] High-performance liquid chromatography (HPLC) HPLC system: Agilent 1100 / 1200 / 1260 series system equipped with online degasser, low pressure quaternary pump, autosampler, temperature controlled column compartment and diode array detector. Flow rate: 1.0 mL / min. Column temperature: 15℃ Autosampler temperature: 5±1℃ Injection volume: 10 μL Column: Agilent Zorbax SB C18, 150x4.6mm, 3.5μm Wavelength: 263nm Solvent A: Water / methanol / TFA 95:5:0.5 v / v / v Solvent B: Water / methanol / TFA 5:95:0.5 v / v / v

[0170] [Table 1]

[0171] [Table 2]

[0172] Example 1: Synthesis of (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonitrile: A 100 mL Schlenk tube was flushed with nitrogen three times. The tube was charged with NMP (30.0 ml, 1.5 vol), the NMP was degassed for three cycles (vacuum / nitrogen), Pd2dba3 (0.38 g, 0.41 mmol, 0.006 eq.) and 1,1'-bis(diphenylphosphino)ferrocene (0.57 g, 1.04 mmol, 0.015 eq.) were added, and the mixture was again degassed for three cycles (vacuum / nitrogen) at JT≦30° C. Nitrogen was then bubbled through the mixture for 15 min, and the solution was then stirred at 20-30° C. for 30 min.

[0173] A 500 mL reactor was charged with (S)-4-chloro-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine (20.0 g, 69.02 mmol, 1.00 eq.), Zn(CN)2 (4.46 g, 37.96 mmol, 0.55 eq.), toluene (60 mL, 3.0 vol) and NMP (30 mL, 1.5 vol). The loose slurry was degassed for 3 cycles (vacuum / nitrogen) at JT≦30°C. The mixture was then bubbled with nitrogen for 15 min and the solution was then stirred at 20-30°C for 30 min. The mixture was warmed to 80-115°C (target: 110°C) and the catalyst solution was added over 2 h at 80-115°C (target: 110°C). After addition was complete, the mixture was cooled to 105-115°C (target: 110°C). The mixture was stirred at RT for 30 min.

[0174] A 500 mL reactor was charged with toluene (200.0 mL, 10.0 vol), ammonia 25% (44.0 mL, 2.2 vol) and water (100.0 mL, 5.0 vol) and stirred at 30-40°C, and the reaction mixture was added to the emulsion at 30-40°C. After addition was complete, the emulsion was stirred for 30 min at 30-40°C, and the phases were allowed to separate for 5 min. The organic phase was then extracted three times with a previously prepared (gas is generated during preparation!) solution of N-acetyl-L-cysteine ​​(5.6 g, 34.32 mmol, 0.5 eq.), soda (8.0 g, 66.04 mmol, 0.96 eq.) and water (100.0 ml, 5.0 vol) for 30 min at 25-35°C, and the phases were allowed to separate for 5 min. The organic phase was then extracted twice with water (100.0 mL, 5.0 vol) at 30-35°C and the phases were allowed to separate for 5 min. The organic phase was then concentrated to 5.0 vol at 40-60°C under reduced pressure (typically 150-300 mbar). Distillation was continued at 40-60°C under reduced pressure (typically 50-200 mbar) while maintaining a constant volume by adding IPA (500.0 mL, 25.0 vol). The product precipitated during the distillation. IPA (40.0 mL, 2.0 vol) was added and the slurry was warmed to 75-82°C and post stirred at this temperature for 30 min. The solution was then cooled to 60-70°C in 60 min and post stirred at 60-70°C for 60 min. The slurry was then cooled to 0-10°C in 4 h and post stirred at 0-10°C for 2 h. The solid was filtered at 0-10° C. and the filter cake was washed (displacement) twice with IPA (40.0 mL, 2.0 vol) at 0-25° C. The wet product was dried in a cabinet at 50° C. to constant weight to give the product (16.2 g) as a solid.

[0175] Recrystallization: A 500 mL reactor was flushed with nitrogen three times and charged with crude (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonitrile (20.0 g, 71.34 mmol), activated carbon (Norit CGP Super) and IPAc (200 mL, 10.0 vol) at JT≦40° C. The slurry was then warmed to 65-75° C. and post-stirred at 65-75° C. for 60 min. The solution was filtered through a conditioned (approximately 75° C.) pressure filter into a second 500 mL reactor. The first reactor and filter were rinsed with IPAc (40.0 ml, 2.0 vol). The solution was concentrated to 4-5 vol at 85-95° C. and atmospheric pressure. Heptane (160.0 mL, 8.0 vol) was added at 85-95°C and the solution was then cooled to 65-75°C in 60 min. The resulting slurry was cooled to 0-10°C in 3 h and post-stirred at 0-10°C for 2 h. The solid was filtered at 0-10°C and the filter cake was washed (displaced) twice with IPAc / heptane 1:2 v / v at 0-25°C. The wet product was dried in a cabinet at 50°C to constant weight to give the product (16.8 g) as a solid.

[0176] Example 2: Synthesis of (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid sodium salt: A 500 mL reactor was flushed with nitrogen three times, charged with water (323 mL, 6.5 vol) and warmed to 20-40°C. (S)-6-(3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonitrile (50.0 g, 178 mmol, 1.0 eq.) and 2-propanol (532 mL, 10.6 vol) were added and the reaction mixture was warmed to 70-85°C. Aqueous sodium hydroxide (30%, 29 mL, 0.58 vol) was added via addition funnel over 30 min and the funnel was rinsed with water (5.0 mL, 0.1 vol). The reaction mixture was stirred at 75-85°C for at least 6 h, cooled to 45-55°C over at least 2 h and further stirred at 45-55°C. The mixture was stirred for 30 min. The resulting suspension was cooled to 15-25°C over at least 4 h and stirred at 15-25°C for at least 30 min. The product was filtered and the filter cake was washed first with a mixture of 2-propanol (136 mL) and water (14 mL) and then with toluene (150 mL). The wet product was dried under vacuum at 45-55°C to give the product as a solid.

[0177] Example 3: Synthesis of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride in crystalline form 2 (as described in WO2018 / 055016): Step 1: Synthesis of 4-[(R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid butyl ester: A 2.5 L glass reactor equipped with a mechanical stirrer and dropping funnel was charged with toluene (780 mL, 3.9 vol), (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid (200 g, 614.8 mmol, 1.0 eq.), piperazine-1-carboxylic acid butyl ester hydrochloride (141.0 g, 633.3 mmol, 1.03 eq.) and triethylamine (217.75 g, 2152 mmol, 3.5 eq.) and the temperature of the light slurry was adjusted to 10-20 °C. T3P 50% w / w in toluene (430.4 g, 676.30 mmol, 1.10 eq.) was directly dosed into the reaction mixture over 1-2 h at 10-20° C. The dosage system was then rinsed with 20 mL of toluene (0.1 vol). The reaction mixture was aged for at least 1 h. The reaction mixture was transferred into an Erlenmeyer flask and water (800 mL, 4 vol) was charged to the reactor. The reaction mixture was quenched over at least 10 min at 10-25° C. on the water charged to the reactor. Caustic soda 30% w / w (123.0 g, 922.2 mmol, 1.5 eq.) was then charged over at least 10 min at 10-25° C. Maximum volume: 2.6 L, 13 vol. The lower aqueous layer was drained off at 15-25°C (fast phase separation, no interphase). Water (200mL, 1vol) was added to the organic layer and the pH was adjusted to 2.5-3.0 with 30% w / w sulphuric acid (approximately 241g) at 15-25°C. The lower aqueous layer was drained off (fast phase separation, no interphase). Water (200mL, 1vol) was added to the organic layer and the mixture was stirred for at least 5min. The phases were allowed to separate for at least 30min and the lower aqueous layer was drained off. The organic layer was concentrated to approximately 30% w / w at 40-60°C (p=100-300mbar) to give a clear yellow solution.

[0178] Step 2: Synthesis of 4-[(R)-2-amino-3-(diethoxy-phosphoryl)-propionyl]-piperazine-1-carboxylic acid butyl ester The batches were calculated based on the amount of (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid used in the preparation of Stage 1. A 1.0 L glass reactor equipped with a mechanical stirrer, dropping funnel and distillation adaptor was charged with the solution of step 1 in toluene (500 g, prepared from 100 g (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid). The solution was concentrated to 215 g at 40-60° C. (50-250 mbar) and transferred to the dropping funnel. The reactor was then charged with TFA (150 mL, 1.5 vol with respect to (R)-2-tert-butoxycarbonylamino-3-(diethoxy-phosphoryl)-propionic acid) and the temperature was adjusted to 45° C. The solution of step 1 was then added dropwise over 2 h at 45° C. (addition with controlled gas evolution). The batch was aged for 1 h and then distillation was started at 45-50° C. and 150 mbar. The pressure was gradually reduced to 100 mbar while the temperature was maintained at 45-50 °C. The total post-mixing time including distillation was 4 h. The reaction mixture was cooled to 10-25 °C with a mixture of water (300 mL, 3 vol) and 25% ammonia (167.6 g, 8.0 eq.). The mixture was quenched. Dichloromethane (300mL, 3vol) was added at 10-25°C. The lower DCM layer was separated and the aqueous layer was re-extracted twice with DCM (150ml, 1.5vol). The DCM layers were combined and washed with 20% aqueous KHCO3 (100mL, 1vol). Toluene was added (92mL, 0.9vol) and the organic layer was concentrated at 40-60°C (stopping distillation at >60°C). More toluene (258mL, 2.6vol) was then added and the solution was concentrated to 300g at 40-60°C (100-400mbar) to give the product as a yellow solution.

[0179] Step 3: Synthesis of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester: Stage 2 (100 g, 254.18 mmol, 1.0 eq., based on titration) was charged as a solution in toluene (approximately 226 g, 44.2% w / w) and water (200 mL, 2 vol) was added. The pH was adjusted to 4.0-5.0 with 33% aqueous HCl (approximately 28 g) at 15-25°C. The stage 2 containing aqueous layer was separated and the organic layer was discarded. The aqueous stage 2 solution was diluted with 3% HOBt monohydrate in THF (274.8 g, 7.8 g HOBt monohydrate + 300 mL THF) and (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylic acid sodium salt (83.3 g, 259 mmol, 1.02 eq.) was added. The pH of the light slurry was adjusted to 5.0-5.5 (target: 5.2) with 33% HCl. EDC (58.47 g, 305.02 mmol, 1.2 eq.) was added in at least 10 portions over at least 1 h at 15-25 °C. The pH of the reaction mixture was monitored and maintained in the range of 4.5-5.5 by addition of 10% K2CO3 or 33% aqueous HCl (few milliliters). The pH remained stable throughout the addition, only dropping to <5.0 towards the end of the addition. During the addition, the reaction mixture became biphasic and the solids gradually dissolved. The reaction mixture was stirred at 15-25 °C for 3 h. The reaction mixture was diluted with toluene (150 mL, 1.5 vol) and the aqueous layer was drained at 15-25 °C. Toluene (150 mL, 1.5 vol) was added at 15-25 °C and the organic layer was washed successively with 10% w / w aqueous K2CO3 (2x150 mL, 2x1.5 vol) and water (100 ml, 1 vol). Toluene (150 mL, 1.5 vol) was added to the organic phase and the product solution was concentrated to <300 g at 40-60 °C (150-300 mbar), diluted with acetic acid (500 mL, 5 vol) and concentrated to <550 g at 40-60 °C (50-200 mbar); IPC: THF <= 0.5% a / a, toluene <= 5.0% a / a, water <= 0.5% w / w. The weight of the solution was adjusted to 686 g (25% w / w, calculated based on theoretical yield) by addition of acetic acid.

[0180] Step 4: Synthesis of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride in crystalline form (I): To a solution of step 3 (171.5 g, 254.18 mmol) in AcOH (490 mL, 2.9 vol) was added ethanol (29.3 g, 635.45 mmol, 2.5 eq.). Acetyl chloride (29.9 g, 381.27 mmol, 1.5 eq.) was then added dropwise over at least 20 min while maintaining the temperature at 25-35° C. The reaction mixture was stirred at 30° C. for 4-5 h and then seeded with 0.5 g of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride and stirred at 30° C. for 30 min. The resulting slurry was then stirred at 30° C. for a further 14 h. AcOEt (860 mL, 5 vol) was added dropwise over at least 2 h at 30° C. The slurry was cooled to 20° C. over 1 h, aged for at least 2 h, and then filtered. The wet product was washed with AcOEt (345 mL, 2 vol), followed by a displacement wash (di The wet product was dried in a cabinet at 45° C. with carrying gas until constant weight was obtained, giving the product (159.4 g, uncorrected) as a white to off-white crystalline solid.

[0181] [Table 3]

[0182] Step 5: Synthesis of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride in crystalline form 2 (as described in WO2018 / 055016): Step 4 (30.0 g, 91.7% w / w, 42.0 mmol) was charged to a reactor and acetone / water 4:1 v / v (105 mL, 3.5 vol, pre-warmed to 50° C.) was added to form a clear solution. The solution was cooled to 30° C., seeded with 0.5 g seed crystals of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride and stirred at 25-35° C. for 30 min. To the resulting slurry was added acetone (360 mL, 12 vol) over 3 h at 25-35° C. The slurry was cooled to 0-10° C. over 2 h, post-stirred at 0-10° C. for 60 min, then filtered. The wet product was washed with acetone (2x75mL, 2.5vol).The wet product was dried to constant weight in a rotary evaporator at 20-35°C with carrying gas (nitrogen gas saturated with water) to give the product as a white solid in crystalline form 2 (described in WO2018 / 055016) in 92% yield.

[0183] Alternatively, the moist product may be dried in the absence of a carrying gas to a water content of 8.2% w / w or less.

[0184] Reference Example 1: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester in a mixture of DCM and concentrated hydrochloric acid: 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy A solution of (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (1.05 g) in DCM (4.0 vol) was split evenly between two 25 mL screw topped vials. The solution was treated with 1.8 vol or 3.6 vol of 32% w / w aqueous HCl and stirred at RT. Samples were taken at the time points listed in Table 2 and analyzed by HPLC to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid ("hydrolysis product"):

[0185] [Table 4]

[0186] Reference Example 2: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester in concentrated hydrochloric acid: A mixture of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (200 mg, 0.30 mmol) in 37% w / w aqueous HCl was stirred under the conditions described in Table 3. Samples were taken at the time points described in Table 3 and analyzed by HPLC to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid ("hydrolysis product"):

[0187] [Table 5]

[0188] Reference Example 3: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester in dilute hydrochloric acid: A mixture of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (200 mg, 0.30 mmol) in a mixture of 37% w / w aqueous HCl and water (see Table 4) was added to obtain the elution products shown in Table 4. Stirring was performed at RT under the conditions described. Samples were taken at the time points described in Table 4 and analyzed by HPLC to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid ("hydrolysis product"):

[0189] [Table 6]

[0190] Example 4: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester with HCl in acetone: A mixture of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (200 mg, 0.30 mmol) in acetone and HCl (see Table 5) was stirred at RT under the conditions described in Table 5. Samples were taken at the time points described in Table 5 and analyzed by HPLC to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid ("hydrolysis product"):

[0191] [Table 7]

[0192] Example 5: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester with HCl in different solvents: HCl gas was gently bubbled through a solution of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester in each solvent (see Table 6) for 20 min, and the mixture was heated at RT under the conditions described in Table 6. Samples were taken at the time points listed in Table 6 and analyzed by HPLC to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)-3-phosphonopropanoic acid ("hydrolysis product"):

[0193] [Table 8]

[0194] Example 6: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester with in-situ generated HCl: A mixture of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (1.0 g), AcO (4.95 eq.) and concentrated aqueous HCl (32% w / w, 1.5 eq) in AcOH (2.0 vol) was stirred at RT for 1.5 h, seeded with crystals of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride and stirred further at RT. After 14 h, the reaction was diluted with AcOH (4 vol) and samples were taken at the time points listed in Table 7 to determine the relative amount of the hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)-3-phosphonopropanoic acid ("hydrolysis product"):

[0195] [Table 9]

[0196] Example 7: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester with in-situ generated HCl: Mixtures of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (1.0 g), AcCl (1.5 eq.) and ethanol (2.5 eq.) in different volumes of AcOH (see Table 8) were stirred at RT. Samples were taken at the time points listed in Table 8 to determine the relative amount of hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropanoic acid ("hydrolysis product"):

[0197] [Table 10]

[0198] Example 8: Cleavage of the diethoxy-phosphoryl group of 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester with in-situ generated HCl: A mixture of starting material (SM) 4-((R)-3-(diethoxy-phosphoryl)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid butyl ester (20 g), AcCl (1.5 eq.) and ethanol (2.5 eq) in AcOH (3 vol) was stirred at 35° C. for 4 h, seeded with crystals of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, stirred at 35° C. for a further 4 h and cooled to RT. Samples were taken at the time points listed in Table 9 to determine the hydrolysis product (R)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamide)-3-phosphonopropane. The relative amounts of acids ("hydrolysis products") were determined:

[0199] [Table 11]

[0200] Example 9: Alternative procedure for the synthesis of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride in crystalline form 2 (as described in WO2018 / 055016): a) Compound·HCl (2.0 g, 3.1 mmol) was dissolved in 44 mL of acetone and 2.3 mL of water at 65 °C. The solution was cooled to 55 °C, seeded with crystalline form 2 of Compound·HCl, 3%, and stirred for 1 h. The mixture was cooled to 15 °C at 3 °C / h to give crystalline form 2 of Compound·HCl (60% yield).

[0201] b) "Compound"·HCl (2.0 g, 3.1 mmol) was dissolved in 6 mL of acetone and 3.5 mL of water at RT. The solution was added at a rate of 10 mL / h to a cooled mixture (5 °C) of 60 mL of acetone containing 50 mg of seed crystals of "Compound"·HCl in crystalline form 2 and stirred overnight to give "Compound"·HCl in crystalline form 2 (78% yield).

[0202] c) "Compound"·HCl (5.0 g, 7.6 mmol) was dissolved in a mixture of acetone and water (4:1 v / v, 20 mL) at 50 °C. The solution was diluted with acetone (32.5 mL) and treated with seed crystals (100 mg) of "Compound"·HCl in crystalline form 2. Acetone (38 mL) was added to the mixture within 1 h and the mixture was cooled to 5 °C at 2.8 °C / h to give "Compound"·HCl in crystalline form 2 (78% yield).

[0203] d) Compound·HCl (18 g, 27.5 mmol) was dissolved in a mixture of acetone and water (4:1 v / v, 63 mL) at 65 °C. The solution was cooled to 30 °C, treated with seed crystals of Compound·HCl (90 mg) of crystalline form 2, and stirred for 1 h. Acetone (216 mL) was added to the mixture within 1.5 h. The mixture was stirred for 1 h, cooled to 5 °C at 5 °C / h, and stirred for another 2 h to give Compound·HCl of crystalline form 2 (yield 87%).

Claims

1. A process for preparing butyl 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylate (the "compound") or a hydrochloride salt thereof, comprising 【Chemical 1】 reacting a compound of formula (I) [Chemical Formula 2] (wherein, R １ and R ２ each independently represent (C １－４ ) alkyl.) with a hydrochloride salt in a mixture comprising an organic solvent and water, The above organic solvent is acetone, toluene, R ３ C(O)OR ４ or any mixture thereof, R ３ represents hydrogen or (C １－２ ) alkyl, and R ４ represents hydrogen or (C １－３ ) alkyl; wherein the amount of water is less than 12 equivalents relative to the amount of the compound of formula (I); A process.

2. R １ and R ２ are the same and represent methyl, ethyl, n-propyl or isopropyl, the method according to claim 1.

3. R １ and R ２ The method according to claim 1, wherein both are ethyl.

4. The process according to claim 1, wherein the hydrochloride salt is added to the reaction mixture as hydrochloric acid gas or the hydrochloride salt is generated in situ by reaction of an electrophilic chloride source with a protic nucleophile.

5. The process according to claim 1, wherein the hydrochloride salt is generated in situ by reaction of an electrophilic chloride source with a protic nucleophile.

6. The hydrochloride salt is formed in-situ by reaction of an electrophilic chloride source selected from (C １－３ ) alkyl-C(O)Cl with a protic nucleophile selected from water and (C １－４ ) alkanol, according to the method of claim 4 or 5.

7. The process according to any one of claims 1 to 5, wherein the amount of the hydrochloride salt added to the reaction mixture as hydrochloric acid gas or generated in situ by reaction of an electrophilic chloride source with a protic nucleophile is between 0.9 and 5.0 equivalents relative to the amount of the compound of formula (I).

8. The organic solvent is R ３ C(O)OR ４ or any mixture thereof, where R ３ represents hydrogen or (C １－２ )alkyl, and R ４ represents hydrogen or (C １－３ )alkyl. The method according to any one of claims 1 to 5.

9. The process according to any one of claims 1 to 5, wherein the organic solvent is acetic acid.

10. The process according to any one of claims 1 to 5, wherein the amount of water is between 0.8 and 2.0 equivalents relative to the amount of the compound of formula (I).

11. The process according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature between 20 °C and 40 °C.

12. The process according to any one of claims 1 to 5, wherein a poor solvent is added to the reaction mixture, and the poor solvent is selected from acetone, ethyl acetate or any mixture thereof.

13. The process according to any one of claims 1 to 5, further comprising the step of recrystallizing crystalline form (I) of the "compound"·HCl from a mixture of acetone and water.

14. A crystalline form of butyl 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylate hydrochloride, characterized by the presence of peaks at the following diffraction angles 2θ in the powder X-ray diffraction diagram: 5.7°, 5.9° and 12.9°. **Claim 15** The crystalline form according to claim 14, characterized by the presence of peaks at the following diffraction angles 2θ in the powder X-ray diffraction diagram: 5.1°, 5.7°, 5.9°, 11.0° and 12.9°. **Claim 16** The crystalline form according to claim 14, characterized by the presence of peaks at the following diffraction angles 2θ in the powder X-ray diffraction diagram: 3.7°, 5.1°, 5.7°, 5.9°, 11.0°, 12.9°, 15.2°, 18.3°, 20.2° and 21.0°.

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