A method of preparing a compound

Abstract

The present invention relates to a new and improved process for the preparation of (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid butyl ester of the formula (XII), to new precursors for the preparation thereof, and to the use thereof for the preparation of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid.

Description

[0001] This invention relates to novel and improved methods for preparing (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid butyl ester of formula (XII), novel precursors for its preparation, and its use in the preparation of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid.

[0002]

[0003] Compound (XII) is a precursor of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I).

[0004]

[0005] Compound (XII) can be converted into compound (I) by ester hydrolysis.

[0006] Compounds of formula (I) can be used as activators of soluble guanylate cyclases as agents for the prevention and / or treatment of lung, cardiopulmonary and cardiovascular diseases, such as for the treatment of pulmonary arterial hypertension (PAH), pulmonary arterial hypertension (PH), pulmonary arterial hypertension associated with chronic obstructive pulmonary disease (PH-COPD), pulmonary arterial hypertension associated with idiopathic interstitial pneumonia (PH-IIP) or chronic thromboembolic pulmonary hypertension (CTEPH).

[0007] Compound of formula (I) and its preparation method are described in WO 2014 / 012934.

[0008] The drawback of the synthesis described in 2014 / 012934 is that it is unsuitable for industrial-scale production because, among other reasons, it requires seven chromatographic purification steps and a chiral chromatographic stage to separate the enantiomers of a racemic mixture. These are typically technically complex and expensive, and consume large amounts of solvent, and should therefore be avoided whenever possible. Furthermore, the separation of enantiomers occurs in the later stages of the synthesis via chiral phase chromatography. This results in a high proportion of the product being unusable for further synthesis.

[0009] Some stages of the synthesis described in WO 2014 / 012934 are characterized by reaction times of several days and low yields, which are significant drawbacks for industrial-scale synthesis efficiency. For example, the reaction time for the preparation of Example 6A is 4 days, and for the preparation of Example 92A, it is 3 days. Furthermore, the use of excess methyl 4-(2-iodoethyl)benzoate in the preparation of Example 92A can lead to polymerization. This forms polystyrene, which must be removed in a complex manner.

[0010] Due to safety and process difficulties, some stages cannot be implemented on an industrial scale. Some reaction stages are carried out at very high dilutions and use very large amounts of reagents, meaning that only a small amount of product can be produced relative to the volume of a batch. Furthermore, in WO4...

[0011] The synthesis disclosed in 2014 / 012934 involves 17 stages, which is why it is very expensive and time-consuming.

[0012] Therefore, there is a need for an industrially feasible synthesis that can reproducibly provide compounds of formula (I) in high total yield, at low production cost and with high purity, while meeting all regulatory requirements.

[0013] A feature of the method according to the invention is that the purification step of the intermediate is carried out by salt formation, thus eliminating the need for a chromatographic purification step. Enantioselective synthesis means that a chiral chromatographic stage is not required to separate the enantiomers of the racemic mixture. The number of synthetic stages in the method according to the invention has been reduced compared to the synthesis disclosed in WO 2014 / 012934.

[0014] Therefore, the method according to the invention is applicable to the reproducible preparation of compound (I) in high overall yield and high purity in industrially feasible synthesis.

[0015] Option 1

[0016]

[0017] Option 2

[0018]

[0019] Option 3

[0020]

[0021] Option 4

[0022]

[0023] Scheme 1 shows the preparation of compound (III) required for the preparation of compound (XII).

[0024] Scheme 2 shows an overview of the synthetic steps for preparing compound (XII) from intermediates of compound (VIII).

[0025] Scheme 3 shows an overview of the synthetic steps for preparing compound (XII) from intermediates of compound (XV).

[0026] Scheme 4 shows an overview of the synthetic steps for preparing the (XII) compound, wherein the reaction mechanism is similar to that shown in Scheme 3, except that the various intermediate stages are not isolated.

[0027] Description of each synthesis stage

[0028] Example 1

[0029] Method Step 1

[0030]

[0031] Method step 1 (Schemes 2 and 3) describes the preparation of 2-(4-cyanophenyl)ethyl 4-methylbenzyl sulfonate of formula (V) from 4-(2-hydroxyethyl)benzyl nitrile of formula (IV). Here, the compound of formula (IV), potassium hydroxide, and 4-toluenesulfonyl chloride (TsCl) are added to an inert solvent, such as a suitable ether, like 2-methyltetrahydrofuran (2-MTHF), tetrahydrofuran (THF), or dioxane, preferably THF, and stirred. The temperature is maintained between -10°C and 0°C until all compounds are added to avoid elimination reactions that could lead to the formation of cyanostyl styrene and its polymerization products. The mixture is then stirred at a temperature between 0°C and 30°C, preferably 22°C, until the conversion is complete.

[0032] Compounds of formula (V) can be separated, for example, by an aqueous workup and subsequent crystallization. Suitable aqueous workup methods are known to those skilled in the art, involving extraction that separates byproducts and excess potassium hydroxide. For example, aqueous workup can be performed with dichloromethane (DCM) and water in the presence of ammonium chloride. Crystallization can occur, for example, in cyclohexane. This involves replacing the solvent with cyclohexane, concentrating under reduced pressure at a temperature of 30°C to 50°C, preferably 41°C, cooling to a temperature of 20°C to 30°C, preferably 22°C, separating the solids, and drying in a drying oven at a temperature of 30°C to 50°C, preferably 40°C.

[0033] This invention provides a method for preparing compound (V).

[0034]

[0035] The characteristic feature is that the compound of formula (IV) reacts with potassium hydroxide and 4-toluenesulfonyl chloride in an inert solvent.

[0036]

[0037] The present invention also provides a method for preparing compounds of formula (V) above, wherein the inert solvent is selected from 2-methyltetrahydrofuran, tetrahydrofuran or dioxane, preferably an ether of tetrahydrofuran.

[0038] The present invention also provides a method for preparing the above-described compound (V), wherein the temperature during the addition of the compound (IV), potassium hydroxide and 4-toluenesulfonyl chloride is maintained between -10°C and 0°C.

[0039] The present invention further provides a method for preparing the compound of formula (V) above, wherein the conversion is carried out at a temperature of 0°C to 30°C, preferably 22°C.

[0040] Example 2

[0041] Method Step 2

[0042]

[0043] To prepare 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzyl nitrile of formula (VII) by method step 2 (schemes 2 and 3), 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate of formula (V) is suspended in a suitable ether (preferably THF), 2-methoxyphenylethylamine of formula (VI) and a tertiary amine base, such as and preferably triethylamine, are added, and the mixture is heated under reflux, preferably for 2 hours. Subsequently, the solvent is replaced with water, and an inorganic acid, preferably hydrochloric acid, more preferably 25% hydrochloric acid, is added at a temperature of 0 to 30°C. The solids in the reaction mixture are separated.

[0044] The compound of formula (VII) is preferably separated as an oil after an aqueous post-treatment. Suitable aqueous post-treatment methods are extractions known to those skilled in the art, capable of separating byproducts, such as excess toluenesulfonic acid. For example, and preferably, the separated solid is mixed with water and stirred, and then the solid is filtered off. This operation can be repeated. The solid is preferably mixed with ethyl acetate at a temperature of 30 to 60°C, more preferably 50°C, and stirred, and the solid is preferably separated at a temperature of 10 to 30°C, more preferably 20°C. This operation can be repeated until the solid is dried at a temperature below atmospheric pressure, preferably 40°C. In a further step, the solid is mixed with a mixture of ethyl acetate and hydrochloric acid (preferably 15% hydrochloric acid) to obtain the hydrochloride salt of the compound of formula (VII), which is dried at a temperature below atmospheric pressure, preferably 40°C. To obtain the free base of the compound of formula (VII), the obtained solid is dissolved in DCM and water, preferably in equal volume proportions, and the pH is adjusted to between 13 and 14 with an alkali (preferably sodium hydroxide solution, more preferably 45% sodium hydroxide solution). The organic phase is separated, washed with water, and concentrated at a temperature below atmospheric pressure, preferably 40°C, to obtain the oil.

[0045] The alkylation of primary amines typically yields a mixture of possible polyalkylated products. An advantage of this method is that the desired monoalkylated product VII is obtained with good purity and yield under optimized reaction and post-treatment conditions. The polyalkylated products formed here are also successfully removed through optimized purification.

[0046] The present invention also provides compounds of formula (VII) and their salts, solvates and solvates of their salts.

[0047]

[0048] The present invention also provides oxalates of compounds of formula (VII).

[0049] The present invention also provides a method for preparing compounds of formula (VII), characterized in that compounds of formula (V) are used.

[0050]

[0051] In the first step, the compound is suspended in a suitable ether in the presence of a tertiary amine base and reacted with a compound of formula (VI).

[0052]

[0053] In the second step, the solvent is converted to water, and an inorganic acid is added.

[0054] The present invention also provides a method for preparing the compound of formula (VII) above, wherein the suitable ether is tetrahydrofuran.

[0055] The present invention also provides a method for preparing the compound of formula (VII) above, wherein the tertiary amine base is triethylamine.

[0056] The present invention also provides a method for preparing the compound of formula (VII) above, wherein the reaction is carried out at a reflux temperature in the first step.

[0057] The present invention also provides a method for preparing the compound of formula (VII) above, wherein the second step is carried out at a temperature of 0°C to 30°C.

[0058] The present invention also provides a method for preparing the compound of formula (VII) above, wherein the inorganic acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0059] Example 3

[0060] Method Step 3

[0061]

[0062] The prior art describes the preparation of compound (I) by reductive amination of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (II) with an amine of formula XVII followed by alkylation, yielding a racemic end product. Subsequently, enantiomers need to be separated in a chiral chromatographic stage. This is technically very complex and expensive, and requires a large amount of solvent. In this invention, a surprisingly efficient method for preparing (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (compound (III)) has been discovered. Using compound (III), an enantiomerically pure end product can be obtained, avoiding the undesirable chiral chromatographic stage.

[0063] To prepare (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (III) in step 3 (Scheme 1), 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (II) (the preparation method is disclosed as Example 4A in WO2014 / 12934) is first added to a suitable solvent. Suitable solvents are esters such as ethyl acetate, and ethers such as diethyl ether, dioxane, and tetrahydrofuran, which are known to those skilled in the art; ethyl acetate is preferred. At a temperature preferably 0-40°C, more preferably 20°C, a tertiary amine base, such as triethylamine and (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium (CAS No.: 192139-92-7), is preferably added in a catalytic amount. Formic acid is added at a temperature preferably -5 to 10°C, more preferably 0 to 5°C, and the resulting gas is removed. Stirring continues at a temperature preferably 20 to 50°C, more preferably 40°C, until the conversion is complete.

[0064] Compound (III) is preferably separated after post-treatment and subsequent crystallization. For post-treatment, the reaction mixture is mixed with, preferably in equal volumes, a mixture of ethyl acetate and an inorganic acid (preferably hydrochloric acid, more preferably 1N hydrochloric acid) and stirred to separate the upper phase. A C6-C8 alkane (preferably heptane, more preferably n-heptane) is added to the upper phase, and the mixture is concentrated at below atmospheric pressure, preferably at a temperature of 20 to 50°C, more preferably 40°C. This step can be repeated. Compound (III) in solid form is separated from the mixture at a preferred temperature of 20°C and dried, preferably under reduced pressure at 40°C.

[0065] The present invention also provides (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (III), as well as its salts, solvates and solvates of its salts.

[0066]

[0067] The present invention also provides a method for preparing compounds of formula (III), characterized in that compounds of formula (II)

[0068]

[0069] The compound was reacted with a tertiary amine base, (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium, and formic acid to give the compound of formula (III).

[0070] The present invention also provides a method for preparing the compound of formula (III) above, wherein the amine base is triethylamine and (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium is used in a catalytic amount.

[0071] The present invention also provides a method for preparing the above-described compound (III), wherein, prior to the reaction, the compound (II) is dissolved in a solvent selected from ethyl acetate, diethyl ether, dioxane and tetrahydrofuran, preferably ethyl acetate.

[0072] The present invention also provides a method for preparing the above-mentioned compound (III), wherein the compound (II) is mixed with an amine base and (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium in a first step, and formic acid is added in a second step.

[0073] The present invention further provides a method for preparing the compound of formula (III) as described above, wherein the compound of formula (II) is mixed with an amine base and (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]ruthenium in a first step at a temperature of 0°C to 40°C, preferably 20°C, and formic acid is added in a second step at a temperature of -5°C to 10°C, preferably 0°C to 5°C.

[0074] The present invention also provides a method for preparing the compound of formula (III) above, wherein, after the addition of formic acid, stirring is continued at a temperature of 20°C to 50°C, preferably 40°C, until the conversion is complete.

[0075] Example 4

[0076] Method Step 4

[0077]

[0078] Method step 4 (Scheme 2) describes the preparation of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (VIII). For this purpose, water is preferably excluded, and more preferably, a solution of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (III) is dissolved in a suitable solvent under a protective gas atmosphere, such as under argon injection. Suitable solvents are those that are liquid at the reaction temperature, such as THF or DCM; DCM is preferred. A suitable base is added to the solution. A suitable base is a sterically hindered secondary amine or a 2,6-disubstituted pyridine, such as 2,6-dimethylpyridine or 2,6-di-tert-butylpyridine. Suitable sterically hindered secondary amines are, for example, diisopropylamine, 2,5-dimethylpiperidine, or 2,2,5,5-tetramethylpiperidine. These compounds yield remarkably better results than sterically unhindered amines or tertiary amines. Not particularly surprising is that the most favorable yields are obtained by using a preferred molar excess of diisopropylamine, based on the compound of formula (III). Diisopropylamine, as a secondary amine, is a base that is not commonly used in this type of reaction. The reaction mixture is cooled to a temperature between -90°C and -50°C, preferably between -78°C and -65°C. While maintaining this temperature range, 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzyl nitrile of formula (VII), preferably added in a 1:1 molar ratio based on the compound of formula (III), and the mixture is stirred.

[0079] Compound (VIII) is preferably separated after aqueous post-treatment and subsequent crystallization. Suitable aqueous post-treatment methods are known to those skilled in the art, including extraction, which can separate byproducts. For example, and preferably, after complete conversion, the reaction mixture can be mixed with a suitable acid (preferably oxalic acid or phosphoric acid, more preferably oxalic acid) and adjusted to a temperature of -10 to 15°C, preferably 0 to 5°C. Diatomaceous earth is added to the mixture and stirred. The solid is filtered off and discarded, the liquid organic phase is washed with water, and the pH is adjusted to 7.5-9, preferably 8, with an alkali (preferably an ammonia solution, more preferably a 27% ammonia solution). The organic phase is separated and preferably concentrated at sub-atmospheric pressure to obtain an oil.

[0080] Compound (VIII) crystallizes by dissolving the oil in ethanol. Compound (VIII) crystallizes at a temperature of 50°C or lower, preferably 40°C or lower, more preferably 40°C, preferably after inoculation. The solid is separated and dried by methods known to those skilled in the art, preferably at below atmospheric pressure, at a temperature of 25°C, and in a nitrogen flow.

[0081] The present invention also provides compounds of formula (VIII), as well as their salts, solvates, and solvates of their salts.

[0082]

[0083] The present invention also provides compounds of formula (VIII-1), their salts, solvates, and solvates of their salts.

[0084]

[0085] in

[0086] R 1 It is a C1-C4-alkyl group.

[0087] The present invention also provides a method for preparing compound (VIII-1).

[0088]

[0089] in

[0090] R 1 It is a C1-C4 alkyl group.

[0091] The characteristic feature is that, in the first step, trifluoromethanesulfonic anhydride is added to the compound of formula (III) at a temperature of -90°C to -50°C in the presence of a base selected from sterically hindered secondary amines and 2,6-disubstituted pyridines.

[0092]

[0093] And in the second step, it reacts with the compound of formula (VII-1).

[0094]

[0095] in

[0096] R 1 It is a C1-C4 alkyl group.

[0097] In the context of this invention, "C1-C4-alkyl" refers to a straight-chain or branched monovalent alkyl group having 1-4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0098] The present invention also provides a method for preparing the compound of formula (VIII-1) above, wherein R 1 It is a methyl group.

[0099] The present invention also provides a method for preparing the compound of formula (VIII-1) above, wherein the reaction is carried out at a temperature of -78°C to -65°C.

[0100] The present invention also provides a method for preparing the compound of formula (VIII-1) above, wherein the sterically hindered secondary amine is selected from diisopropylamine, 2,5-dimethylpiperidine and 2,2,5,5-tetramethylpiperidine.

[0101] The present invention also provides a method for preparing a compound of formula (VIII-1), wherein the base is diisopropylamine.

[0102] The present invention also provides a method for preparing the (VIII-1) compound, wherein the temperature is from -78°C to -65°C, preferably -76°C.

[0103] The present invention also provides a method for preparing a compound of formula (VIII-1), wherein the compound of formula (III) has been dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0104] The present invention also provides a method for preparing the above-described compound (VIII-1), wherein the base is in molar excess, preferably in a ratio of 3:1, based on the compound (III).

[0105] The present invention also provides a method for preparing the above-described compound (VIII-1), wherein trifluoromethanesulfonic anhydride is added in excess, preferably in a ratio of 1.5:1, based on the compound (III).

[0106] The present invention also provides a method for preparing the above-described compound (VIII-1), wherein the compound (VII-1) is used in a molar ratio of 1:1 to 1.1:1, based on the compound (III).

[0107] The present invention also provides a method for preparing the compound of formula (VIII-1) above, wherein the method is carried out in the absence of water, preferably in a protective gas atmosphere, and more preferably while argon is being injected.

[0108] The present invention also provides a method for preparing the compound of formula (VIII-1) above, wherein the method is carried out in the absence of water, preferably in a protective gas atmosphere, and more preferably while argon is being injected.

[0109] Example 5

[0110] Method Step 5

[0111]

[0112] To prepare 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzyl nitrile of formula (XIII) in step 5 (Scheme 3), aluminum chloride is first stirred until dissolved with a suitable alkyl thiol, preferably n-dodecyl thiol (dodecyl thiol), preferably in a molar ratio between 1:1 and 1:3, more preferably 1:1.8. 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzyl nitrile of formula (VII) is added at a temperature of 0 to 40°C, preferably 10 to 20°C, and the mixture is stirred for several hours, preferably at a temperature of 30 to 50°C, more preferably 40°C.

[0113] It has been found, surprisingly, that preparation using aluminum chloride is advantageous because the compound of formula (XIII), as an aluminum complex (Al complex), is insoluble in a suitable solvent, such as DCM or toluene, and precipitates out. The solubility of the Al complex depends on the solvent; for example, it is soluble in THF. This unforeseen situation can be advantageously used for the purification of the reaction mixture, as the resulting reaction product is separated into an insoluble Al complex and washed with a suitable solvent (preferably DCM or toluene, more preferably DCM). Subsequently, the complex can be dissolved in a suitable solvent (preferably THF), and the compound of formula (XIII) can be released from the complex by adding an excess of tartrate, preferably potassium sodium tartrate solution, based on a molar excess of the compound of formula (VII). The release from the complex by adding tartrate can be repeated.

[0114] Compounds of formula (XIII) are preferably separated after post-treatment with an alkaline aqueous solution. A suitable method for post-treatment with an alkaline aqueous solution is extraction, known to those skilled in the art, which can separate the byproducts. For this purpose, for example, the solvent is changed to DCM, an aqueous ammonia solution, preferably 27% ammonia solution, is added, the mixture is washed with water, and the organic phase is concentrated into an oil.

[0115] The present invention also provides compounds of formula (XIII) and their salts, solvates and solvates of their salts.

[0116]

[0117] The present invention also provides a method for preparing the compound of formula (XIII), characterized in that aluminum chloride is mixed with a suitable alkyl thiol in a first step and reacted with the compound of formula (VII) in a solvent of dichloromethane or toluene in a second step.

[0118]

[0119] The present invention also provides a method for preparing the compound of formula (XIII) above, wherein a suitable alkyl thiol is n-dodecyl thiol.

[0120] The present invention also provides a method for preparing the compound of formula (XIII) above, wherein the solvent is toluene and / or dichloromethane, preferably dichloromethane.

[0121] The present invention also provides a method for preparing the above-described compound (XIII), wherein a suitable alkyl thiol is added in a molar ratio of 1:1 to 1:3, based on the compound (VII), more preferably in a molar ratio of 1:1.8, based on the compound (VII).

[0122] The present invention also provides a method for preparing the above-described compound (XIII), wherein the compound (VII) is added at a temperature of 0°C to 40°C, preferably 10°C to 20°C.

[0123] The present invention also provides a method for preparing the compound of formula (XIII) above, wherein the conversion in the second step is carried out at a temperature of 30°C to 50°C, more preferably 40°C.

[0124] The present invention also provides a method for preparing the above-described compound (XIII), wherein the insoluble compound of the formed (XIII) is isolated and dissolved in tetrahydrofuran, and then a tartrate solution is added.

[0125] Example 6

[0126] Method steps 6A and 6B describe the preparation of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzyl nitrile of formula (XIV).

[0127] Method step 6A:

[0128]

[0129] To prepare 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzyl nitrile of formula (XIV) by method step 6A (Scheme 3), 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzyl nitrile of formula (XIII) is dissolved in a suitable solvent, such as an ether or a haloalkane, preferably DCM. The hydroxyl group of the compound of formula (XIII) is protected by a silyl protecting group at a temperature of 0°C to 40°C, preferably 20°C to 35°C. The silyl protecting group used can be a silyl protecting group known to those skilled in the art, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), or tert-butyldimethylsilyl (TBDMS); preferably tert-butyldimethylsilyl (TBDMS). For this purpose, the compound of formula (XIII) is mixed with a suitable silyl chloride (preferably tert-butyldimethylsilyl chloride) in the presence of an amine base (preferably imidazole) and stirred at a temperature of 0°C to 40°C, preferably 20°C to 35°C, until the conversion is complete. The amine base is present in a 1:1 molar ratio or in excess relative to the compound of formula (XIII), preferably in a 1.5-fold molar excess.

[0130] Prior to concentration, the reaction mixture can be purified using an alkaline aqueous solution known to those skilled in the art. For this purpose, for example, an aqueous solution of potassium carbonate is added to the reaction mixture, the organic phase is repeatedly washed with water, and the organic phase is dried with sodium sulfate.

[0131] A preferred alternative purification can be achieved by precipitating the compound of formula (XIV) as an oxalate. For this purpose, after washing the reaction mixture with water, the solvent of the organic phase is converted to methanol, and the mixture is heated to 40°C to 80°C, preferably 65°C. After adding excess oxalic acid based on the compound of formula (XIV), the mixture is stirred at a temperature of 40°C to 65°C, preferably 50°C to 55°C, and then cooled to a temperature of 0°C to 20°C, preferably 5°C to 10°C. The precipitated solid is separated, suspended, and stirred in a mixture of water and an inert solvent that exhibits phase separation from water, such as DCM, toluene, or ether, preferably DCM. After adjusting the pH to 10.5 to 12.5 with a suitable base (e.g., and preferably sodium hydroxide solution), the phase is separated and the organic phase is concentrated.

[0132] Concentration is carried out at 25°C to 70°C, preferably 30°C to 50°C, more preferably 35°C, and preferably at a pressure below atmospheric pressure, to obtain a compound of formula (XIV) as an oil.

[0133] The present invention also provides compounds of formula (XIV) and their salts, solvates and solvates of their salts.

[0134]

[0135] This invention also provides compounds of formula (XIV-1), their salts, solvates, and solvates of their salts.

[0136]

[0137] in

[0138] R 2 It is a silyl protecting group.

[0139] The present invention also provides a method for preparing compound of formula (XIV-1).

[0140]

[0141] in

[0142] R 2 It is a silyl protecting group.

[0143] Characterized by compound of formula (XIII)

[0144]

[0145] It reacts with a suitable silyl chloride in the presence of an amine base.

[0146] In the context of this invention, "silyl protecting group" is a silyl protecting group known to those skilled in the art, and can convert reactive functional groups into non-reactive forms using organosilicon compounds. Trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), or tert-butyldimethylsilyl (TBDMS) are preferred, with tert-butyldimethylsilyl (TBDMS) being particularly preferred.

[0147] In the context of this invention, a suitable silyl chloride is a silyl chloride used to prepare the corresponding silyl protecting group.

[0148] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein the amine base is an imidazole.

[0149] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein R 2 It is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl and tert-butyldimethylsilyl.

[0150] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein R 2 It is tert-butyldimethylsilyl.

[0151] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein a suitable silyl chloride is selected from trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, tert-butyldiphenylsilyl chloride and tert-butyldimethylsilyl chloride.

[0152] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein a suitable silyl chloride is tert-butyldimethylsilyl chloride.

[0153] The present invention also provides a method for preparing a compound of formula (XIV-1), wherein the amine base is present in a molar ratio of 1.5:1 or in excess, based on a compound of formula (XIII).

[0154] Method step 6B:

[0155]

[0156] Alternatively, the compound of formula (XIV) can be prepared in step 6B (Scheme 4) from 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate of formula (V) and 2-(2-aminoethyl)phenol of formula (XVII). For this purpose, the compound of formula (V) is dissolved in a suitable solvent (e.g., ether, preferably DCM or THF, more preferably THF), and 2-(2-aminoethyl)phenol of formula (XVII) is preferably added in a ratio of 2:1 or more based on the compound of formula (V), and triethylamine is preferably added in a ratio of 3:1 or more based on the compound of formula (V). The reaction mixture is heated for several hours, preferably 20 to 60 hours, more preferably 46 hours, preferably at a temperature corresponding to the boiling temperature of the reaction mixture. If DCM is not used as a solvent, it is preferable to use DCM instead. This can be achieved, for example, by removing the original solvent under reduced pressure and at a temperature below 60°C, followed by the addition of DCM. The solution can then be washed by known methods, for example, preferably with sodium bicarbonate once or several times, and optionally further concentrated, for example, preferably at a temperature below 45°C.

[0157] Add imidazole to the resulting solution, preferably in a ratio of 2:1 to 5:1 based on the compound of formula (V), more preferably in a ratio of 3:1, and stir at a temperature of 20 to 35°C, more preferably at room temperature, until the conversion is complete.

[0158] Purification with an alkaline aqueous solution, as known to those skilled in the art, can then be performed. For this purpose, the following method is preferably conceived: washing the reaction mixture once or several times with water, and replacing the solvent with methanol. Adding oxalic acid at a temperature of 40 to 70°C, preferably 50 to 55°C, and stirring the mixture. After cooling to 0 to 20°C, preferably 5 to 10°C, separating the solids and washing with methanol. Suspending the residue in DCM or a mixture of toluene and water (preferably DCM and water) in a preferred volume ratio of 1:1, and mixing with a concentrated alkali (preferably a sodium hydroxide solution, more preferably a 45% sodium hydroxide solution) at a temperature of 15 to 40°C, preferably 25 to 35°C, to obtain a pH of 10.5 to 12.5. After adding water, separating the organic phase, preferably concentrating it at below atmospheric pressure. The compound of formula (XIV) is obtained as an oil.

[0159] One advantage of this method is that the alkylation of 2-(2-aminoethyl)phenol of formula (V) does not pre-protect the hydroxyl functional group of phenol (which can enter the alkylation reaction under basic conditions), and can yield the desired monoalkylated product of the primary amine.

[0160] The present invention also provides a method for preparing compound of formula (XIV-1).

[0161]

[0162] in

[0163] R 2 It is a silyl protecting group.

[0164] The compound characterized by formulas (XVI) and (V)

[0165]

[0166] In the first step, coupling is performed in the presence of an amine base, such as triethylamine, and the reaction product is reacted with a suitable silyl chloride in the second step, also in the presence of an amine base.

[0167] The present invention also provides a method for preparing the compound of formula (XIV-1) above, wherein the amine base in the first step is triethylamine.

[0168] The present invention also provides a method for preparing the compound of the above formula (XIV-1), wherein the first step is carried out in a suitable ether as a solvent.

[0169] The present invention also provides a method for preparing compounds of the above formula (XIV-1), wherein a suitable ether is dichloromethane or tetrahydrofuran.

[0170] The present invention also provides a method for preparing the above-described compound (XIV-1), wherein the compound (XVI) is used in a molar ratio of 2:1 or higher, based on the compound (V).

[0171] The present invention also provides a method for preparing the above-described compound (XIV-1), wherein triethylamine is used in a molar ratio of 3:1 or higher, based on the compound of formula (V).

[0172] The present invention also provides a method for preparing the compound of the above formula (XIV-1), wherein the conversion in the first step is carried out at a boiling temperature for several hours, preferably 20 to 60 hours, more preferably 46 hours.

[0173] The present invention also provides a method for preparing the compound of the above formula (XIV-1), wherein the amine base in the second step is an imidazole.

[0174] The present invention also provides a method for preparing the above-described compound (XIV-1), wherein the amine base in the second step is used in a molar ratio of 2:1 to 5:1, preferably 3:1, based on the compound of formula (V).

[0175] The present invention also provides a method for preparing the compound of the above formula (XIV-1), wherein the second step is carried out at a temperature of 20°C to 35°C.

[0176] Example 7

[0177] Method Step 7

[0178]

[0179] To prepare (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (XV) in step 7 (Scheme 3), (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (III) is added to a suitable solvent. Suitable solvents are those that are liquid at the reaction temperature, such as THF or DCM; DCM is preferred. A suitable base is added to the solution. A suitable base is a sterically hindered secondary amine or a 2,6-disubstituted pyridine. Suitable sterically hindered secondary amines are, for example, diisopropylamine, 2,5-dimethylpiperidine, or 2,2,5,5-tetramethylpiperidine, preferably diisopropylamine. It is particularly preferred to add an excess of diisopropylamine, more preferably 3 equivalents of diisopropylamine, based on the compound of formula (X). These compounds yield remarkably better results than sterically unhindered amines or tertiary amines. Particularly surprising is the most favorable yield achieved using diisopropylamine.

[0180] The reaction mixture is cooled to -90°C to -50°C, preferably -78°C to -65°C, and trifluoromethanesulfonic anhydride is added, preferably in excess, more preferably 1.5 equivalents, based on the compound of formula (III), and the mixture is stirred. While maintaining the above temperature range, 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzylnitrile of formula (XIV) dissolved in DCM is added, preferably in an equimolar amount based on the compound of formula (III), more preferably 1.0 equivalent to 1.1 equivalents, based on the compound of formula (III), and the mixture is stirred until the conversion is complete. Subsequently, the reaction mixture is heated to 10 to 30°C, preferably 20°C.

[0181] Prior to concentration, the reaction mixture can be purified using an acidic aqueous solution known to those skilled in the art. For this purpose, the reaction mixture is acidified with an inorganic acid (preferably phosphoric acid or hydrochloric acid, more preferably hydrochloric acid), optionally washed with water, and the organic phase is separated.

[0182] Concentration is carried out at 30°C to 80°C, preferably 30°C to 60°C, more preferably 40°C, and preferably at a pressure below atmospheric pressure, to obtain a compound of formula (XV) as an oil.

[0183] Optionally, the resulting oil can be filtered through silica gel. For this purpose, the oil is dissolved in a suitable solvent (preferably DCM), filtered through silica gel, and diluted with a suitable solvent, preferably a mixture of ethyl acetate and n-hexane in a 1:2 ratio (ethyl acetate: n-hexane). Subsequently, the product solution is concentrated again under the above conditions.

[0184] The present invention also provides compounds of formula (XV) and their salts, solvates and solvates of their salts.

[0185]

[0186] This invention also provides compounds of formula (XV-1), their salts, solvates, and solvates of their salts.

[0187]

[0188] in

[0189] R 2 It is a silyl protecting group.

[0190] The present invention also provides a method for preparing compounds of formula (XV-1).

[0191]

[0192] in

[0193] R 2It is a silyl protecting group.

[0194] Characterized in that, in the first step, at a temperature of -90°C to -50°C, in the presence of a base selected from sterically hindered secondary amines and 2,6-disubstituted pyridines and trifluoromethanesulfonic anhydride, a compound of formula (III) is added.

[0195]

[0196] And in the second step, it reacts with the compound of formula (XVI-1).

[0197]

[0198] in

[0199] R 2 It is a silyl protecting group.

[0200] The present invention also provides a method for preparing the compound of the above formula (XV-1), wherein the sterically hindered secondary amine is selected from diisopropylamine, 2,5-dimethylpiperidine and 2,2,5,5-tetramethylpiperidine.

[0201] The present invention also provides a method for preparing the compound of the above formula (XV-1), wherein the base is diisopropylamine.

[0202] The present invention also provides a method for preparing the compound of the above formula (XV-1), wherein the temperature is preferably from -78°C to -65°C, and more preferably -76°C.

[0203] The present invention also provides a method for preparing the above-mentioned compound (XV-1), wherein the compound (III) has been dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0204] The present invention also provides a method for preparing the above-mentioned compound (XV-1), wherein trifluoromethanesulfonic anhydride is added in molar excess based on the compound of formula (III), preferably in a ratio of 1.5:1.

[0205] The present invention also provides a method for preparing the above-mentioned compound (XV-1), wherein the base is in excess based on the compound of formula (III), preferably in a ratio of 3:1.

[0206] The present invention also provides a method for preparing the above-mentioned compound (XV-1), wherein the molar ratio of the compound (XIV-1) is from 1:1 to 1.1:1 based on the compound (III).

[0207] The present invention also provides a method for preparing the compound of the above formula (XV-1), wherein the method is carried out in the absence of water, preferably in a protective gas atmosphere, and more preferably while argon is being injected.

[0208] Example 8

[0209] Method Step 8

[0210]

[0211] To prepare (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (XVI) in step 8 (Scheme 3), (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (XV) is mixed in a suitable alcohol (preferably methanol) with a high concentration of hydrochloric acid (preferably 37% or 25% hydrochloric acid) at a temperature of 10°C to 40°C, preferably 25°C, until the conversion is complete.

[0212] After neutralization with an aqueous ammonia solution (preferably 30% ammonia solution), the compound of formula (VI) can be extracted in solid form. These solids can be stirred in a mixture of water and dichloromethane, and the organic phase can be washed with water and concentrated.

[0213] The obtained solid can also be dissolved in a mixture of methanol and water at reflux temperature, and surprisingly, with relatively high enantiomeric purity, can be obtained by cooling to room temperature without the addition of chiral reagents. This is particularly advantageous for the preparation of enantiomeric pure active ingredients.

[0214] The present invention also provides compounds of formula (XVI) and their salts, solvates and solvates of their salts.

[0215]

[0216] The present invention also provides a method for preparing compounds of formula (XVI), characterized in that the compounds of formula (XV-1)

[0217]

[0218] in

[0219] R 2 It is a silyl protecting group.

[0220] It reacts with inorganic acids.

[0221] The present invention also provides a method for preparing the above-described compound (XVI), wherein the inorganic acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0222] The present invention also provides a method for preparing compounds of the above formula (XVI), wherein the conversion is carried out at a temperature of 10°C to 40°C, preferably 25°C.

[0223] The present invention also provides a method for preparing compounds of the above formula (XVI), wherein the conversion is carried out in methanol.

[0224] The present invention also provides a method for preparing the above-described compound (XVI), wherein after the reaction, the mixture is mixed with an ammonia solution, preferably a 30% ammonia solution, and the compound (VI) is extracted in solid form.

[0225] Example 9

[0226] Method step 9A:

[0227]

[0228] To prepare (IX)-5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in step 9A (Scheme 3), (XVI)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile in formula (XVI) is suspended in a high concentration of hydrochloric acid (preferably 25% hydrochloric acid) at a temperature of 90°C to 110°C, preferably 103°C, until the conversion is complete. The reaction product can be used directly in the next stage.

[0229] Alternatively, the reaction product can be cooled to a temperature of 15°C to 50°C, preferably 40°C, the suspension can be filtered, and the filtrate can be used in the next stage.

[0230] The present invention also provides compounds of formula (IX), their salts, solvates, and solvates of their salts.

[0231]

[0232] The present invention also provides a method for preparing compounds of formula (IX), characterized in that the compounds of formula (XVI)

[0233]

[0234] It reacts with inorganic acids.

[0235] The present invention also provides a method for preparing the compound of formula (IX) above, wherein the inorganic acid is hydrochloric acid, preferably 25% hydrochloric acid.

[0236] The present invention further provides a method for preparing the compound of formula (IX) above, wherein the conversion is carried out at a temperature of 90°C to 110°C, preferably 103°C.

[0237] Method step 9B:

[0238]

[0239] In alternative method step 9B (Scheme 2), the compound of formula (IX) can be prepared from (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (VIII). For this purpose, the compound of formula (VIII) is suspended in a high concentration of hydrobromic acid (preferably 48% hydrobromic acid) and stirred at a temperature of 90°C to 110°C, preferably 108°C, until the conversion is complete. Subsequently, the reaction product is first cooled to a temperature of 15°C to 40°C, preferably 25°C, and washed with DCM; the aqueous phase is used for the next stage.

[0240] Process 9B produces toxic methyl bromide; therefore, the gases generated during the reaction must be collected by a gas scrubber. Furthermore, hydrobromic acid, as a reactant, is highly corrosive.

[0241] The present invention also provides a method for preparing compounds of formula (IX), characterized in that compounds of formula (VIII)

[0242]

[0243] It reacts with hydrobromic acid at temperatures ranging from 90°C to 110°C.

[0244] The present invention also provides a method for preparing the compound of formula (IX) above, wherein 48% hydrobromic acid is used.

[0245] The present invention also provides a method for preparing the compound of formula (IX) above, wherein the conversion is carried out at a temperature of 108°C.

[0246] Example 10

[0247]

[0248] Method Step 10A:

[0249] To prepare butyl 5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (IX) in step 10A (schemes 2 and 3), the butyl 5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (IX) is heated to boiling and stirred until conversion is complete in an inorganic acid (preferably hydrochloric acid) and a suitable alcohol (e.g., butanol, preferably n-butanol) as a solvent. Any aqueous solvent components present, for example, due to the precursor and formed during the reaction are removed. This can be achieved, for example, by distillation with the continuous addition of an organic solvent until the boiling temperature of the organic solvent is reached. The step is preferably carried out at sub-atmospheric pressure. Subsequently, cooling to 10°C to 30°C, preferably 22°C, and purification with an alkaline aqueous solution is performed. Optionally, the mixture is cooled, filtered, and then purified with an alkaline aqueous solution using the filtrate.

[0250] Purification methods using alkaline aqueous solutions are known to those skilled in the art; for alkaline aqueous solution purification, it is preferable to add ethyl acetate and an alkaline aqueous solution, preferably an ammonia solution or potassium carbonate and water, stir, and remove and discard the aqueous phase. In the second step, it is preferable to add water and sodium chloride to the remaining organic phase, stir, and remove and discard the aqueous phase. In the third step, it is preferable to add water to the remaining organic phase, stir, and remove and discard the aqueous phase. In the final step, the remaining organic phase is concentrated at a temperature of 30°C to 80°C, preferably 40°C to 70°C, more preferably 55°C, preferably at a pressure below atmospheric pressure, to obtain compound (X) as an oil.

[0251] Optionally, the obtained oil is dissolved in DCM and methanol and filtered with silica gel, and the filtrate is concentrated again under the above conditions to obtain oil.

[0252] One advantage of this method is that water present or formed during the reaction can be removed very effectively from the reaction mixture via azeotropic distillation, thus shortening the reaction time before complete conversion. Butanol is noteworthy in this regard compared to other solvents, as it removes a significantly larger amount of water from the reaction mixture based on the amount of solvent distilled compared to other solvents (e.g., acetonitrile). This has a favorable effect on distillation time. On an industrial scale, shorter distillation times result in lower operating costs and equipment downtime, as well as lower energy costs. Furthermore, the solvent used for azeotropic distillation is also the reagent used to form butyl ester, eliminating the need for a separate solvent. Another advantage of this method is that the end of the reaction can be indicated by the internal temperature at which the boiling point of butanol is reached under the selected distillation conditions (distillation pressure) without further analytical studies. This is particularly advantageous on an industrial scale.

[0253] The present invention also provides compounds of formula (X) and their salts, solvates and solvates of their salts.

[0254]

[0255] The present invention also provides a method for preparing a compound of formula (X), characterized in that the compound of formula (IX)

[0256]

[0257] It reacts with n-butanol in the presence of inorganic acids.

[0258] The present invention also provides a method for preparing the compound of formula (X) above, wherein n-butanol is used.

[0259] The present invention also provides a method for preparing the compound of formula (X) above, wherein the inorganic acid is hydrochloric acid.

[0260] The present invention also provides a method for preparing the compound of formula (X) above, wherein the conversion is carried out at a boiling temperature.

[0261] Method step 10B:

[0262]

[0263] Alternatively, butyl (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (X) can be obtained from compounds of formulas (III) and (XIV) without the need to separate intermediates (method step 10B - scheme 4). For this purpose, method steps 7, 8, 9A, and 10A are performed sequentially, and the corresponding products as oils are obtained from the method steps and used directly in the corresponding next stage.

[0264] The present invention also provides a method for preparing compound (X).

[0265]

[0266] Characterized in that, in the first step, trifluoromethanesulfonic anhydride is added to the compound of formula (III) at a temperature of -90°C to -50°C in the presence of a base selected from sterically hindered secondary amines and 2,6-disubstituted pyridines.

[0267]

[0268] In the second step, it reacts with the compound of formula (XIV-1) at a temperature of -90°C to -50°C.

[0269]

[0270] in

[0271] R 2 It is a silyl protecting group.

[0272] In the third step, the reaction product reacts with hydrochloric acid, and in the fourth step, the reaction product reacts with butanol in the presence of an inorganic acid.

[0273] The present invention also provides a method for preparing the compound of formula (X) above, wherein the sterically hindered secondary amine is selected from diisopropylamine, 2,5-dimethylpiperidine and 2,2,5,5-tetramethylpiperidine.

[0274] The present invention also provides a method for preparing the compound of formula (X) above, wherein the base is diisopropylamine.

[0275] The present invention also provides a method for preparing the compound of formula (X) above, wherein the temperature in the first and second steps is from -78°C to -65°C, preferably -76°C.

[0276] The present invention also provides a method for preparing the above-mentioned compound (X), wherein the compound (III) has been dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0277] The present invention also provides a method for preparing the above-mentioned compound (X), wherein trifluoromethanesulfonic anhydride is added in excess, preferably in a ratio of 1.5:1, based on the compound (III).

[0278] The present invention also provides a method for preparing the above-mentioned compound (X), wherein the base is in molar excess, preferably in a ratio of 3:1, based on the compound (III).

[0279] The present invention also provides a method for preparing the above-described compound (X), wherein the compound (XIV-1) is used in a molar ratio of 1:1 to 1.1:1, based on the compound (III).

[0280] The present invention also provides a method for preparing the compound of formula (X) above, wherein the method is carried out in the absence of water, preferably in a protective gas atmosphere, and more preferably while argon is being injected.

[0281] The present invention also provides a method for preparing the compound of formula (X) above, wherein the butanol used is n-butanol.

[0282] The present invention also provides a method for preparing the compound of formula (X) above, wherein the inorganic acid is hydrochloric acid.

[0283] The present invention also provides a method for preparing the compound of formula (X) above, wherein the conversion in the third step is carried out at a temperature of 90°C to 110°C, preferably 103°C, and the conversion in the fourth step is carried out at a boiling temperature.

[0284] Example 11

[0285] Method Step 11

[0286]

[0287] To prepare compound (XII), (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (method step 11-scheme 4) of formula (X) is dissolved in an inert polar solvent (e.g., a suitable ether, acetone, or acetonitrile, preferably acetonitrile), preferably at a temperature of 10°C to 40°C, more preferably 25°C. Then, distillation is preferably carried out at a temperature of 40°C to 60°C and below atmospheric pressure, preferably 80 mbar to 120 mbar, more preferably 120 mbar, and acetonitrile is added. This step can be repeated.

[0288] Add 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] of formula (XI) to the solution, preferably in an amount of 1 to 2 equivalents, more preferably 1.2 equivalents, based on the compound of formula (X). Add an additive to the solution, selected from alkali metal carbonates, such as sodium carbonate, potassium carbonate, or cesium carbonate, or alkali metal hydroxides, such as potassium hydroxide or sodium hydroxide, or tetraalkylammonium carbonate, such as tetramethyl-, tetraethyl-, tetrapropyl-, or tetrabutylammonium carbonate, benzyltrimethyl-, benzyltriethyl-, benzyltripropyl-, or benzyltributylammonium carbonate; preferably cesium carbonate is used. The additive is added in molar excess based on the compound of formula (X), preferably in an amount of 2 to 4 equivalents, more preferably 2 equivalents. Stir the mixture until it is completely converted to the compound of formula (XII). Preferably, a larger amount of the additive, preferably cesium carbonate, can be added to the reaction mixture, and the mixture is stirred again. Filter the resulting suspension. Wash with acetonitrile before discarding the filter residue.

[0289] Alternatively, the compound of formula (XII) can be separated into an oil. To separate the oil, the filtrate is concentrated at a temperature of 15°C to 60°C, preferably 30°C to 50°C, more preferably 40°C, to obtain the oil. Concentration is preferably carried out at a pressure below atmospheric pressure.

[0290] The present invention also provides compounds of formula (XII) and their salts, solvates and solvates of their salts.

[0291]

[0292] The present invention also provides a method for preparing compound (XII-1).

[0293]

[0294] in

[0295] R 3 and R 4 Independently C1-C4-alkyl,

[0296] Its characteristic is that it is a compound of formula (X-1).

[0297]

[0298] in

[0299] R 3 and R 4 Independently C1-C4-alkyl,

[0300] Reacts with compound of formula (XI) in the presence of alkali metal carbonates, alkali metal hydroxides, or tetraalkylammonium carbonates.

[0301]

[0302] The present invention also provides a method for preparing compounds of formula (XII).

[0303]

[0304] Its characteristic is that the compound of formula (X)

[0305]

[0306] Reacts with compound of formula (XI) in the presence of alkali metal carbonates, alkali metal hydroxides, or tetraalkylammonium carbonates.

[0307]

[0308] The present invention also provides a method for preparing the compound of formula (XII-1) above, wherein a suitable ether, acetone or acetonitrile is used as a solvent, preferably acetonitrile.

[0309] The present invention also provides a method for preparing the compound of formula (XII-1) above, wherein an alkali metal carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate is used, preferably cesium carbonate.

[0310] The present invention also provides a method for preparing the compound of formula (XII-1) above, wherein an alkali metal hydroxide selected from sodium hydroxide and potassium hydroxide is used.

[0311] The present invention also provides a method for preparing the compound of the above formula (XII-1), wherein tetraalkylammonium carbonate is used.

[0312] The present invention also provides a method for preparing the above-mentioned compound (XII-1), wherein the alkali metal carbonate, alkali metal hydroxide or tetraalkylammonium carbonate is used in molar excess, preferably in a molar ratio of 2:1 to 4:1 based on the compound of formula (X), and more preferably in a molar ratio of 2:1 based on the compound of formula (X).

[0313] The present invention also provides a method for preparing the above-described compound (XII-1), wherein the compound (XI) is preferably used in a molar ratio of 1:1 to 2:1 based on the compound (X), and more preferably in a molar ratio of 1.2:1 based on the compound (X).

[0314] Compound (I) can be prepared from compound (XII) or (XII-A) by ester hydrolysis methods known to those skilled in the art. For example, ester hydrolysis can be carried out in a manner similar to that described in Example 23 of WO 2014 / 012934.

[0315] Experimental Section

[0316] Abbreviations and acronyms

[0317] abs. Waterless

[0318] acac (acetylacetonato)

[0319] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0320] cat. catalysis

[0321] CI chemical ionization (MS)

[0322] coe cyclooctene

[0323] D. Number of days

[0324] TLC (Thin Layer Chromatography)

[0325] DCM dichloromethane

[0326] DMA dimethylacetamide

[0327] DMF (dimethylformamide)

[0328] DMSO (dimethyl sulfoxide)

[0329] ee enantiomerism excess

[0330] Electron impaction ionization (EI) method

[0331] Enantiomers / Enantiomers

[0332] eq equivalent

[0333] ESI Electrospray Ionization (MS)

[0334] EtOAc (ethyl acetate)

[0335] GC-MS (Gas Chromatography-Mass Spectrometry)

[0336] % by weight

[0337] h hours (number of hours)

[0338] HPLC (High-Performance Liquid Chromatography)

[0339] ID inner diameter

[0340] iPrOAc isopropyl acetate

[0341] iPrOH isopropanol

[0342] conc. concentrated

[0343] l rise

[0344] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0345] LDA (Lithium diisopropylamino)

[0346] LiHMDS bis(trimethylsilyl)aminolithium

[0347] min (minutes)

[0348] MS mass spectrometry

[0349] MTBE 2-methoxy-2-methylpropane

[0350] NMR (Nuclear Magnetic Resonance) spectroscopy

[0351] NMP N-methyl-2-pyrrolidine

[0352] org. organic

[0353] Ph phenyl

[0354] pTsOH p-Toluenesulfonic acid

[0355] R f Retention coefficient (TLC)

[0356] RP-HPLC (Reverse High Performance Liquid Chromatography)

[0357] RRT Relative Residence Time

[0358] R t Duration of stay

[0359] RT room temperature

[0360] TESCl Triethylsilane

[0361] THF Tetrahydrofuran

[0362] v / v (volume ratio of solution)

[0363] T int Internal temperature

[0364] T out external temperature

[0365] DM water (demineralized water)

[0366] aq. aqueous solution

[0367] Analysis method:

[0368] Method A

[0369] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 228 nm (range: 6 nm), the oven temperature was 25 °C, and the column was a Chiralpak AD-H with a length of 250 mm, an inner diameter of 4.6 mm, and a particle size of 5 μm. The mobile phase consisted of: A: n-heptane, and B: isopropanol + 0.1% diethylamine. The gradient program was: initial 1 mL / min 80% eluent A, 20% eluent B; 16 min 1 mL / min 40% eluent A, 60% eluent B. The sample solvent was ethanol + 0.1% diethylamine, and the analytical solution was approximately 1.0 mg / mL of the substance dissolved in the sample solvent. The injection volume was 10 μL.

[0370] R t Enantiomer 1: 7.6 min, Enantiomer 2: 8.5 min

[0371] Method B

[0372] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 206 nm (range: 6 nm), the oven temperature was 30 °C, and the column was a Chiralpak AD-H with a length of 250 mm, an inner diameter of 4.6 mm, and a particle size of 5 μm. The mobile phase consisted of: A: n-heptane, and B: ethanol + 0.1% diethylamine. The gradient program was: initial 1 mL / min 70% eluent A, 30% eluent B; 12 min 1 mL / min 40% eluent A, 60% eluent B. The sample solvent was ethanol + 0.1% diethylamine, and the analytical solution was approximately 1.0 mg / mL of the substance dissolved in the sample solvent. The injection volume was 5 μL.

[0373] R t Enantiomer 1: 5.8 min (RRT 1.00), Enantiomer 2: 7.2 min (RRT 1.25)

[0374] Method C

[0375] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 204 nm (range: 6 nm), the oven temperature was 45 °C, and the column was a Chiralpak AD-H with a length of 250 mm, an inner diameter of 4.6 mm, and a particle size of 5 μm. The mobile phase consisted of: A: n-heptane, and B: ethanol + 0.2% trifluoroacetic acid + 0.1% diethylamine. The gradient program was 1.5 min at 1 ml / min with 60% eluent A and 40% eluent B. The sample solvent was ethanol, and the analytical solution contained approximately 1.0 mg / ml of the substance dissolved in the sample solvent. The injection volume was 10 μl.

[0376] R t Enantiomer 1: 2.9 min RRT 1.00, Enantiomer 2: 3.7 min RRT 1.28

[0377] Method D

[0378] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 230 nm (range: 6 nm), the oven temperature was 40 °C, and the column was a Chiralpak AD-H with a length of 250 mm, an inner diameter of 4.6 mm, and a particle size of 5 μm. The mobile phase consisted of A: n-heptane and B: ethanol + 0.1% diethylamine. The gradient program was 1 min at 1 ml / min with 70% eluent A and 30% eluent B. The sample solvent was ethanol + 0.1% diethylamine, and the analytical solution contained approximately 2.0 mg / ml of the substance dissolved in the sample solvent. The injection volume was 10 μl.

[0379] R t Enantiomer 1: 4.9 min (RRT 1.00), Enantiomer 2: 5.7 min (RRT 1.16)

[0380] Method E

[0381] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 226 nm, with a range of 6 nm. The oven temperature was 35 °C. The column was a Chiralpak IB, 250 mm in length, 4.6 mm in inner diameter, and 5 μm in particle size. The mobile phase consisted of: A: n-heptane, and B: isopropanol + 0.1% ethanolamine. The gradient program was 1.5 min at 1 ml / min with 80% eluent A and 20% eluent B. The sample solvent was n-heptane:isopropanol 1:1. The analytical solution contained approximately 2.0 mg / ml of the substance, dissolved in the sample solvent. The injection volume was 10 μl.

[0382] R t Enantiomer 1: 4.1 min, Enantiomer 2: 4.5 min

[0383] Method F

[0384] Transformation 1:

[0385] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 228 nm (range: 6 nm), the oven temperature was 40 °C, and the column was a Chiralpak OJ-H with a length of 250 mm, an inner diameter of 4.6 mm, and a particle size of 5 μm. The mobile phase consisted of A: n-heptane and B: ethanol + 0.1% diethylamine. The gradient program was 1 min at 1 ml / min with 60% eluent A and 40% eluent B. The sample solvent was ethanol, and the analytical solution contained approximately 1.5 mg / ml of the substance dissolved in the sample solvent. The injection volume was 10 μl.

[0386] R t Enantiomer 1: 10.68 min, Enantiomer 2: 12.13 min

[0387] Transformation 2:

[0388] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 228 nm (range: 6 nm), the oven temperature was 40 °C, and the column was a Lux 3μCellulose-3 (Phenomenex) with a length of 150 mm, an inner diameter of 4.6 mm, and a particle size of 3 μm. The mobile phase consisted of: A: n-heptane, and B: ethanol + 0.1% diethylamine. The gradient program was 1 min 1 ml / min 75% eluent A and 25% eluent B. The sample solvent was ethanol, and the analytical solution contained approximately 1.0 mg / ml of the substance dissolved in the sample solvent. The injection volume was 10 μl.

[0389] R t Enantiomer 1: 7.6 min, Enantiomer 2: 8.6 min

[0390] Method G

[0391] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 226 nm, with a range of 6 nm. The oven temperature was 30 °C. The column was a Chiralpak AD-H, 250 mm in length, 4.6 mm in inner diameter, and 5 μm in particle size. The mobile phase consisted of: A: n-heptane, and B: isopropanol + 0.1% diethylamine. The gradient program was 1 min at 1 ml / min with 96% eluent A and 4% eluent B. The sample solvent was isopropanol + 0.1% diethylamine. The analytical solution contained approximately 2.0 mg / ml of the substance dissolved in the sample solvent. The injection volume was 10 μl.

[0392] R t Enantiomer 1: 8.6 min, Enantiomer 2: 10.7 min

[0393] Method H

[0394] Instruments: Waters SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.25ml 99% formic acid, Eluent B: 1L acetonitrile + 0.25ml 99% formic acid; Gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; Oven: 50℃; Flow rate: 0.40ml / min; UV detection: 210nm.

[0395] Method I

[0396] Instruments: Waters SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.25ml 99% formic acid, Eluent B: 1L acetonitrile + 0.25ml 99% formic acid; Gradient: 0.0min 95% A → 6.0min 5% A → 7.5min 5% A; Oven: 50℃; Flow rate: 0.35ml / min; UV detection: 210nm.

[0397] Method J

[0398] Instruments: Micromass Quattro Premier with Waters UPLC; Column: Thermo HypersilGOLD 1.9μm 50x 1mm; Eluent A: 1L water + 0.5ml 50% formic acid, Eluent B: 1L acetonitrile + 0.5ml 50% formic acid; Gradient: 0.0min 97% A → 0.5min 97% A → 3.2min 5% A → 4.0min 5% A; Oven: 50℃; Flow rate: 0.3ml / min; UV detection: 210nm.

[0399] Method K

[0400] Mass spectrometry instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.0x50mm 3.5μm; Eluent A: 1L water + 0.01mol ammonium carbonate, Eluent B: 1L acetonitrile; Gradient: 0.0min 98% A → 0.2min 98% A → 3.0min 5% A → 4.5min 5% A; Oven: 40℃; Flow rate:

[0401] 1.75 ml / min; UV detection: 210 nm

[0402] Method L

[0403] MS instrument type: Waters Synapt G2S; UPLC instrument type: Waters Acquity I-CLASS; Column: Waters, HSST3, 2.1 x 50 mm, C18 1.8 μm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 2% B → 2.0 min 2% B → 13.0 min 90% B → 15.0 min 90% B; Oven: 50℃; Flow rate: 1.20 ml / min; UV detection: 210 nm.

[0404] Method M

[0405] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 226 nm, with a range of 40 nm. The column was a Zorbax Bonus-RP, 150 mm in length, 3.0 mm in inner diameter, and 3.5 μm in particle size. The mobile phase consisted of: A: water + 0.1% TFA, and B: ACN.

[0406] +0.1% TFA / methanol = 2+1, gradient program: 0.0 min 50% B → 12.0 min 70% B →

[0407] 17.0 min 90% B → 25.0 min 90% B; Flow rate: 0.60 ml / min; Sample solvent: isopropanol + 0.1% diethylamine; Analytical solution: Dissolve approximately 35 mg of the substance in 25 ml of ACN, and then add water + 0.1% TFA (0.7 mg / ml) to a final volume of 50 ml; Injection volume: 3 μl

[0408] Method N

[0409] High-performance liquid chromatography (HPLC) was performed using a constant-temperature column oven, a UV detector, and a data evaluation system. The measurement wavelength was 210 nm. The column was an XBridge BEH Phenyl, 50 mm in length, 4.6 mm in inner diameter, and 2.5 μm in particle size. The mobile phase consisted of: A: 0.66 g (NH4)2HPO4 and 0.58 g (NH4)H2PO4 in 1 L of millipore water; B: ACN. The gradient program was: 0.0 min 95% B → 8.3 min 80% B → 11.0 min 80%. The flow rate was 1.2 mL / min. The sample solvent was ACN + water, and the injection volume was 3 μL.

[0410] Raw materials and intermediates

[0411] Example 1

[0412] 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate

[0413]

[0414] In a 40 L reaction vessel, 12.6 L of tetrahydrofuran and 0.62 kg (11.05 mol) of potassium hydroxide (powder, 85%) were cooled to -10 °C, and a solution of 813.3 g (5.53 mol) of 4-(2-hydroxyethyl)benzyl nitrile in 1.2 L of tetrahydrofuran was added over 13 min. Subsequently, 1.370 kg (7.18 mol) of 4-toluenesulfonyl chloride was added in portions; the mixture was stirred at -10 °C for 20 min, heated to 22 °C, and stirred at 22 °C for 1.5 h. 12.2 L of water and 12.2 L of dichloromethane were added, and the mixture was stirred for 20 min, separating the organic phase. The aqueous phase was washed with 12.2 L of dichloromethane, and the combined organic phases were washed with 12.2 L of saturated ammonium chloride aqueous solution.

[0415] Two batches of organic phase were concentrated to 8.75 L under reduced pressure at 45 °C, and the residue was metered into 40.7 L of cyclohexane over 10 min. The container was rinsed with 1 L of dichloromethane, and the rinse solution was added to the cyclohexane. The mixture was concentrated to 24.4 L under reduced pressure at 41 °C; 24.4 L of cyclohexane was added, and the mixture was concentrated again to 24.4 L under reduced pressure at 41 °C. The suspension was cooled to 22 °C and stirred for 30 min. The solid was filtered off, washed with 8.2 L of cyclohexane, and dried in a vacuum drying oven at 40 °C.

[0416] Yield: 2.82 kg; 84.6% of theoretical value.

[0417] 1 H-NMR, DMSO:2.41(s,3H),2.99(t,2H),4.29(t,2H),7.21-7.42(dd,4H),7.52-7.72(dd,4H)

[0418] LC-MS (Method H):R t = 1.03 min, 302.1 [M+H] +

[0419] Example 2

[0420] 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzylnitrile

[0421]

[0422] In a reaction vessel, 1.507 kg (5.00 mol) of cyanophenylethyl toluenesulfonate (Example 1) was suspended in 3.8 L of tetrahydrofuran and heated under reflux (approximately 77 °C) for 2 hours together with 2.27 kg (15.0 mol) of 2-methoxyphenylethylamine and 1.012 kg (10.0 mol) of triethylamine. The mixture was cooled to 50 °C and 10.7 L of water was added. The solvent was distilled off under reduced pressure until only water remained. The residue was cooled to 22 °C and 6.78 L of hydrochloric acid (25%) was added over 40 min. The mixture was stirred for 30 min, the solid was filtered off by suction and washed with 1 L of water.

[0423] Two batches of solid were stirred with 15 L of water for 30 min, filtered by suction, and washed with 7.5 L of water. This process was repeated. The wet product was stirred with 7.5 L of ethyl acetate at 50 °C for 1.5 h, cooled to 22 °C, stirred at 22 °C for 1 h, filtered, washed with 5 L of ethyl acetate, and dried in a vacuum drying oven at 40 °C to obtain 2.13 kg. The dried product was stirred in 2.2 L of ethyl acetate and 5.38 L of hydrochloric acid (15%), filtered by suction, washed with 2.15 L of water, and dried in a vacuum drying oven at 40 °C to obtain 1.63 kg of hydrochloride.

[0424] The hydrochloride salt was dissolved in 8.25 L of dichloromethane and 8.25 L of water. The pH was adjusted to 13-14 using a 45% sodium hydroxide solution. The phase was separated, and the organic phase was washed with 2.75 L of water. The organic phase was concentrated under reduced pressure at 40 °C, 3 L of dichloromethane was added, and the mixture was concentrated again to obtain 1.44 kg of oil.

[0425] Yield: 1.44 kg; 51.5% of theoretical value.

[0426] 1 H-NMR,2.59-2.72(m,4H),2.77(s,4H),3.77(s,3H),6.80-6.98(m,2H),7.08-7.21(m,2H),7.41(d,2H),7.72(d,2H)

[0427] LC-MS (Method H):R t = 0.63 min, 281.2 [M+H] +

[0428] Example 3

[0429] (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile

[0430]

[0431] First, 1.0 kg of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxynitrile and 10.0 L of ethyl acetate were added to a 30 L stainless steel reactor. 1.175 kg of triethylamine was added metered over 15 min at 20 °C. 18.5 g of ruthenium (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] (CAS No.: 192139-92-7) was added to the solution at 20 °C. 1.337 kg of formic acid was added metered over 1 hour from 0 °C to 5 °C (gas release). The reaction was stirred at an internal temperature of 40 °C for 4 hours. Monitoring showed complete conversion after only 2 hours at 40 °C (laboratory HPLC). The reaction mixture was cooled to 20 °C and stirred overnight at 20 °C to release the gas. For post-treatment, the reaction mixture was mixed with 4.1 L of ethyl acetate and 4.1 L of 1N hydrochloric acid and stirred for another 15 min. Separation of the product phase. Approximately 13.9 L of a dark brown upper organic phase was obtained. The upper phase containing the product was mixed with 13.9 L of n-heptane. The mixture was concentrated under reduced pressure (approximately 800 mbar, external temperature approximately 40 °C) for approximately 2.5 hours until approximately 17.6 L of distillate was obtained. Another 13.9 L of n-heptane was added, and the mixture was concentrated again for approximately 2.5 hours until approximately 17.6 L of distillate was obtained (final volume of the mixture approximately 7 L). The mixture was cooled to approximately 20 °C and stirred overnight at 20 °C. The product was separated by filtration, and the crystals were washed twice with 3.7 L of n-heptane each time. The wet product was dried in a vacuum drying oven at an external temperature of approximately 40 °C for approximately 17 hours to constant mass.

[0432] Yield: 0.975 kg; 96% of theoretical value.

[0433] 1 H-NMR,DMSO(NBR 305-22-1):1.60-1.85(m,2H),1.90-2.05(m,2H),2.75-2.93(m,2H),4.65-4.70(m,1H),5.62(d,1H),7.85(d,1H),8.0(d,1H)

[0434] LC-MS (Method H):R t = 0.52 min 175.1 [M+H] +

[0435] Enantiomer purity (HPLC method D): 98.03% ee

[0436] Example 4

[0437] (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile

[0438]

[0439] In a 6L flask, a solution of 121.2 g (0.696 mol) of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 3) in 220 mL of dichloromethane was mixed with 211.2 g (2.09 mol) of diisopropylamine and cooled to -76°C under argon atmosphere. Over 85 min, 333.6 g (1.18 mol) of trifluoromethanesulfonic anhydride was added metered at -76°C to -69°C, followed by rinsing with 20 mL of dichloromethane, and the mixture was stirred for 20 min. Subsequently, over 35 min, a solution of 292.5 g (1.044 mol) of 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzylnitrile (Example 3) in 720 mL of dichloromethane was added metered at -75°C to -67°C, followed by rinsing with 80 mL of dichloromethane, and the mixture was stirred for 2 hours. Add 172.1 g (1.19 mol) of oxalic acid to the reaction mixture, remove the cooling bath, and stir the mixture overnight. Add 216 g of diatomaceous earth, adjust the reaction mixture to 0-5°C, and stir for 30 min. Filter the solid by suction. Wash the filter cake with 1680 ml of cold dichloromethane, and wash the filtrate with 2 L of water. Mix the organic phase with 2 L of water and adjust the pH to 8 with 40 ml of ammonia solution (27%), separating the aqueous phase. Concentrate the organic phase under reduced pressure at 40°C on a rotary evaporator to obtain an oil (380.3 g). Dissolve the oil in 758 ml of ethanol under reflux, cool to 40°C, inoculate the product, and further cool to room temperature. Filter the solid by suction, wash with 300 ml of ethanol, and dry in a vacuum drying oven at 25°C under a nitrogen stream.

[0440] Yield: 167.8g; (55.2% of theoretical value)

[0441] Enantiomer purity (HPLC method F): 87.9% ee

[0442] LC-MS (Method H): R t = 1.31 min 437.2 [M+H] +

[0443] Example 5

[0444] 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzylnitrile

[0445]

[0446] In a 2L flask, 155.6 g (1.167 mol) of aluminum chloride and 429.5 g (2.122 mol) of dodecyl mercaptan were stirred until dissolved (15 min). Over 30 min, a solution of 119.0 g (0.424 mol) of 4-(2-{[2-(2-methoxyphenyl)ethyl]amino}ethyl)benzyl nitrile (Example 2) in 418 mL of toluene was added at 10–20 °C. The mixture was washed with 42 mL of toluene and stirred overnight at 40 °C. The resulting solid was filtered off by suction, washed with 530 mL of dichloromethane, stirred with 800 mL of dichloromethane, and filtered off by suction. The wet product was dissolved in 835 mL of tetrahydrofuran, and 526 mL (2.33 mol) of saturated (360 g / L) potassium sodium tartrate solution was added under cooling. The two-phase mixture was filtered off by suction, the solid was stirred with 1 L of ethyl acetate, and filtered off by suction. The purified solid was suspended in 835 mL of tetrahydrofuran and stirred for 30 min with 526 mL (2.33 mol) of saturated (360 g / L) sodium potassium tartrate solution. The solid was filtered off from the filtrate containing the product and washed with 200 mL of tetrahydrofuran. The filtrates containing the product were combined, the organic phase was separated and concentrated. The residue was dissolved in 835 mL of dichloromethane, alkalized with 31 mL of ammonia solution (27%), and washed three times with 309 mL of water each time. The combined organic phases were washed with 155 mL of dichloromethane and concentrated to give an oil.

[0447] Crude yield: 70.8g; 62.6% of theoretical value.

[0448] LC-MS (Method I): R t = 1.20 min, 267.2 [M+H] +

[0449] Example 6

[0450] 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzylnitrile

[0451]

[0452] Method A:

[0453] In a 2L flask, 68.99 g (0.26 mol) of 4-(2-{[2-(2-hydroxyphenyl)ethyl]amino}ethyl)benzyl nitrile (Example 5) was dissolved in 690 mL of dichloromethane. Under cooling, 68.43 g (0.44 mol) of tert-butyldimethylsilyl chloride and 26.5 g (0.39 mol) of imidazole were added at 23°C to 33°C, and the mixture was stirred at room temperature for 16 hours. Subsequently, a solution of 60.85 g of potassium carbonate in 420 mL of water was added, and the organic phase was washed three times with 350 mL of water each time. The combined organic phases were washed with 80 mL of dichloromethane, dried over sodium sulfate, and concentrated on a rotary evaporator at 35°C to give 116.5 g of crude product.

[0454] Crude yield: 116.5g; 118% of theoretical value.

[0455] LC-MS (Method J): R t = 2.21 min, 381.3 [M+H] + 382.2

[0456] Method B:

[0457] At 25–35 °C, 2-(2-aminoethyl)phenol (9.1 g, 66.4 mmol, 2.0 equivalent) and triethylamine (13.8 ml, 99.5 mmol, 3.0 equivalent) were added to a solution of cyanophenethyl toluenesulfonate (10 g, 33.2 mmol, 1.0 equivalent) in THF (130 ml). The reaction mixture was then heated to reflux for 46 hours. Subsequently, THF was removed under reduced pressure at below 60 °C, and the remaining crude product was mixed with DCM (50 ml). The solution was then washed with saturated sodium bicarbonate solution (2 × 50 ml), and the organic phase was concentrated at below 45 °C.

[0458] Imidazole (6.8 g, 99.5 mmol, 3.0 equivalents) was added to the DCM solution (40 ml), followed by the addition of tert-butyl-dimethylsilyl chloride (14.0 g, 92.9 mmol, 2.8 equivalents) in portions. The reaction mixture was then stirred at 25–35 °C for 2 hours. After the reaction was complete, the reaction mixture was washed with water (2 × 100 ml). The solvent was replaced with methanol (100 ml) by vacuum distillation, and the mixture was heated to 65 °C. Oxalic acid (4.5 g, 49.7 mmol, 1.5 equivalents) was then added, and the mixture was stirred at 50–55 °C for 1–2 hours. The reaction mixture was gradually cooled to 5–10 °C and stirred for another 1–2 hours. The solid was then filtered off and washed with methanol (2 × 20 ml). The filtrate was then suspended in DCM / water (137 ml each) and stirred at 25–35 °C for several hours. Subsequently, 45% NaOH (4.5 ml) was added to obtain a pH of 10.5–12.5. After 1 hour, 70 ml of water was added and the phase was separated. The organic phase was concentrated under reduced pressure. The resulting residue corresponded to the target substance (6.78 g, 37%).

[0459] Yield: 6.78g; 37% of theoretical value.

[0460] Purity (area): 91.3% (Method N, R) t 11min)

[0461] Example 7

[0462] (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile

[0463]

[0464] In a 1 L flask, a solution of 15.0 g (86.1 mmol) of (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 3) in 250 mL of dichloromethane was mixed with 36.2 mL (0.26 mol) of diisopropylamine and cooled to -76 °C under argon atmosphere. Over 30 min, 24.6 mL (0.15 mol) of trifluoromethanesulfonic anhydride was added at -74 °C to -68 °C, and the mixture was stirred for 30 min. Subsequently, over 46 min, a solution of 49.2 g (0.13 mol) of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzylnitrile (Example 6) in 100 mL of dichloromethane was added at -75 °C to -72 °C, the mixture was rinsed with 20 mL of dichloromethane, and stirred for 2 hours. 9.93 g (86.1 mmol) of 85% phosphoric acid was added to the reaction mixture, and the reaction mixture was washed twice with 500 ml of water each time at room temperature. The combined aqueous phases were washed with 300 ml of dichloromethane, and the combined organic phases were concentrated under reduced pressure at 40 °C on a rotary evaporator to give an oil (96.6 g).

[0465] The oil was dissolved in 50 ml of dichloromethane and filtered through 150 g of silica gel. The product was eluted with 800 ml of ethyl acetate / n-hexane at a ratio of 1:2. The product solution was concentrated under reduced pressure in a rotary evaporator at 40 °C to give oil (79.3 g).

[0466] The product was dissolved in 50 ml of dichloromethane, filtered through 150 g of silica gel, and eluted with 750 ml of ethyl acetate / n-hexane at a ratio of 1:2. The eluent was concentrated on a rotary evaporator at 35 °C to give 48.2 g of crude product.

[0467] Crude product: 48.2g; 104% of theoretical value.

[0468] LC-MS (Method K): R t = 3.70 min 537.2 [M+H] +

[0469] Example 8

[0470] (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile

[0471]

[0472] In a 1 L flask, 48.2 g (not more than 86.1 mmol) of (5S)-5-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl][2-(4-cyanophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 7) was suspended in 550 mL of methanol, and 101.8 g of concentrated hydrochloric acid was added. The solution was stirred overnight at room temperature, and 150.9 g of 30% ammonia solution was added under cooling. The mixture was concentrated at 40 °C on a rotary evaporator. The solid residue was stirred for 30 min at room temperature in 480 mL of demineralized water and 250 mL of dichloromethane; the lower organic phase was washed with 450 mL of water and concentrated at 35 °C on a rotary evaporator to give 27.9 g.

[0473] Yield: 27.9g; 76.8% of theoretical value.

[0474] Enantiomer purity (HPLC method A): 91.4% ee

[0475] The residue was refluxed in 100 ml methanol / 10 ml demineralized water and heated. The suspension was cooled to room temperature and stirred for 2 hours. The solid was filtered off by suction, washed with 15 ml methanol, and dried in a vacuum drying oven at 50 °C.

[0476] Yield: 12.96g; 35.6% of theoretical value.

[0477] Enantiomer purity (HPLC method A): 98.6% ee

[0478] Example 9

[0479] (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0480]

[0481] Method A:

[0482] In a 25 ml flask, 1.0 g (2.4 mmol) of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 8) was suspended in 5.79 g of concentrated hydrochloric acid and stirred at 100 °C for 24 hours. The reaction solution was used directly in the next reaction stage (Example 10).

[0483] Method B:

[0484] In a 6L flask equipped with a gas scrubber (contents: 600g ethanolamine, 1200g 5% sodium hydroxide solution, 1200g isopropanol, and approximately 0.5g bromothymol blue), 332.5g (0.76mol) of (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 4) was heated to 108°C and stirred for 24 hours in 3210g (2.15ml) of 48% hydrobromic acid. The solution was cooled to 25°C and washed twice with 650ml of dichloromethane each time. The lower aqueous phase product was used in the next stage (Example 10). The sample was purified for analytical purposes.

[0485] LC-MS (Method H): R t = 0.73 min, 461.2 [M+H] +

[0486] Example 10

[0487] (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino

[0488] Butyl 5,6,7,8-tetrahydroquinoline-2-carboxylate

[0489]

[0490] Method A:

[0491] In a 6L flask, 1.5L of n-butanol was added to the aqueous product ((5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (Example 9). The solution was heated to boiling, and the butanol / water mixture was distilled off while continuously adding 6L of butanol until the temperature at the top of the column reached 117°C. The mixture was cooled to room temperature, and the precipitated salt was filtered off by suction filtration. The filter cake was washed with 600ml of butanol. The combined filtrates were concentrated under reduced pressure on a rotary evaporator at 65°C to give 521.7g. The residue was stirred with 2.2L of ethyl acetate and 1.1L of 14% ammonia solution for 30min to separate the organic phase. The residue was washed twice with 1L of water each time and concentrated under reduced pressure on a rotary evaporator at 40°C to give 409.6g of oil.

[0492] The oil was dissolved in 500 ml of dichloromethane, and then filtered successively through a filter covered with 1 kg of silica gel using 8 L of dichloromethane and 2 L of methanol. The product solution was concentrated on a rotary evaporator to obtain 337.8 g of oil.

[0493] Yield: 337.8g; 77.6% of theoretical value.

[0494] LC-MS (Method H): R t = 1.34 min, 573.3 [M+H] +

[0495] The sample was purified for analytical purposes.

[0496] 1 H-NMR, (400MHz, CDCl3): δ = 0.88 1.06(m,6H),1.36-1.53(m,4H),1.65-1.91(m,6H),2.05-2.31(m,2H),2.63-3.31(m,10H),4.19-4.34(m,2H),4.34-4.48(m,3H),6.69-6 .83(m,1H),6.88-6.96(m,2H),7.08-7.21(m,3H),7.71-7.85(m,1H),7.85–7.97(m,2H),8.00-8.15(m,1H),10.40-10.59(br.s,1H)ppm.

[0497] Method B

[0498] In an inertized 2L reactor, 850ml of dichloromethane containing (5R)-5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxynitrile (Example 3) (40g, 1.0 equivalent) was first added. Then, diisopropylamine (3.0 equivalent, 69.6g) was added, and the solution was cooled to T. out = -90℃. At T int At -77 to -67°C, a solution of trifluoromethanesulfonic anhydride (1.5 equivalents, 60 ml) and dichloromethane (150 ml) was metered in over approximately 1 hour. The mixture was then stirred for another 45 minutes. Finally, at T... int A solution of 4-(2-{[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}ethyl)benzyl nitrile (Example 6) (1.05 equivalent, 70 g) and dichloromethane (200 ml) was metered in over approximately 30 min at -78 to -70 °C. The mixture was then stirred for 1.5 hours. The mixture was then heated to T over 1 hour. int =20℃. First, add 3.6% hydrochloric acid (610 ml) to the second 2L reactor. Add the reaction mixture and stir for 5 min. Allow the phases to separate, separating the aqueous phase (discard). At standard pressure and T... out The organic phase was concentrated to the stir limit at 60°C. 25% hydrochloric acid was added, and the mixture was stirred at standard pressure and T. out The mixture was distilled at 85°C until it became dry. Afterward, it was heated to reflux (T0).int =103℃, T out =125℃) and stir for another 5 hours. Then cool the mixture to T int =40℃ and stir for another 14 hours. Then, filter the resulting suspension, add n-butanol (800 ml) to the filtrate, and concentrate the mixture until the internal temperature reaches T. int =88℃. Add n-butanol again (800 ml), and concentrate the mixture to T under the same conditions. int =90℃. Add n-butanol again (800 ml), and concentrate the mixture to T under the same conditions. int =102℃. Add n-butanol (800 ml) for the final step, and concentrate the mixture to the stir limit under the same conditions. Cool the solution to T. int =22℃. Add ethyl acetate (800ml), demineralized water (400ml), and potassium carbonate (44g), and stir the mixture for another 10 minutes. Allow the phases to separate, and discard the aqueous phase. Add demineralized water (385ml) and sodium chloride (43kg) to the organic phase, and stir the mixture for 10 minutes. Allow the phases to separate, and discard the aqueous phase. Add demineralized water (200ml) to the organic phase, and stir the mixture for 10 minutes. Allow the phases to separate, and discard the aqueous phase. Under reduced pressure of 120 mbar and T out Concentrate the organic phase to the limit of stirability at 45-55℃. Cool the solution to T. int =22℃ and distributed.

[0499] Yield: 68.3 kg solution, purity 23.1%, 52%

[0500] Purity (area): 66.6% (Method N, R) t (11 min)

[0501] Example 11

[0502] (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate

[0503]

[0504] At room temperature, 197.2 g (0.56 mol) of 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] was added to a 6 L flask containing 337 g (0.56 mol) of (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 10) in 3765 g of acetonitrile. 551.3 g (1.70 mol) of cesium carbonate was added to the solution, and the mixture was stirred for 21 hours until conversion was complete. Subsequently, the salt was filtered off by suction and washed with 600 mL of acetonitrile. The combined filtrates were concentrated at 40 °C on a rotary evaporator to give 484.4 g of oil.

[0505] Crude yield: 484.4g; 103% of theoretical value.

[0506] Enantiomer purity (HPLC method B): 100.0% ee

[0507] LC-MS (Method L): R t = 14.63 min 841.36 [M+H] + .

Claims

1. A method for preparing compound of formula (X), , Its features are, In the first step, trifluoromethanesulfonic anhydride is added to compound (III) at a temperature of -78°C to -65°C in the presence of a base selected from sterically hindered secondary amines and 2,6-disubstituted pyridines. (III) In the second step, it reacts with the compound of formula (XIV) at a temperature of -78°C to -65°C. In the third step, the reaction product is finally reacted with hydrochloric acid at a temperature of 90°C to 110°C, and in the fourth step, the reaction product is reacted with n-butanol in the presence of hydrochloric acid, wherein the solution is heated to boiling and the butanol / water mixture is distilled off with continuous addition of n-butanol until the temperature at the top of the column reaches 117°C, further wherein all intermediate products are not separated or purified.

2. A method for preparing compound of formula (IX), (IX) , Its features Compounds of formula (XVI) (XVI) It reacts with hydrochloric acid at temperatures ranging from 90°C to 110°C.

3. A method for preparing compounds of formula (XVI), (XVI) Its features Compound of formula (XV-1) (XV-1) in R 2 It is a silyl protecting group. It reacts with hydrochloric acid in methanol.

4. (5S)-5-{[2-(4-cyanophenyl)ethyl][2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxynitrile of formula (XVI) (XVI) And its salt.

5. A method for preparing compounds of formula (XV-1), (XV-1) Its features are, In the first step, at a temperature of -90°C to -50°C, in the presence of 3 equivalents of diisopropylamine and trifluoromethanesulfonic anhydride, compound of formula (III) is added. (III) And in the second step, it reacts with the compound of formula (XVI-1). (XIV-1), in R 2 It is a silyl protecting group.

6. A method for preparing compound of formula (XIV-1), (XIV-1) Its features Compounds of formulas (XVII) and (V) (XVII) and (V) In the first step, coupling is performed in the presence of triethylamine at a molar ratio of 3:1 or higher, based on compound (V); and The reaction product is also reacted with a suitable silyl chloride in the presence of an amine base in the second step.

7. A method for preparing compounds of formula (III), characterized in that... Compound of formula (II) (II) In the first step, the compound is reacted with triethylamine and ruthenium chloride (p-cymene)[(R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine], and in the second step, formic acid is added at a temperature of -5 to 10°C to remove the generated gas. Stirring is continued at a temperature of 20 to 50°C to obtain compound (III). (III)。

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