Synthesis of cyclopropanecarboxylic acid

Abstract

The present disclosure provides methods for preparing substituted cyclopropane compounds. The present disclosure relates to processes for preparing substituted cyclopropane-containing compounds with defined stereochemistry that have utility in the preparation of pharmaceutical compounds, particularly plasma kallikrein (pKAL) inhibitors, novel compounds, compounds obtained and obtainable from the processes, pharmaceutical formulations comprising any one of the above, and uses of said pharmaceutical compounds and pharmaceutical formulations in therapy. The development and execution of the synthesis of hundreds of grams of drug substance is often the rate-limiting step in the period from the designation of a development candidate to the initiation of Phase I clinical trials.

Description

[Technical Field]

[0001] The present disclosure relates to processes for preparing compounds containing substituted cyclopropanes with defined stereochemistry that have utility in the preparation of pharmaceutical compounds, particularly plasma kallikrein (pKAL) inhibitors, novel compounds, compounds obtained and obtainable from the processes, pharmaceutical formulations comprising any one of the above, and uses of said pharmaceutical compounds and pharmaceutical formulations in therapy. [Background technology]

[0002] The development and execution of hundreds of grams of drug substance synthesis is often the rate-limiting step in the time period between candidate designation and the initiation of Phase I clinical trials. In many cases, the initial discovery pathway provides a good starting point, and the reaction chemist has the role of refining some of the reaction conditions and workup to improve yield and purity, allowing for safe scale-up of the various steps, as well as finding isolation procedures that avoid chromatography as much as possible.

[0003] Currently, reaction chemists have to deal with sophisticated methods that often require expensive catalysts that are difficult to handle, as well as a large number of sp 3 and are faced with increased synthetic length and complexity due to the use of targeted drugs with stereocenters.

[0004] Cyclopropanes have become a common structural motif in medicinal chemistry because they often offer the advantage of restricted conformational freedom at the expense of reduced steric bulk and increased stability against oxidative metabolism compared to lower alkyl or other cycloalkyl substituents.

[0005] Certain oral pKAL inhibitors having a cyclopropane motif are disclosed in unpublished PCT Application No. PCT / US2022 / 020482.

[0006] The following route, shown in Scheme 1, was a discovered chemical route that was used to prepare some of the compounds of the present application.

[0007] Scheme 1 [ka] The conversion of compound 1 to compound 2 resulted in undesired side reactions and required chromatography to purify the compound to an adequate extent.

[0008] When the synthetic route is scaled up for pilot plant production, steps such as those shown in Scheme 1 are not suitable for commercial manufacture.

[0009] New routes to prepare key intermediates such as compound 3 in Scheme 1 are needed.

[0010] The disclosed method is a safe, scalable, and chromatography-free synthesis method that provides efficient resolution via the (S)-1-(1-naphthyl)ethylamine salt. For example, the synthesis of (2RS,3RS)-3-(4-methylpyrimidin-2-yl)cyclopropanecarboxylic acid is provided in three steps (58% yield) from 2-chloro-4-methylpyrimidine and its resolution via the (S)-1-(1-naphthyl)ethylamine salt or the (+)-dehydroabietylamine salt. The present disclosure provides, inter alia, the unexpected development of the palladium-catalyzed conjugate addition of potassium vinyltrifluoroborate to 2-chloro-4-methylpyrimidine to form an intermediate used in novel cyclopropane compounds via reaction with nitrogen ylides derived from t-bromobutyl acetate and DABCO. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] No. PCT / US2022 / 020482 Summary of the Invention [Means for solving the problem]

[0012] The invention is outlined in the following paragraphs.

[0013] 1. A process for the preparation of the trans racemate of formula (I), comprising: [ka] (In the formula, P 1 is a protecting group (e.g., tert-butyl), R 1 is H or optionally substituted C1-C6 alkyl The compound of formula (II): [ka] (In the formula, R 1 is defined above for compounds of formula (I), reacting (optionally in situ) with a nitrogen ylide, prepared as follows: α-haloesters (e.g., methyl chloroacetate and tert-butyl bromoacetate) By reacting with a tertiary amine (e.g., DABCO), forming a quaternary ammonium salt; followed by cleavage with an alkali metal base (e.g., Cs2CO3 or K2CO3) and / or an organic base (e.g., DBU), In a polar aprotic solvent (e.g., acetonitrile), Treat at high temperatures (e.g., 70-80°C), The process results in the formation of the compound of formula (I) (e.g., with high diastereoselectivity, e.g., 50:1, relative to the corresponding cis racemate).

[0014] 2. The process of paragraph 1, wherein the alpha haloester is tert-butyl bromoacetate.

[0015] 3. The process of paragraph 1 or 2, wherein the tertiary amine is DABCO.

[0016] 4. The process of any of the preceding paragraphs, wherein the alkali metal base is Cs2CO3.

[0017] 5. The process of any of the preceding paragraphs, wherein the polar aprotic solvent is acetonitrile.

[0018] 6. The process of any of the preceding paragraphs, wherein the elevated temperature is 70 to 80°C.

[0019] 7. The process of any of the preceding paragraphs, wherein the reaction is carried out for 12 to 30 hours, e.g., 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, e.g., 20 hours.

[0020] 8. The process described in paragraph 1, wherein the steps, reagents, and conditions are: [ka] (In the formula, R 1 and P 1 is defined above for compounds of formula (I).

[0021] 9. The compound of formula (II) is converted into an intermediate of formula (III): [ka] (In the formula, R 1 is as defined above for compounds of formula (I), and L 1 represents a leaving group such as a halogen, particularly Cl), The process of any of the preceding paragraphs, wherein the compound is prepared by reacting with a vinyl trihaloborate (vinyl trifluoroborate, especially a salt thereof such as potassium).

[0022] 10. The protecting group P 1is removed from the compound of formula (I) by a) or b) below to give a free carboxylic acid of formula (IV): [ka] is released as the trans racemate (e.g., in high diastereomeric purity, particularly essentially free of the cis racemate): a) Acidolysis using an organic acid (e.g., TFA) in a chlorinated solvent (e.g., DCM) or b) Saponification using an alkali metal hydroxide (such as sodium hydroxide) in an aqueous medium (such as THF and water) A process according to any of the preceding paragraphs, followed by acidification (e.g. with aqueous hydrochloric acid) to liberate the free acid from the salt so formed.

[0023] 11. A process for resolving a compound of formula (IV) essentially into one or the other of its enantiomeric forms to obtain, for example, a compound of formula (V) (absolute configuration as shown): [ka] For example, the resolution can be carried out by reaction with an optically pure chiral amine, such as (S)-1-(naphthalen-2-yl)ethanamine or (S)-1-(naphthalen-1-yl)ethanamine, In a suitable solvent (such as ethyl acetate, isopropanol, and dimethyl carbonate), The process wherein a mixture of diastereomeric salts is formed and the preferred diastereomeric salt is crystallized from the mixture and recovered by filtration.

[0024] 12. The free acid is converted to the salt by rinsing the salt with an excess of an aqueous solution of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide); 12. The process of paragraph 11, wherein the organic base is removed by treatment in the presence of a non-miscible organic solvent (e.g., toluene or MTBE) and recovered from the salt by retaining the aqueous solution.

[0025] 13. The process of paragraph 12, wherein the aqueous solution is acidified with an inorganic acid (e.g., hydrochloric acid) to a pH of 3-4 to precipitate the free acid as a solid, and the solid is recovered by filtration.

[0026] 14. The process of any one of paragraphs 11 to 14, wherein the compound of formula (V) is enantiomerically enriched, particularly having an enantiomeric purity (ee value) of 90% or more, for example 91, 92, 93, 94, 95, 96, 96, 97, 98, 99, or 100%, particularly 99%.

[0027] 15.R 1 But C 1~3 The process of any of the preceding paragraphs wherein alkyl is, for example, methyl, ethyl, propyl or isopropyl, particularly methyl.

[0028] 16.P1 is C 1~4 The process of any of the preceding paragraphs wherein the alkyl is, for example, t-butyl.

[0029] 17. A compound of formula (V) is reacted with an arylamine of formula (VI): [ka] (In the formula, R 2 is H or C 1~3 is alkyl, and L 2 is a leaving group, for example a halogen, in particular Cl), to obtain a compound of formula (VII): [ka]

[0030] 18. The compound of formula (VII) is prepared by reacting with compound (VIIa): [ka] 18. The process of paragraph 17, wherein

[0031] 19. The compound of formula (VII) is a compound (VIIb): [ka] 18. The process of paragraph 17, wherein

[0032] 20. A compound of formula (VII) is reacted with a compound of formula (VIII) [ka] to form a compound of formula (IX) [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 and R 2 is defined above).

[0033] 21. The compound of formula (VII) is compound (VIIa), and the compound of formula (IX) is compound (IXa): [ka] 21. The process of paragraph 20, wherein

[0034] 22. The compound of formula (VII) is compound (VIIb), and the compound of formula (IX) is compound (IXb): [ka] 21. The process of paragraph 20, wherein

[0035] 23. A compound obtained or obtainable from any one of the preceding paragraphs.

[0036] 24. A compound of formula (I), (II), (IV), (V), (VI), (VII), (VIIa), (VIII), (IX), (IXa), or (IXb).

[0037] 25. A pharmaceutical composition comprising a compound according to paragraph 22 or 23 and an excipient, diluent, or carrier.

[0038] 26. A compound according to paragraph 23 or 24, or a pharmaceutical composition according to paragraph 25, for use in therapy, particularly as a pKAL inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0039] Compound synthesis The compounds of the present disclosure can be synthesized according to the schemes described below and in the Examples below. The reagents and conditions described are for illustrative purposes only and are not intended to be limiting. As will be recognized by those skilled in the art, various analogs can be prepared by modifying the synthetic reaction, such as by using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, catalyst, activator, etc.).

[0040] In one aspect, the present disclosure provides methods for improved synthesis of compounds of formula (I), (II), (III), (IV), (V), (VII), and (IX) above, or salts thereof. It will be recognized that certain disclosed compounds are novel intermediates for other disclosed compounds and are also an aspect of the present disclosure. In some embodiments of compounds of formula (I), (II), (III), (IV), (V), (VII), and (IX), R 1 is C 1~6 As used herein, alkyl refers to straight or branched chain alkyl, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. In one embodiment, alkyl refers to straight chain alkyl. C 1~6 Alkyl refers to alkyl groups having up to six carbons. 1~3Alkyl refers to an alkyl group having up to 3 carbons. As used herein, optionally substituted alkyl refers to an alkyl group in which 1 or 2 carbon atoms in the alkyl group have been replaced with a heteroatom independently selected from N, O, and / or the alkyl group is substituted with 1 to 6 of the R groups described below. 3 That is, it means having a group: R 3 is oxo, hydroxy, halogen (F, Cl, etc.), CN, C 1~3 Alkyl, C 3~5 Cycloalkyl, -OC 1~3 Alkyl (e.g., -OCH3), -(O) with 1 to 6 halogen groups (e.g., CF3 or OCHF2) 0~1 C 1~3 Alkyl, one or more OR 4 C with group 1~3 Alkyl, -C(O)C 1~3 Alkyl NR 4 R 5 , -SO2C 1~3 Alkyl, -SO2NR 4 R 5 , -NR 4 R 5 (NH2, etc.) R 4 is H or C such as -CH3 1~3 is alkyl, R 5 is H or C such as -CH3 1~3 It is alkyl.

[0041] General synthesis of selected cyclopropanecarboxylic acids In one aspect, the present disclosure provides a method for synthesizing compound S1.4, or a salt thereof. In some embodiments, the present disclosure provides a method for synthesizing compound S1.4 (trans racemate) or a salt thereof. In some embodiments, the present disclosure provides a method for synthesizing compound S1.4 (optically enriched) or a salt thereof. In some embodiments, such a method is as shown in Scheme A below:

[0042] Scheme A [ka] (In the formula, Cy B , X A , and Pr G each of which is as defined herein).

[0043] In step S-1, compound S1.1 undergoes a coupling reaction with a vinyl compound under appropriate conditions to give vinyl compound S1.2. Those skilled in the art will recognize that sp 2 -sp 2 It will be appreciated that a variety of conditions suitable for forming the bond are well known. In some embodiments, S-1 comprises a Suzuki-Miyaura reaction, the conditions of which are well known to those of skill in the art.

[0044] In some embodiments, step S-1 comprises treating S1.1 with a vinyl boron compound (e.g., vinyl boronic acid, pinacol ester, or vinyl trifluoroborate) under appropriate conditions. In some embodiments, step S-1 comprises treating S1.1 with potassium vinyl trifluoroborate under appropriate conditions.

[0045] In some embodiments, step S-1 includes the presence of a suitable base (e.g., pyridine, triethylamine, DBU, tetramethylguanidine, CsF, NaOH, KOH, Na2CO3, K3PO4, Cs2CO3, or K2CO3). In some embodiments, step S-1 includes using K2CO3 as the base.

[0046] In some embodiments, step S-1 includes a suitable precatalyst or catalyst (e.g., Pd(OAc)2·2(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), PdCl2(PPh3)2, or Pd(OAc)2·dppf). In some embodiments, step S-1 includes a suitable precatalyst, such as Pd(OAc)2. In some embodiments, step S-1 includes a suitable catalyst ligand, such as dppf. In some embodiments, step S-1 includes the precatalyst Pd(OAc)2·dppf. In some embodiments, step S-1 includes the precatalyst PdCl2·dppf. In some embodiments, step S-1 includes the precatalyst PdCl2·(PPh3)2.

[0047] In some embodiments, step S-1 is performed at a temperature of about 60°C to about 120°C. In some embodiments, step S-1 is performed at a temperature of about 80°C to about 100°C. In one embodiment, step S-1 is performed at a temperature of about 90°C.

[0048] In some embodiments, step S-1 includes a suitable solvent (e.g., dioxane, water, THF, ethanol, or a combination thereof). In some embodiments, the solvent in step S-1 is or includes dioxane. In some embodiments, the solvent in step S-1 is or includes water. In some embodiments, the solvent in step S-1 is or includes a mixture of dioxane and water.

[0049] In some embodiments, step S-1 comprises an inert atmosphere. In some embodiments, step S-1 comprises an atmosphere that is substantially devoid of oxygen gas. In some embodiments, step S-1 comprises a nitrogen gas atmosphere. In some embodiments, step S-1 comprises an argon gas atmosphere.

[0050] In some embodiments, step S-1 comprises filtration.

[0051] In some embodiments, step S-1 includes purification. In some embodiments, the purification operation of step S-1 is or includes distillation. In some embodiments, step S-1 includes vacuum distillation. In some embodiments, step S-1 includes purification by vacuum distillation.

[0052] In some embodiments, the present disclosure provides: a) Formula Cy B -X A (In the formula, Cy B and X A is as defined herein) to obtain a compound S1.1, b) Cy B -X A is reacted with a vinyl boronate reagent under appropriate conditions to give a heteroaromatic vinyl compound of formula S1.2: [ka] or a salt thereof.

[0053] In step S-2, the vinyl compound S1.2 is cyclopropanated under appropriate conditions to yield the trans-racemic cyclopropane ester S1.3. Without being bound by any particular theory, in some embodiments, step S-2 involves reacting the vinyl group with ammonium ylide to yield S1.3. In some embodiments, step S-2 involves forming an ammonium halide salt from an alpha halogen ester (e.g., t-butyl bromoacetate, methyl chloroacetate) with a tertiary amine or nucleophile (e.g., DABCO, quinuclidine, O-methylquinine, triphenylphosphine, etc.) prior to contacting with the compound of formula S1.2. In some embodiments, step S-2 involves forming the ammonium halide salt prior to contacting with the compound of formula S1.2. In some embodiments, step S-2 involves forming the ammonium halide salt prior to contacting with the compound of formula S1.2. In some embodiments, step S-2 involves forming the ammonium halide salt after contacting with the compound of formula S1.2.

[0054] In some embodiments, step S-2 includes a suitable base (e.g., CsCO, KCO, DBU, AgCO, potassium tert-butoxide, tetramethylguanidine, triethylamine, etc.). In some embodiments, step S-2 includes a suitable base selected from ground CsCO or ground KCO. In some embodiments, step S-2 includes ground CsCO.

[0055] In some embodiments, step S-2 comprises a suitable solvent (e.g., acetonitrile, dichloromethane, dimethylformamide, tetrahydrofuran, toluene, or dioxane). In some embodiments, step S-2 comprises acetonitrile.

[0056] In some embodiments, step S-2 is performed at a temperature of about 20°C to about 100°C. In some embodiments, step S-2 is performed at a temperature of about 70°C to about 90°C. In some embodiments, step S-2 is performed at a temperature of about 80°C.

[0057] In some embodiments, the present disclosure provides: a) heteroaromatic vinyl compounds of formula S1.2: [ka] (In the formula, Cy B as defined herein); b) reacting a heteroaromatic vinyl compound of formula S1.2 under appropriate conditions to give a cyclopropane ester of formula S1.3: [ka] or a salt thereof (wherein Pr G is a suitable protecting group as defined herein.

[0058] In step S-3, the cyclopropane ester S1.3 is converted to the trans racemic cyclopropane acid S1.4 under appropriate conditions. G The group is removed to provide S1.4. In some embodiments, step S-3 includes a suitable acid (e.g., trifluoroacetic acid, hydrochloric acid, sulfuric acid, tosylic acid, or phosphoric acid). In some embodiments, step S-3 includes a suitable solvent (e.g., dichloromethane, methanol, ethyl acetate, water, or a combination thereof). In some embodiments, step S-3 includes a suitable base (e.g., sodium hydroxide). In some embodiments, step S-3 is performed at a temperature of about 0°C to about 100°C. In some embodiments, step S-3 is performed at a temperature of about 5°C to about 25°C. In some embodiments, step S-3 is performed at a temperature of about 15°C.

[0059] In some embodiments, the present disclosure provides: a) obtaining a cyclopropane ester of formula S1.3; [ka] b) reacting a cyclopropane ester of formula S1.3 under appropriate conditions to provide a carboxylic acid of formula S1.4: [ka] or a salt thereof.

[0060] In step S-4, the enantiomerically enriched cyclopropanoic acid S1.4 (optically enriched) is isolated from the trans-racemic cyclopropanoic acid S1.4. In some embodiments, step S-4 comprises chiral chromatography. In some embodiments, step S-4 comprises chiral resolution under appropriate conditions (e.g., chiral salts). Chiral salts are well known in the art, and non-limiting examples include crystallization agents such as arylamines and amino alcohols. In some embodiments, step S-4 comprises a chiral salt selected from (+)-dehydroabietylamine, (R)-(+)-1-(2-naphthyl)ethylamine, (S)-(-)-1-(2-naphthyl)ethylamine, or (S)-(-)-1-(1-naphthyl)ethylamine. In some embodiments, step S-4 comprises a chiral resolving agent. In some embodiments, step S-4 comprises the resolving agent (S)-(-)-1-(1-naphthyl)ethylamine. In some embodiments, step S-4 comprises a recrystallization step. In some embodiments, step S-4 comprises one, two, or more recrystallizations. In some embodiments, step S-4 comprises a suitable solvent (e.g., ethyl acetate, isopropyl acetate, acetonitrile, ethanol, dioxane, methanol, dichloromethane, chloroform, isopropanol, tetrahydrofuran, toluene, IMS (industrial methylated spirits, ethanol:methanol=95:5), methanol, tert-butyl methyl ether, water, dioxane, 1,2-dimethoxyethane, 2-methyltetrahydrofuran, dimethyl carbonate, diethyl carbonate, ethylene carbonate, or a combination thereof). In some embodiments, the suitable (re)crystallization solvent is or comprises dimethyl carbonate. In some embodiments, step S-4 comprises one, two, or three recrystallizations with a co-crystallizing agent (e.g., (+)-dehydroabietylamine, (R)-(+)-1-(2-naphthyl)ethylamine, (S)-(−)-1-(2-naphthyl)ethylamine, or (S)-(−)-1-(1-naphthyl)ethylamine).In some embodiments, step S-4 comprises recrystallizing (S)-(-)-1-(1-naphthyl)ethylamine once, twice, or three times. In some embodiments, step S-4 comprises recrystallizing (S)-(-)-1-(1-naphthyl)ethylamine once, twice, or three times in dimethyl carbonate under reflux conditions. In some embodiments, step S-4 comprises washing the solid with a solvent (e.g., dimethyl carbonate). In some embodiments, step S-4 comprises a recrystallization solvent and compound at a relative concentration of about 0.10 mL / mmol to about 20 mL / mmol. In some embodiments, step S-4 comprises a recrystallization solvent and compound at a relative concentration of about 0.25 mL / mmol to about 12 mL / mmol. In some embodiments, step S-4 comprises a recrystallization solvent and compound at a relative concentration of about 0.50 mL / mmol to about 4 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 0.75 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 0.25 mL / mmol to about 1.75 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 0.5 mL / mmol to about 1.25 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 2 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 4 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 12 mL / mmol. In some embodiments, step S-4 includes the recrystallization solvent and compound at a relative concentration of about 20 mL / mmol. In some embodiments, step S-4 comprises cooling a refluxing solution of S1.4 and a co-crystallization agent (e.g., (+)-dehydroabietylamine, (R)-(+)-1-(2-naphthyl)ethylamine, (S)-(−)-1-(2-naphthyl)ethylamine, or (S)-(−)-1-(1-naphthyl)ethylamine) at a rate of about 0.2° C. / hour.In some embodiments, step S-4 further comprises treating the recrystallized chiral salt with a suitable base (e.g., aqueous NaOH) under appropriate conditions, optionally in the presence of a suitable solvent (e.g., dichloromethane or methyl tert-butyl ether), to obtain cyclopropanoic acid S1.4 (optically enriched). In some embodiments, step S-4 comprises treating an extracted solution of S1.4 (optically enriched) with a suitable acid (e.g., aqueous HCl). In some embodiments, step S-4 comprises treating an extracted solution of S1.4 (optically enriched) with a suitable acid to an endpoint of about pH 3-4 (e.g., about 3.44). In some embodiments, step S-4 comprises recovering the precipitated S1.4 (optically enriched) by filtration.

[0061] In some embodiments, the present disclosure provides: a) obtaining a trans racemic cyclopropanecarboxylic acid of formula S1.4; [ka] b) contacting the trans racemic cyclopropanecarboxylic acid of formula S1.4 with a chiral chemical environment (e.g., chiral chromatography or a chiral co-crystallizing agent such as a chiral amine base) under appropriate conditions to produce the cyclopropanecarboxylic acid of formula S1.4 (optically enriched): [ka] or a salt thereof.

[0062] In certain embodiments, each of the above synthetic steps can be performed sequentially, with isolation of each intermediate after each step. Alternatively, each of steps S-1, S-2, S-3, and S-4 shown in Scheme A above can be performed in a manner that does not involve isolation of one or more of intermediates S1.2, S1.3, or S1.4.

[0063] In certain embodiments, all steps of the above synthetic methods can be performed to prepare the desired final product, while in other embodiments, two, three, four, five, or more sequential steps can be performed to prepare an intermediate or the desired final product.

[0064] It will be appreciated that in the optically enriched compounds described herein, it is useful to provide at least one means of physical separation by the physicochemical properties of the stereoisomers (e.g., diastereomers or enantiomers).

[0065] Although a single enantiomer (optically enriched) of formula S1.4 is shown, it will be recognized that the other enantiomer can be isolated and enriched from the resolution described herein in step S-4 when a resolving agent such as (R)-(+)-1-(1-naphthyl)ethylamine is used to yield a compound with the opposite stereochemistry at each chiral center.

[0066] In some embodiments, Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms, provided that Cy B 0 to 4 -R B In some embodiments, Cy is substituted with a group. B 0 to 3 -R B In some embodiments, Cy is a pyrimidinyl group substituted with a cysteine ​​group. B 0 to 4 -R B In some embodiments, Cy is a pyridinyl group substituted with a cysteine ​​group. B 0 to 3 -R B In some embodiments, Cy is a pyrazinyl group substituted with a cysteine ​​group. B 0 to 3 -R B In some embodiments, Cy is a pyridazinyl group substituted with a group. B 0 to 2 -R B In some embodiments, Cy is a 1,2,3-triazinyl group substituted with a cysteine ​​group. B 0 to 2 -R BIn some embodiments, Cy is a 1,2,4-triazinyl group substituted with a cysteine ​​group. B 0 to 2 -R B It is a 1,3,5-triazinyl group substituted with a group.

[0067] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0068] In some embodiments, Cy B teeth, [ka] is selected from the group consisting of:

[0069] In some embodiments, Cy B teeth, [ka] is.

[0070] In some embodiments, Cy B teeth, [ka] is.

[0071] In some embodiments, each R B are independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where each R is independently hydrogen; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN; a hydroxyl protecting group, or an amino protecting group.

[0072] In some embodiments, R B An example of R is oxo. B An example of R is halogen. In some embodiments, R B An example of R is fluorine. B An example of R is chlorine. B An example of R is -CN. In some embodiments, R B A single example of is -NO. In some embodiments, R B A single example of is -N(R). In some embodiments, R B An example of R is -NHR. B An example of R is -NH. In some embodiments, R B An example of is -N(R)C(O)R. In some embodiments, R B An example of R is -OR. In some embodiments, R B A single example of is -OMe. In some embodiments, R B An example of R is -OCF. In some embodiments, R B An example is -OCHF2.

[0073] In some embodiments, R B An example of R is a C1-6 aliphatic substituted with halogen, oxo, -OR, or -CN. B An example of R is a C1-6 aliphatic group substituted with a halogen. B An example of R is methyl. B An example of R is -CF. In some embodiments, R B An example is -CHF2.

[0074] In some embodiments, R B An example of is -OR, where each R is hydrogen or C optionally substituted with halogen. 1~6 independently selected from aliphatic.

[0075] In some embodiments, R B An example of is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0076] In some embodiments, X A is halogen, triflate, mesylate, or tosylate. A is a halogen. In some embodiments, X A is chloro, bromo, or iodo. In some embodiments, X A is triflate, mesylate, or tosylate. A is chloro. In some embodiments, X A is bromo. In some embodiments, X A is iodine. In some embodiments, X A is a triflate.

[0077] In some embodiments, Pr G is a suitable carboxylic acid protecting group. In some embodiments, Pr G is methyl. In some embodiments, Pr G is ethyl. In some embodiments, Pr G is tert-butyl. In some embodiments, Pr G is benzyl.

[0078] The following numbered embodiments illustrate, but are not limiting of, certain aspects of the present disclosure.

[0079] 1. Optically enriched compound of formula S1.4: [ka] or a salt thereof, wherein Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms (provided that Cy B0 to 4 -R B substituted with a group; Each R B are independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R is independently hydrogen; a C1-6 aliphatic optionally substituted with halogen, oxo, or —CN; a hydroxyl protecting group, or an amino protecting group. And, a) obtaining a trans racemic cyclopropanecarboxylic acid of formula S1.4; [ka] b) contacting the trans racemic cyclopropanecarboxylic acid of formula S1.4 with a chiral chemical environment (e.g., chiral chromatography or a chiral co-crystallizing agent such as a chiral amine base) under appropriate conditions to produce an optically enriched cyclopropanecarboxylic acid of formula S1.4: [ka] or a salt thereof.

[0080] 2. The method of embodiment 1, wherein the chiral chemical environment comprises a chiral co-crystallization agent and step b) comprises a recrystallization step.

[0081] 3. The method of any one of embodiments 1-2, wherein the co-crystallization agent comprises a chiral amine base.

[0082] 4. The method of embodiment 3, wherein the chiral amine base is selected from (+)-dehydroabietylamine, (R)-(+)-1-(2-naphthyl)ethylamine, (S)-(-)-1-(2-naphthyl)ethylamine, or (S)-(-)-1-(1-naphthyl)ethylamine.

[0083] 5. The method of embodiment 4, wherein the chiral amine base is (S)-(-)-1-(1-naphthyl)ethylamine.

[0084] 6. The method of any one of the preceding embodiments, wherein step b) comprises a suitable recrystallization solvent (e.g., ethyl acetate, isopropyl acetate, acetonitrile, ethanol, dioxane, methanol, dichloromethane, chloroform, isopropanol, tetrahydrofuran, toluene, IMS (industrial methylated spirits, ethanol:methanol=95:5), methanol, tert-butyl methyl ether, water, dioxane, 1,2-dimethoxyethane, 2-methyltetrahydrofuran, dimethyl carbonate, diethyl carbonate, ethylene carbonate, or a combination thereof).

[0085] 7. The method of embodiment 7, wherein the recrystallization solvent is or comprises dimethyl carbonate.

[0086] 8. The method of any one of the preceding embodiments, wherein step b) comprises one, two, or three recrystallizations from (S)-(-)-1-(1-naphthyl)ethylamine in dimethyl carbonate under reflux conditions.

[0087] 9. The method of any one of the preceding embodiments, wherein step b) comprises washing the solid with dimethyl carbonate.

[0088] 10. The method of any one of the preceding embodiments, wherein step b) comprises a solvent for recrystallization and compound at a relative concentration of about 0.25 mL / mmol to about 12 mL / mmol.

[0089] 11. The method of embodiment 10, wherein step b) comprises a solvent for recrystallization and a compound at a relative concentration of about 0.75 mL / mmol.

[0090] 12. The method of any one of the preceding embodiments, wherein step b) comprises cooling the refluxing solution of S1.4 and co-crystallization agent at a rate of about 0.2° C. / hr.

[0091] 13. The method of any one of the preceding embodiments, comprising treating the recrystallized chiral salt formed in step b) with a suitable base (e.g., aqueous NaOH) under appropriate conditions, optionally in the presence of a suitable solvent (e.g., dichloromethane or methyl tert-butyl ether), to obtain optically enriched cyclopropanoic acid S1.4.

[0092] 14. The method of embodiment 13, wherein the base is aqueous NaOH.

[0093] 15. The method of embodiment 13 or 14, wherein the solvent is dichloromethane.

[0094] 16. The method of any one of the preceding embodiments, comprising treating the optically concentrated extract solution of S1.4 with a suitable acid (e.g., aqueous HCl).

[0095] 17. The method of embodiment 16, comprising treating the optically concentrated extract solution of S1.4 to an endpoint of about pH 3 to 4 (e.g., about pH 3.44).

[0096] 18.Furthermore, c) Cyclopropane esters of formula S1.3: [ka] (Wherein, Pr G is a suitable carboxylic acid protecting group; d) reacting the cyclopropane ester of formula S1.3 under appropriate conditions to give a carboxylic acid of formula S1.4: [ka] or a salt thereof.

[0097] 19. The above-mentioned Pr G 19. The method of claim 18, wherein is t-butyl.

[0098] 20. The method of embodiment 18 or 19, wherein step d) comprises a suitable acid (e.g., trifluoroacetic acid, hydrochloric acid, sulfuric acid, tosylic acid, or phosphoric acid).

[0099] 21. The method of embodiment 18 or 19, wherein step d) comprises a suitable base (e.g., sodium hydroxide).

[0100] 22. The method of any one of embodiments 18-21, wherein step d) comprises a suitable solvent (e.g., dichloromethane, methanol, ethyl acetate, water, or a combination thereof).

[0101] 23.Furthermore, e) heteroaromatic vinyl compounds of formula S1.2: [ka] and f) reacting the heteroaromatic vinyl compound of formula S1.2 under appropriate conditions to produce a cyclopropane ester of formula S1.3: [ka] or a salt thereof.

[0102] 24. The method of embodiment 23, wherein step f) comprises an alpha halogen ester (e.g., t-butyl bromoacetate, methyl chloroacetate) and a tertiary amine or nucleophile (e.g., DABCO, quinuclidine, O-methylquinine, triphenylphosphine).

[0103] 25. The method of embodiment 24, wherein step f) comprises t-butyl bromoacetate and DABCO.

[0104] 26. The method of any one of embodiments 23-25, wherein step g) comprises a suitable base (e.g., Cs2CO3, K2CO3, DBU, Ag2CO3, potassium tert-butoxide, tetramethylguanidine, triethylamine, etc.).

[0105] 27. The method of embodiment 26, wherein step f) comprises grinding Cs2CO3.

[0106] 28. The method of any one of embodiments 23-27, wherein step f) comprises a suitable solvent (eg, acetonitrile, dichloromethane, dimethylformamide, tetrahydrofuran, toluene, or dioxane).

[0107] 29. The method of embodiment 28, wherein step f) comprises acetonitrile.

[0108] 30.Furthermore, g) Formula Cy B -X A Compound S1.1 (where X A is a halogen, triflate, mesylate, or tosylate; h) Cy B -X A is reacted with a vinyl boronate reagent under appropriate conditions to give a heteroaromatic vinyl compound of formula S1.2: [ka] or a salt thereof.

[0109] 31.X a 31. The method of embodiment 30, wherein is halogen (e.g., chloro).

[0110] 32. The method of embodiment 30 or 31, wherein the vinyl boronate is potassium vinyl trifluoroborate.

[0111] 33. The method of any one of embodiments 30-32, wherein step h) comprises the presence of a suitable base (e.g., pyridine, triethylamine, DBU, tetramethylguanidine, CsF, NaOH, KOH, Na2CO3, K3PO4, Cs2CO3, or K2CO3).

[0112] 34. The method of embodiment 33, wherein the suitable base is K2CO3.

[0113] 35. The method of any one of embodiments 30-34, wherein step h) comprises a suitable precatalyst or catalyst (e.g., Pd(OAc)2·2(2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), PdCl2(PPh3)2, or Pd(OAc)2·dppf).

[0114] 36. The method of embodiment 35, wherein step h) comprises Pd(OAc)2·dppf.

[0115] 37. The method of any one of embodiments 30-36, wherein step h) comprises a suitable solvent (e.g., dioxane, water, THF, ethanol, or a combination thereof).

[0116] 38. a) Cyclopropane esters of formula S1.3: [ka] (Wherein, Pr G is a suitable carboxylic acid protecting group, Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms (provided that Cy B 0 to 4 -R B substituted with a group; Each R Bare independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R is independently hydrogen; a C1-6 aliphatic optionally substituted with halogen, oxo, or —CN; a hydroxyl protecting group, or an amino protecting group. and b) reacting a cyclopropane ester of formula S1.3 under appropriate conditions to provide a carboxylic acid of formula S1.4: [ka] or a salt thereof.

[0117] 39. a) heteroaromatic vinyl compounds of formula S1.2: [ka] [In the formula, Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms (provided that Cy B 0 to 4 -R B substituted with a group; Each R B are independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R is independently hydrogen; a C1-6 aliphatic optionally substituted with halogen, oxo, or —CN; a hydroxyl protecting group, or an amino protecting group. and b) reacting a heteroaromatic vinyl compound of formula S1.2 under appropriate conditions to give a cyclopropane ester of formula S1.3: [ka] or its salts (Wherein, Pr G is a suitable carboxylic acid protecting group.

[0118] 40. a) Formula Cy B -X A Compound S1.1: [In the formula, Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms (provided that Cy B 0 to 4 -R B substituted with a group; Each R B are independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R is independently hydrogen; a C1-6 aliphatic optionally substituted with halogen, oxo, or —CN; a hydroxyl protecting group, or an amino protecting group; X A is a halogen, triflate, mesylate, or tosylate] and b) Cy B -X A is reacted with a vinyl boronate reagent under appropriate conditions to give a heteroaromatic vinyl compound of formula S1.2: [ka] or a salt thereof.

[0119] 41. Cy B However, 0 to 3 -R B The method of any one of the preceding embodiments, wherein the aryl group is a pyrimidinyl group substituted with a group.

[0120] 42. CyB but, [ka] 10. The method of any one of the preceding embodiments, wherein

[0121] 43. Cy B but, [ka] 10. The method of any one of the preceding embodiments, wherein

[0122] 44. Cy B The method of any one of the preceding embodiments, wherein is methyl.

[0123] 45. The compound of formula 1.4 is [ka] 10. The method of any one of the preceding embodiments, wherein

[0124] 46. ​​The compound of formula 1.3 is [ka] 10. The method of any one of the preceding embodiments, wherein

[0125] 47. The compound of formula 1.2 is [ka] 10. The method of any one of the preceding embodiments, wherein

[0126] 48. The compound of formula 1.1 is [ka] 10. The method of any one of the preceding embodiments, wherein

[0127] 49. The method of any one of the preceding embodiments, wherein said optically enriched compound of formula S1.4 has an enantiomeric excess of 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

[0128] 50. Compound of formula S1.4: [ka] or a salt thereof [wherein: Cy B is a 6-membered heteroaryl having 1 to 3 nitrogen atoms (provided that Cy B 0 to 4 -R B substituted with a group; Each R B are independently selected from halogen, —CN, —NO, N(R), —N(R)C(O)R, —OR; C aliphatic optionally substituted with halogen, oxo, —OR, or —CN, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R is independently hydrogen; a C1-6 aliphatic optionally substituted with halogen, oxo, or -CN; a hydroxyl protecting group, or an amino protecting group.

[0129] 51. Cy B However, 0 to 3 -R B The compound of embodiment 50, wherein the R is a pyrimidinyl group substituted with a group.

[0130] 52. Cy B but, [ka] 51. The compound of embodiment 50, wherein

[0131] 53. Cy B but, [ka] 51. The compound of embodiment 50, wherein

[0132] 54.R B The compound of any one of embodiments 50-53, wherein is methyl.

[0133] 55.Compound: [ka] Or its salt.

[0134] 56.Compound: [ka] Or its salt.

[0135] 57. The compound of any one of embodiments 55 or 56, having an enantiomeric excess of greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99%.

[0136] definition Compounds of the present disclosure include those generally described above, but are further exemplified by the classes, subclasses, and chemical species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entireties.

[0137] Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0138] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclyl," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C3-C7 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0139] The term "heteroatom" refers to one or more oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(including N-substituted pyrrolidinyl).

[0140] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0141] The term "halogen" or "halo" includes fluoro, chloro, bromo or iodo, especially fluoro, chloro or bromo, especially fluoro or chloro.

[0142] The term "aryl" refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, provided that at least one ring in the system is aromatic and each ring in the system has 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, an 8- to 10-membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0143] The terms "heteroaryl" and "heteroar-" refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on the heteroaromatic ring). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms include optionally substituted rings.

[0144] As used herein, the terms "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. In this context, the term "nitrogen," when used in reference to a ring atom, includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may be NR (as in N-substituted pyrrolidinyl).

[0145] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to a heterocycle-substituted alkyl group, where the alkyl and heterocyclic moieties independently are optionally substituted.

[0146] The term "protecting group" as used herein means that a specific functional moiety, e.g., O, S, or N, is masked or blocked, allowing a reaction to occur selectively with another reactive moiety of a multifunctional compound, as needed. Suitable protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Green and P.G.M. Buts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. In certain embodiments, the protecting group reacts selectively in good yield to provide a protected substrate that is stable to the reaction to which it is subjected. The protecting group is preferably selectively removable by readily available, preferably non-toxic, reagents that do not attack other functional groups. The protecting group forms a separable derivative (more preferably, without generating a new stereocenter). The protecting group preferably has minimal additional functional groups to avoid further reaction sites. Non-limiting examples of hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromomethyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4', 4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol)-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethyl) Dithio)pentanoic acid ester (levulinoyl dithioacetal), pivalic acid ester, adamantoate, crotonate ester, 4-methoxycrotonate, benzoic acid ester, p-phenylbenzoic acid ester, 2,4,6-trimethylbenzoic acid ester (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-Dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyric acid ester, 4-nitro-4-methylpentanoic acid ester, o-(dibromomethyl)benzoic acid ester, 2-formylbenzenesulfonic acid ester, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid ester, 2-(methylthiometh (oxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2- or 1,3-diols, protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidine orthoester, 1,Examples include 2-dimethoxyethylidene orthoesters, α-methoxybenzylidene orthoesters, 1-(N,N-dimethylamino)ethylidene derivatives, α-(N,N'-dimethylamino)benzylidene derivatives, 2-oxacyclopentylidene orthoesters, di-t-butylsilylene groups (DTBS), 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivatives (TIPDS), tetra-t-butoxydisiloxane-1,3-diylidene derivatives (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate. The amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-furanylmethyl carbamate (Fmoc), 2-trimethylsilylmethyl carbamate (Teoc), 2-furanylmethyl carbamate (Teoc), 2-trimethylsil ... phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-Dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzoyl Dimethylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl) [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl ) benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivatives, N'-p-toluenesulfonyl, Aminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborinyl Carbamates, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-Trimethylbenzylcarbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenoxy)acetamide Nyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3 -Diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl)-2-methylpropanol N-(4-hydroxy-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-Dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1 -cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitramine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide , o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridine sulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-meth 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',Examples of protecting groups include (8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. While exemplary protecting groups are detailed herein, it will be recognized that the present disclosure is not limited to these protecting groups. Rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and used in the methods of the present disclosure. Additionally, a variety of protecting groups are described in Greene and Wuts, supra.

[0147] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar and non-polar solvents.

[0148] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14Compounds having the structure of the present invention, including the replacement of a carbon with a C-enriched carbon, are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present disclosure. In some embodiments, the compounds of the present disclosure are provided as a single enantiomer or a single diastereoisomer. A single enantiomer refers to an enantiomeric excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. A single diastereoisomer refers to an excess of 80% or more, for example, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. When a particular enantiomer is preferred, it can be obtained substantially free of the opposite enantiomer in some embodiments, sometimes referred to as "optically enriched." As used herein, "optically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 80% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 90%, 91%, 92%, 93%, 94%, 95%, 98%, or 99% by weight of the preferred enantiomer. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or prepared by asymmetric synthesis.See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen SH et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0149] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.

[0150] symbol [ka] indicates the point of attachment of a chemical moiety to the rest of the molecule or chemical formula, except when used as a bond to indicate unknown or mixed stereochemistry.

[0151] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0152] When used herein in reference to a value, the term "about" refers to a value that is similar relative to the referenced value. Generally, a person skilled in the art familiar with the context will understand the relevant degree of variation that "about" encompasses in that context. For example, in some embodiments, the term "about" can encompass a range of values ​​that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the reference value.

[0153] Examples of pharmaceutically acceptable salts include, but are not limited to, acid addition salts of strong inorganic acids such as HCl and HBr salts, and addition salts of strong organic acids such as methanesulfonate salts.

[0154] In the context of this specification, "comprising" should be interpreted as "including." Embodiments of the invention comprising certain features / elements are also intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the associated elements / features.

[0155] Where technically appropriate, embodiments of the invention may be combined.

[0156] Technical references, such as patents and applications, are incorporated herein by reference.

[0157] Any embodiment specifically and expressly recited herein may form the basis of a disclaimer, either alone or in combination with one or more further embodiments.

[0158] Subject headings are used herein to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0159] The Background section of this specification contains relevant technical information which may be used as a basis for amendment.

[0160] The present invention is further illustrated by the following examples. [Example]

[0161] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While these general methods are directed to the synthesis of specific compounds of the present disclosure, it will be understood that the following general methods, and others known to those of skill in the art, are applicable to all compounds and subclasses and species of each of these compounds described herein.

[0162] General Considerations: All nonaqueous reactions were carried out in oven- or heat-gun-dried glassware under an inert atmosphere of nitrogen, using standard techniques for handling air-sensitive materials. Cesium carbonate was obtained from Fluorochem (catalog 050215), ground to a fine powder (with a pestle and mortar), passed through a stainless steel sieve (150 μm) under a nitrogen atmosphere, dried (120 °C, 80 mbar, 24–48 h), and sieved again before use. (+)-Dihydroabietylamine was obtained from TCI (catalog D1588, 90% purity), adjusted for purity, and used as is. Acetonitrile (HPLC grade) was dried over 4 Å molecular sieves for 24 h. All other chemicals and solvents (HPLC grade or anhydrous as needed) were purchased from commercial sources and used as received. Dicalite is a brand of diatomaceous earth (Kieselguhr) provided by Dicalite Minerals Corporation. 396 MHz ( 1 H), and 100MHz ( 13 NMR spectra were measured on a Jeol 400YH spectrometer operating at 100°C.

[0163] Data were processed using Jeol Delta software, and shifts are reported in ppm. Proton and carbon chemical shifts refer to residual protonated solvent. Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad line), and dd (double doublet). Coupling constants (J) are given in hertz (Hz) and are accurate to 0.3 Hz. The solvent used for the sample is specified in the specific experimental procedure for each compound. UPLCMS data were acquired using a Waters Acquity system using one of two methods: Method A (Waters Acquity BEH C18, 1.7 μm, 2.1 × 50 mm, 0.4 mL / min, A: H2O:MeCN = 95:5 + 0.1% 28% NH3 aqueous solution, B: H2O:MeCN = 5:95 + 0.1% 28% NH3 aqueous solution; gradient: 0–0.2 min 100% A, 0.2 × 3.5 min ramp to 100% B, 3.5–4.5 min 100% B). Method B (Waters Acquity CSHC 181.7 μm, 2.1 × 50 mm, 0.4 mL / min, A: 95:5 HO:MeCN + 0.1% HCOOH, B: 5:95 HO:MeCN + 0.1% HCOOH, gradient: 0–0.2 min 100% A, 0.2–3.5 min ramping to 100% B, 3.5–4.5 min ramping to 100% B. Purity was calculated from relative peak area (total absorbance from 215–350 nm). Chiral SFC was performed on a Shimadzu Nexera SFC system using a Phenomenex Lux Cellulose 2 column (4.6 × 250 mm, 2 mL / min, 40 °C) and a gradient of scCO [A]:MeOH (+0.1% diethylamine) [B] (gradient: 0–1 min 15% B, 1–9 min ramping to 40% B). Enantiomeric excess was calculated from the area of ​​each peak at 254 nm. High-resolution mass spectra were recorded using an Agilent 6530 accurate-mass quadrupole time-of-flight (Q-TOF) LC / MS system operating in positive ionization mode. m / z values ​​are reported in Daltons. High-resolution values ​​were calculated from the molecular formula to four decimal places, and all observed values ​​were within a 5 ppm tolerance. Combustion analysis data were obtained by OEA Laboratories Ltd., Callington, Cornall, UK, and are the average of replicate measurements. Melting points were obtained in open tubes using a Buchi B545 melting point apparatus and are uncorrected. TLC was performed on silica gel 60 F254 glass-backed plates (Merck KGaA, Darmstadt, Germany) and visualized with UV light or 0.5% aqueous KMnO4. Rf values ​​are reported for the solvent system used. Flash chromatography refers to column chromatography on silica gel using a glass column (Silicycle, 40-63 μm, pore size 60 Å). Preparative reversed-phase column chromatography is performed using Biotage SfOAr C 18 A Biotage Isolera system equipped with a cartridge (30 g, 30 μm, 25 mL / min) was used with a gradient (A: HO + 0.1% HCOOH, B: MeCN + 0.1% HCOOH, A:B = 95:5 (3 column volumes), then ramped to 75:25 over 5 column volumes and held for 5 column volumes).

[0164] DrySyn refers to a range of metal reaction heating blocks available from Asynt (Isleham, nr. Ely, Cambridgeshire, UK). For controlled cooling of the recrystallization, a PolyBLOCK Parallel Chemistry Reaction Block from HEL Group Ltd. was used.

[0165] Example 1 Scheme B. Process for preparing compound (1S,2S)-4. [ka]

[0166] Step 1. Preparation of 4-methyl-2-vinylpyridine (2). [ka] A 5 L, three-neck flask equipped with a mechanical stirrer, nitrogen inlet (via a long needle), and outlet was charged with water (500 mL). K2CO3 (538 g, 3.90 mol) was added slowly with vigorous stirring until a clear solution was obtained (approximately 15 min). To this was added 1,4-dioxane (2.5 L, stabilized with BHT), and the mixture was sparged with nitrogen at room temperature for 3 h. 2-Chloro-4-methylpyrimidine (250 g, 1.95 mol) and potassium vinyl trifluoroborate (302 g, 95% purity, 2.14 mol) were added, and sparging was continued for an additional 30 min. Pd(OAc)2 (4.36 g, 19.4 mmol) and dppf (10.8 g, 19.4 mmol) were added. A reflux condenser (with nitrogen inlet) and thermocouple were attached, and the mixture was heated to 90 °C (internal temperature) using an isomantle for 15 h. The reaction vessel was cooled in an ice bath. The mixture was diluted with EtO (2 L) and stirred for 30 minutes. The mixture was filtered through a pad of Dicalite (0.5 kg). The filtrate was concentrated on a rotary evaporator (bath temperature 42 °C, final pressure 90 mbar) to give a dark brown liquid (approximately 1 kg). 1HAnalysis by NMR indicated a mixture of the product and dioxane (20:80, w / w). The mixture was distilled under vacuum using a 15 cm Vigreux column (DrySyn at 65 °C, 110-130 mbar) to remove residual dioxane (bp 46-38 °C). The mixture was then transferred to a 500 mL round-bottom flask and further distilled (DrySyn at 92 °C, 30-37 mbar) to give 4-methyl-2-vinylpyrimidine (203 g) as a colorless liquid. 1 Analysis by H NMR showed that the product contained 11% (w / w) dioxane. The yield was therefore calculated to be 181 g (77%). The product was stored at -20 °C until needed. UPLCMS (Waters Acquity BEH C 18 , 1.7 μm, 2.1 × 50 mm, 0.4 mL / min, A: H2O:MeCN = 95:5 + 0.1% 28% NH3 aqueous solution, B: H2O:MeCN = 95:5 + 0.1% 28% NH3 aqueous solution, Gradient: 0-0.2 min 100% A, 0.2-3.5 min ramp to 100% B, 3.5-4.5 min 100% B). RT = 1.92 min; [M + H] + 121, purity 99.8%, 1 H NMR (396 MHz, CDCl3, ppm) δ8.54 (d, J 5 Hz, 1H), 7.00 (d, J 5 Hz, 1H), 6.85 (dd, J 18, 10 Hz, 1H), 6.61 (dd, J 18, 2 Hz, 1H), 5.71 (dd, J 10, 2 Hz, 1H), 2.52 (s, 3H).

[0167] Step 2. Preparation of (rac-trans)-tert-butyl-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylate (3). [ka] A dry 5 L three-neck flask was equipped with a mechanical stirrer, a temperature probe connected to a heating mantle, and a nitrogen inlet. DABCO (140 g, 1.25 mol) was added to the flask under nitrogen via a solid addition funnel. Anhydrous MeCN (1.55 L, 3.5 ppm HO by KF titration) was added, and the mixture was stirred for 5 minutes to give a colorless solution. tert-Butyl bromoacetate (245 g, 1.25 mol) was added to the pressure-equalizing addition funnel and washed with anhydrous MeCN (100 mL). The tert-butyl bromoacetate solution was added via the addition funnel over 30 minutes, during which time the temperature rose to 44 °C. The colorless solution was stirred at 23 °C for 60 minutes to ensure complete conversion to the ammonium ylide. 1 The reaction mixture was confirmed by H NMR. 4-Methyl-2-vinylpyrimidine (113 g, 89% purity, 836 mmol, remaining in 1,4-dioxane) was added and washed into the flask with anhydrous MeCN (20 mL). Dried powdered CsCO (particle size <150 μm, 409 g, 1.25 mol) was added in one portion to the stirred reaction mixture via a solid addition funnel to give a fine suspension. The resulting mixture was heated to 80 °C (internal temperature) over 30 min and maintained for 20 h. The reaction was cooled to 50 °C. The mixture was diluted with EtOAc (1.2 L) and filtered through a 3 cm pad of Dicalite filter aid, washing the filter cake with EtOAc (1 L). The filtrate was concentrated under reduced pressure to give a dark brown oil containing some solids, which was cooled in an ice bath and treated with EtOAc (1 L) and aqueous HCl (2 M, 500 mL each) to pH 4. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 500 mL). The combined extracts were washed with sodium phosphate buffer (0.5 M, pH 7, 2 × 500 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give crude trans-rac-tert-butyl-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylate (190 g, estimated yield 86%) as a brown oil, which was used directly in the next step. A small sample was purified for analysis by flash column chromatography (heptane: EtOAc = 7:1 to 3:1) to give a colorless oil. UPLCMS (Waters Acquity BEHC 18, 1.7 μm, 2.1–50 mm, 0.4 mL / min, A: 95:5 H2O:MeCN + 0.1% 28% NH3 aqueous solution, B: 95:5 H2O:MeCN + 0.1% 28% NH3 aqueous solution; Gradient: 0–0.2 min 100% A, 0.2–3.5 min ramp to 100% B, 3.5–4.5 min 100% B), RT = 3.23 min; m / z [M + H] + 235 and [M + H isobutylene] + 179, 100% purity. 1 H NMR(396 MHz,CDCl3) δ8.40(d, J 5 Hz,1H),6.94(d, J 5 Hz,1H),2.70(ddd, J 4,6.8,8 Hz,1H),2.45(s, 3H), 2.21(ddd, J 4, 5.8, 8.2 Hz, 1H), 1.60~1.54(m, 2H), 1.45(s, 9H).

[0168] Step 3. Preparation of (rac-trans)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (rac-4). [ka] Trifluoroacetic acid (840 mL) was charged to a 3 L round-bottom flask equipped with a magnetic stir bar under nitrogen and cooled to an internal temperature of 10 °C in an ice-water bath. A solution of (rac-trans)-tert-butyl-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylate (crude, 190 g) in DCM (290 mL) was added via addition funnel over 18 min, during which time the temperature rose to 19 °C. Upon completion of the addition, the mixture was stirred for an additional 10 min. The ice bath was removed, and the brown solution was stirred at room temperature for an additional 60 min. The solution was concentrated under reduced pressure, and the residue was coevaporated from toluene (3 × 500 mL) to give a viscous brown oil (approximately 420 g). The residue was cooled in an ice bath while aqueous NaOH (2 M, approximately 1020 mL) was added slowly (to pH 4). The mixture was stirred in an ice bath for 60 min, and the solid was collected by filtration, washed with water (2-250 mL), and dried overnight by suction. The title compound was obtained as an off-white solid (112 g, 75%). Recrystallization from EtOAc gave colorless needles. mp = 172.5-173 °C. UPLCMS (Waters Acquity CSHC 18 , 1.7μm, 2.1~50mm, 0.4mL / min, A:H2O:MeCN=95:5+0.1%HCOOH, B:H2O:MeCN=5: 95 + 0.1% HCOOH, gradient: 0~0.2 min 100%A, 0.2~3.5 min ramp to 100%B, 3.5~4.5 min 100%B), RT=1.94 min, [M + H] + 179, purity: 98.5%. Chiral SFC: room temperature = 4.55 min (S,S) and 5.42 min (R,R) = 50:50. 1 H NMR(396 MHz,CD3OD,ppm) δ 8.47(d, J 5.2 Hz,1H),7.17(d, J 5.2 Hz,1H),2.67(ddd, J 3.8,6,9 Hz,1H) ), 2.47(s, 3H), 2.20(ddd, J 3.8, 5.6, 8.7 Hz, 1H), 1.65~1.57(m, 2H).

[0169] Step 4. Preparation of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (S,S-4). [ka] (S)-(-)-1-(1-naphthyl)ethylamine (45.40 g, 266 mmol) was dissolved in dimethyl carbonate (100 mL), and (rac-trans)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (47.26 g, 266 mmol) was added with additional dimethyl carbonate (100 mL). The mixture warmed and almost all solids dissolved, after which a solid began to precipitate. The resulting viscous slurry was heated under reflux, at which point most of the solid dissolved. After 30 minutes, the solution was allowed to cool to room temperature with stirring overnight. The solid was filtered, washed with dimethyl carbonate (100 mL and 80 mL), and dried to give a colorless solid (40.86 g), which was analyzed by chiral SFC chromatography. The ratio of diastereomeric salts was (S,S):(R,R) = 94.6:5.4 (ee = 89.2%). The solid was then suspended in dimethyl carbonate (400 mL) and heated under reflux for 40 min. The suspension was cooled to room temperature, and the solid was filtered and washed with dimethyl carbonate (2-80 mL) to give a colorless solid (37.79 g), which was analyzed by chiral SFC chromatography. The ratio of diastereomeric salts was (S,S):(R,R) = 98.7:1.3 (ee = 97.4%). This batch (37.79 g) was combined with another batch (2.64 g, de = 98%) and triturated with hot dimethyl carbonate (200 mL) as described above for 40 min. The suspension was cooled to room temperature, and the solid was filtered and washed with dimethyl carbonate (2-50 mL) to give a colorless solid (38.95 g, 82% of theory), which was analyzed by chiral SFC chromatography. The diastereomeric salt ratio was (S,S):(R,R) = 99.4:0.6 (ee = 98.8%). Needle crystals (derived from dimethyl carbonate) mp = 164-165 °C. 1H NMR(396 MHz, CD3SOCD3) δ8.49(d, J 5 Hz, 1H), 8.17(d, J 8 Hz, 1H), 7.93(d, J 9.6 Hz, 1H), 7.81(d, J 8.4 Hz, 1H), 7.73(d, J 8.8 Hz, 1H), 7.56~7.49(m, 3H), 7.17(d, J 5 Hz, 1H), 4.93(q, J 6.4 Hz, 1H), 2.48~2.43(m, 1H), 2.40(s, 3H), 1.99~1.95(m, 1H), 1.43(d, J 6.4 Hz), 3H), 1.44~1.38(m, 2H).

[0170] (S)-(-)-(1-Naphthyl)ethylamine·(1S,2S)-4 salt (64.43 g, 185 mmol) was suspended in DCM (200 mL) and cooled in an ice-water bath. Aqueous NaOH (6 M, 46.1 mL, 277 mmol) was added in small portions over 10 min. The mixture was stirred for 10 min to give a clear, slightly brownish, two-phase mixture. The mixture was transferred to a separatory funnel with water (2 × 10 mL). The organic layer was separated, and the aqueous layer was washed with dichloromethane (4 × 50 mL). The aqueous layer was cooled in an ice-water bath and treated with concentrated HCl to pH 3–4. The precipitated solid was collected by filtration and washed with water (3 × 20 mL) to give (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (31.38 g, 95%). mp = 192-194 °C, UPLCMS (same method as previous step), RT = 1.86 min; [M + H] + 179, Purity: 100%. Chiral SFC (S,S):(R,R) = 99.76:0.24 (99.5% ee). 1 H NMR(396 MHz,CD3OD,ppm)δ 8.46(d, J 5.6 Hz,1H),7.17(d, J 5.6 Hz,1H),2.67(ddd, J 3.7,6.0,9.5 Hz,1H) ), 2.47(s, 3H), 2.19(ddd, J 3.9, 5.5, 8.4 Hz, 1H), 1.64~1.57(m, 2H).

[0171] Example 2. Scheme 2. Suzuki-Miyaura reaction for the preparation of 4-methyl-2-vinylpyrimidine (2). [ka] Step S-1 was further carried out according to the parameters in Table 1, and each reaction was carried out in a manner similar to the details described in Step 1 of Example 1.

[0172] [Table 1]

[0173] To address the issue of product volatility, the vinylboronic acid pinacol ester was replaced with potassium vinyltrifluoroborate (entries 3 and 4, under "low water" and traditional "wet" conditions), resulting in similar yields of 3 but a much higher concentration of the impurity 10. The formation of 11 is readily explained by a Heck reaction of 3 with 2. However, after conjugate addition of a vinylboron species on the palladium-coordinated vinylpyrimidine 3, 10 appears to have been generated by protodepalladation rather than the expected β-hydride elimination to give diene 12 (Scheme 3).

[0174] Scheme 3 [ka] Two trial reactions (entries 5 and 6) using bis(triphenylphosphine)palladium chloride under conventional conditions with potassium phosphate or cesium carbonate as the base and under "high water" conditions did not improve the yield but appeared to suppress the formation of 10.

[0175] The best results were obtained using palladium acetate and dppf as catalysts in dioxane / water containing potassium carbonate as the base (entries 7 and 8). A slight increase in the number of equivalents of vinyl boronate helped reduce the formation of 11, and the amount of palladium added was reduced to 1 mol%, maximizing the overall concentration to 0.66 M without reducing the yield. The amount of water was chosen so that potassium carbonate formed an easily stirrable, nearly saturated solution (lower amounts caused the carbonate to form sticky agglomerates that stuck to the stirrer). To simplify the workup, the cooled reaction mixture was diluted with either diethyl ether or dioxane, filtered (to remove inorganic salts), carefully concentrated under reduced pressure on a rotary evaporator, and purified by distillation through a Vigreux column (bp = 73 °C / 26 mbar). This afforded the vinylpyrimidine 3 in 77% yield (containing approximately 10% w / w dioxane), which would likely have been higher if compound 3 had been less volatile.

[0176] We investigated whether dioxane could be replaced with THF (more volatile, less toxic, entry 9), but the conversion to 3, although clean, was slow and incomplete. One consequence of having to use potassium vinyltrifluoroborate (in combination with only 2 equivalents of potassium carbonate) was the observed significant exothermic behavior and evolution of carbon dioxide, both of which were manageable on a 2-molar scale.

[0177] This intriguing observation of the conjugate addition product (10) prompted us to react compound 3 with the ammonium ylide derived from t-butyl bromoacetate and DABCO in refluxing acetonitrile (Scheme 4).

[0178] Example 3. Cyclopropanation of 4-methyl-2-vinylpyrimidine (3). Scheme 4 [ka] The quaternary ammonium salt was formed by stirring DABCO and t-butyl bromoacetate in anhydrous acetonitrile at room temperature for 40 minutes. Vinylpyrimidine and cesium carbonate were added, and the mixture was heated to reflux. A pilot reaction indicated that the reaction would yield the desired cyclopropane (3) in high purity; however, using two equivalents of ammonium ylide did not proceed to completion, and adding more reagents did not result in any change. This problem was easily resolved by grinding the cesium carbonate to less than 150 μm and drying it. Thus, after heating overnight, the cyclopropanation was complete, and after aqueous workup, compound 3 was obtained as an oil in 86% yield. The crude product 1 H NMR indicated the presence of a pyrimidine-containing by-product, likely the related cis-cyclopropane (14) (ratio 3:14 = 50:1). A pure sample of trans-cyclopropane 3 was obtained by column chromatography, and the stereochemistry was confirmed by NOESY NMR experiments.

[0179] Gaunt et al. Angew. Chem. Int. Ed. 2003, 42, 828-831; Angew. Chem. Int. Ed. 2006, 45, 6024-6028. and Guo et al. Org. Lett. 2017, 19, 6494-6497 describe enantioselective cyclopropanations using chiral quinuclidine surrogates of DABCO. Attempted cyclopropanations of 2 using tert-butyl bromoacetate and the catalysts O-methylquinine, DHQD-PHAL, and (R)-(-)-3-hydroxyquinuclidine (Chart 1) in acetonitrile at reflux were unsuccessful. Although the presence of the required N-alkylammonium salt was observed by LCMS, no cyclopropane was formed in either reaction.

[0180] Chart 1 Potential chiral catalyst for the cyclopropanation of 3 [ka]

[0181] Example 4. Preparation of (rac-trans)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (rac-4).

[0182] Although 3 was an oil, it was obtained in good yield and purity, and we decided to convert it to the crystalline carboxylic acid rac-4 without further purification. Removal of the t-butyl ester in a mixture of trifluoroacetic acid and dichloromethane was straightforward.

[0183] Scheme 5 [ka] However, isolation of racemic acid 4 proved more difficult. After removal of trifluoroacetic acid, the residue (pH 1) was freely soluble in water; however, when the pH was adjusted to 4–5 (with little attention paid to the total amount of water present), multiple extractions with dichloromethane or ethyl acetate were required, and successive extractions with dichloromethane were necessary to obtain good recovery. Addition of 2 M aqueous sodium hydroxide to the crude trifluoroacetate salt of rac-4 resulted in the formation of crystals, which were easily recovered by filtration, although yields were variable. The pKas of rac-4 were determined to be 2.66 for the pyrimidine and 4.21 for the carboxylic acid. Therefore, although the acid began to crystallize around pH 2, optimal conditions for recovery appear to be at its isoelectric point of pH 3.44. The final workup consisted of removing the trifluoroacetic acid and dichloromethane under reduced pressure, followed by the slow addition of aqueous sodium hydroxide under cooling to a pH of approximately 3.5. The crude acid was then recovered by filtration and washed with water.

[0184] of the acid isolated by crystallization from aqueous solution 1Analysis by H NMR showed no sign of rac-15. An LCMS trace of the acid isolated by solvent extraction and recrystallized to remove most of the trans isomer showed two peaks (RT = 0.82 min (minor) and 1.94 min (major), both m / z = 179 [M + H]). + ), the latter corresponding to the desired trans isomer, and the former to the apparently more polar cis isomer. Without wishing to be bound by theory, the cis isomer was much more polar and represented a smaller proportion of the mixture, suggesting that the crystallization procedure may have removed it. A sample of pure compound rac-15 was isolated from the mother liquor of the recrystallization of rac-4, followed by reverse-phase chromatography. 1 The structure was confirmed by 1 H NMR and high-resolution mass spectrometry.

[0185] This procedure is therefore the final step in a three-step preparation of the trans racemic acid 4, free of its cis isomer, in 58% overall yield without the use of chromatography.

[0186] Synthesis of (rac-cis)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (rac-cis-15).

[0187] Analytical samples were collected from the mixture of several small-scale trial reactions after the final deprotection step. Instead of precipitation as described for rac-4, the crude product was extracted with DCM to recover a mixture of rac-4 and rac-15. Recrystallization from EtOAc was used to remove most of the trans isomer, and the cis isomer was readily isolated using preparative reversed-phase chromatography to give 20 mg of a colorless solid after lyophilization. UPLCMS [Method B] RT = 0.82 min; m / z 179 [M+H] + Purity: 100%. HRMS:C9H 11 N2O2(M+H) + Calculated value: 179.0821; measured value 179.0814. 1H NMR(396 MHz,CD3OD,ppm)δ8.50(d, J 5.2 Hz,1H),7.19(d, J 5.2 Hz,1H),2.77(q, J 8.2 Hz,1H),2.49(s, 3H), 2.20(dt, J 6.6, 8.2 Hz, 1H), 1.88(ddd, J 4.4, 6.6, 8.2 Hz, 1H), 1.48(dt, J 4.4, 8.2 Hz, 1H). 13 CNMR(396 MHz,CD3OD,ppm)174.9,168.9,167.5,157.5,120.0,28.0,23.7,22.8,13.2.

[0188] Example 5. Chiral Resolution Eleven bases were screened. Four crystalline salts were obtained by reacting (+)-dehydroabietylamine 16 (Cheng, et. al., J. Med. Chem., 2011, 54, 957-969), (R)- and (S)-1-(2-naphthyl)ethylamine ((R))-17 and (S)-17), and (S)-1-(1-naphthyl)ethylamine ((S)-18) (Chart 2) with acid 4. Each of these salts was then recrystallized from selected solvents (Table 2), and the enrichment of the desired (1S,2S)-4 enantiomer was measured by chiral analytical SFC. The other seven, namely, cinchonidine, quinine, O-methylquinine, (R)-(+)-α-methylbenzylamine, (S)-prolinamide, (S)-arginine, and (S)-phenylglycinol, did not yield crystalline salts. Chart 2 [ka] [Table 2] Recrystallization of the (+)-dehydroabietylamine salt (16, first column of data) from THF (entry 6) was highly selective; unfortunately, the undesired acid resulted in the formation of a less soluble salt, and the enantiomers of dehydroabietylamine are not commercially available. Noting that recrystallization from IMS (entry 8) gave a diastereomeric salt ratio favoring the (1S,2S)-acid 4, we developed a resolution method based on a) removal of most of the unwanted diastereomeric salt by crystallization from THF (3.4 mL / mmol (rac-4)), followed by b) a single recrystallization from hot IMS with controlled heating and cooling to 0 °C (4 mL / mmol of concentrated salt). This procedure afforded the (1S,2S)-4-dehydroabietylamine salt (de = 100%) in 23% yield (46% of theory) on a 3 g scale. However, recrystallization and cleavage of the dehydroabietylamine salt is technically more difficult than either of the 1-(1-naphthyl)ethylamine salts, and (+)-dehydroabietylamine is relatively expensive, has a higher molecular weight, and the highest grade available is only 90% pure.

[0189] A solvent screen with (R)-(+)-1-(2-naphthyl)ethylamine (rac-4 and (R)-(+)-17, second column of data) gave poor results, while ethyl acetate (entry 1) and isopropanol (entry 5) gave diastereomeric ratios slightly better than 3:1, with the undesired acid (the (1R,2R)-acid diastereomer) predominating. Switching to (S)-(-)-1-(2-naphthyl)ethylamine (rac-4 and (S)-(-)-17, third column of data) gave primarily the (1S,2S)-acid diastereomer in a 94:6 ratio after two recrystallizations from ethyl acetate (entry 1), with poor mass recovery.

[0190] Therefore, we focused on the (S)-(-)-1-(1-naphthyl)ethylamine salts (rac-4 and (S)-(-)-18, column 4 of the data), which recrystallized successfully from ethyl acetate and isopropyl acetate (entries 1 and 2) to yield the desired (1S,2S)-acid diastereomeric salts. Three recrystallizations from ethyl acetate (28 mL / g) were required to increase the decibel to 98%. However, examination of the mother liquor by SFC and LCMS revealed a peak corresponding to the acetamide derivative of the amine (19). Although compound 19 did not contaminate the desired acid salt and remained in the mother liquor, the formation of 19 reduced the salt yield and necessarily increased the time of the recrystallization procedure, suggesting that this problem would only increase with scale. Therefore, alternative solvents of similar polarity were investigated (entries 11–14). Of these, the ethers dioxane, DME, and 2-MeTHF gave satisfactory results in terms of increasing dr, but the first two were not ideal due to their toxicity, and 2-MeTHF gave poor crystal quality.

[0191] [ka] Trial recrystallization of the diastereomeric mixture of salts using dimethyl carbonate showed that 17 mL / g (5.8 mL / mmol) was critical for complete dissolution under reflux, and that crystallization of the salt occurred very rapidly upon cooling to approximately 75 °C (41% mass recovery). Another trial using PolyBLOCK (12 mL / g, 100–18 °C for several hours, starting at a dr = 86:14) yielded a 60% mass recovery and a dr = 99:1. Further refinement of the procedure demonstrated that only two recrystallizations were necessary to obtain a single diastereomeric salt. The optimized procedure consisted of forming the salt in dimethyl carbonate (0.75 mL / mmol rac-4) and recovering the solid (dr = 94.6:5.4) after cooling, which was then triturated twice with additional hot dimethyl carbonate (3.4 mL / mmol and 1.7 mL / mmol) to raise the dr to 99.8:0.2. The yield was 41% (82% of theory) on a scale of approximately 50 g.

[0192] The procedure for cleaving the salt consisted of stirring the salt with excess aqueous sodium hydroxide, extracting the (S)-(-)-(1-naphthyl)ethylamine into MTBE, acidifying the aqueous solution to pH 3.5 with concentrated hydrochloric acid, and recovering the crystallized free acid ((1S,2S)-4, 95% yield) by filtration.

[0193] Exemplary salt synthesis using (+)-16 (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid, (1S,2S)-4, (via (+)-dehydroabietylamine salt) (rac-trans)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (rac-4) (8.53 g, 42.6 mmol) and (+)-dehydroabietylamine (90% pure, 15.3 g, 48.1 mmol) were suspended in THF (144 mL), and the mixture was heated to reflux until a clear solution formed (approximately 45 min). The solution was allowed to cool to room temperature and then placed in a refrigerator (8 °C) overnight. The solid was filtered, washed with cold THF (3 × 25 mL, −20 °C), and dried to give a colorless solid (11.36 g, 8% THF content, 53%), which was an 11:89 mixture of diastereomeric salts derived from the (1S,2S)-acid and (1R,2R)-acid enantiomers, respectively. The mother liquor was concentrated under reduced pressure to give a brown solid (13.66 g, estimated to contain 9.29 g of salt, 47%, dr = 87:13, (1S,2S)-4:(1R,2R)-4). 3 g of this solid (containing approximately 2.04 g of diastereomeric salt) was suspended in IMS (12 mL) and placed in a PolyBLOCK apparatus preheated to 85 °C and stirred until dissolved (approximately 30-45 min). The vial was subjected to the following gradient: 85 to 60 °C (-0.2 °C / min over 2 h), held at 60 °C for 1 h, then cooled to 0 °C at -0.35 °C / min. The resulting solid was collected by filtration, washed with cold IMS (-20 °C, 4 × 5 mL), and dried under vacuum. Thus, the (+)-dehydroabietylamine salt of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid was obtained (1.50 g, 74% yield (adjusted for residual EtOH), 7% w / w). Chiral SFC: RT = 4.55 min, ee = 100%. 1H-NMR(396MHz,CD3OD,ppm)δ 8.40(d, J 5 Hz,1H),7.16(d, J 8 Hz,1H),7.10(d, J 5 Hz,1H),6.96(dd, J 8,2 Hz,1H),6.87(d, J 2 Hz,1H),2.94-2.75(m,4H),2.59(ddd, J 9,5,4 Hz,1H),2.41-2.35(m, 1H), 2.11(ddd, J 8, 5, 4 Hz, 1H), 1.921.73(m, 4H), 1.58-1.32(m, 6H), 1.24(s, 3H), 1.19(d, J 7Hz, 6H), 1.07(s, 3H).

[0194] Cleavage of dehydroabietylamine salt The (+)-dehydroabietylamine salt of (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid (3.76 g, 8.10 mmol) was suspended in DCM (20 mL) at room temperature under nitrogen, and aqueous NaOH (6 M, 2.05 mL, 12.2 mmol) was added. The mixture was stirred for 45 minutes and transferred to a separatory funnel with water (2 mL). The organic layer was separated, and the aqueous layer was washed with DCM (2 × 10 mL). The aqueous layer was treated with concentrated aqueous HCl to pH 4. The precipitated solid was collected by filtration and washed with water (2 × 5 mL) to give (1S,2S)-2-(4-methylpyrimidin-2-yl)cyclopropane-1-carboxylic acid, (1S,2S)-4 (1.41 g, 98%). Chiral SFC: RT = 4.62 min, ee = 100%.

[0195] While a number of embodiments of the present disclosure have been described, it will be apparent that the basic examples of the present invention can be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be understood that the scope of the present disclosure is to be defined by the appended claims rather than by the specific embodiments represented by way of example.

Claims

1. A process for the preparation of the trans racemate of formula (I), comprising: 【Chemistry 65】 (In the formula, P １ is a protecting group (e.g., tert-butyl), R １ is H or optionally substituted C1-C6 alkyl The compound of formula (II): 【Hua 66】 (In the formula, R １ is defined above for compounds of formula (I), reacting (optionally in situ) with a nitrogen ylide, prepared as follows: α-haloesters (e.g., methyl chloroacetate and tert-butyl bromoacetate) By reacting with a tertiary amine (e.g., DABCO), forming a quaternary ammonium salt; Subsequently, an alkali metal base (e.g., Cs ２ CO ３ or K ２ CO ３ ) and / or an organic base (such as DBU), In a polar aprotic solvent (e.g., acetonitrile), Treating at high temperature (e.g., 70-80°C), The process of forming the compound of formula (I) (e.g., with high diastereoselectivity, e.g., 50:1, relative to the corresponding cis racemate).

2. 2. The process of claim 1, wherein the alpha haloester is tert-butyl bromoacetate.

3. 3. The process of claim 1 or 2, wherein the tertiary amine is DABCO.

4. The alkali metal base is Cs ２ CO ３ 10. A process according to any preceding claim, wherein:

5. 10. The process of any preceding claim, wherein the polar aprotic solvent is acetonitrile.

6. 10. The process of any preceding claim, wherein the elevated temperature is 70 to 80°C.

7. 10. A process according to any preceding claim, wherein the reaction is carried out for 12 to 30 hours, for example 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, for example 20 hours.

8. 10. The process of claim 1, wherein the steps, reagents, and conditions are: 【Hua 67】 (In the formula, R １ and P １ is defined above for compounds of formula (I).

9. The compound of formula (II) is reacted with an intermediate of formula (III): 【Chemistry 68】 (In the formula, R １ is as defined above for compounds of formula (I), and L １ represents a leaving group such as a halogen, particularly Cl), 2. The process of claim 1, wherein the compound is prepared by reacting with a vinyl trihaloborate (vinyl trifluoroborate, especially a salt thereof such as potassium).

10. The protecting group P １ is removed from the compound of formula (I) by a) or b) below to give a free carboxylic acid of formula (IV): 【Chemical Formula 69】 is released as the trans racemate (e.g., in high diastereomeric purity, particularly essentially free of the cis racemate): a) Acidolysis using an organic acid (e.g., TFA) in a chlorinated solvent (e.g., DCM) or b) Saponification using an alkali metal hydroxide (such as sodium hydroxide) in an aqueous medium (such as THF and water) 10. A process according to any preceding claim, followed by acidification (e.g. with aqueous hydrochloric acid) to liberate the free acid from the salt so formed.

11. A process for resolving a compound of formula (IV) essentially into one or the other of its enantiomeric forms to obtain, for example, a compound of formula (V) (absolute configuration as shown), which comprises: 【Chemistry 70】 For example, the resolution can be carried out by reaction with an optically pure chiral amine, such as (S)-1-(naphthalen-2-yl)ethanamine or (S)-1-(naphthalen-1-yl)ethanamine, By carrying out the reaction in a suitable solvent (e.g., ethyl acetate, isopropanol, and dimethyl carbonate), The process wherein a mixture of diastereomeric salts is formed and the preferred diastereomeric salt is crystallized from the mixture and recovered by filtration.

12. The free acid is prepared by converting the salt to an aqueous solution of an excess of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), 12. The process of claim 11, wherein the organic base is removed by treatment in the presence of a non-miscible organic solvent (e.g., toluene or MTBE) and recovered from the salt by retaining the aqueous solution.

13. 13. The process of claim 12, wherein the aqueous solution is acidified with an inorganic acid (e.g., hydrochloric acid) to a pH of 3-4 to precipitate the free acid as a solid, and the solid is recovered by filtration.

14. 15. The process of any one of claims 11 to 14, wherein the compound of formula (V) is enantiomerically enriched, particularly having an enantiomeric purity (ee value) of 90% or more, such as 91, 92, 93, 94, 95, 96, 96, 97, 98, 99, or 100%, particularly 99%.

15. R １ But C １～３ 10. A process according to any preceding claim, wherein alkyl is, for example, methyl, ethyl, propyl or isopropyl, in particular methyl.

16. P1 is C １～４ 10. The process of any preceding claim, wherein the alkyl is, for example, t-butyl.

17. The compound of formula (V) is reacted with an arylamine of formula (VI): [Chemical Formula 71] (In the formula, R ２ is H or C １～３ alkyl, and L ２ is reacted with a leaving group, for example a halogen, in particular Cl, to give a compound of formula (VII): 【Chemical Formula 72】

18. The compound of formula (VII) is compound (VIIa): 【Chemical Formula 73】 18. The process of claim 17, wherein

19. The compound of formula (VII) is compound (VIIb): 【Chemical 74】 18. The process of claim 17, wherein

20. a compound of formula (VII) with a compound of formula (VIII) 【Chemistry 75】 to produce a compound of formula (IX) 【Chemical 76】 or a pharmaceutically acceptable salt thereof (wherein R １ and R ２ is as defined above).

21. The compound of formula (VII) is compound (VIIa), and the compound of formula (IX) is compound (IXa): 【Chemical 77】 21. The process of claim 20, wherein

22. The compound of formula (VII) is compound (VIIb), and the compound of formula (IX) is compound (IXb): 【Chemical Formula 78】 21. The process of claim 20, wherein

23. A compound obtained or obtainable from any one of the preceding claims.

24. A compound of formula (I), (II), (IV), (V), (VI), (VII), (VIIa), (VIII), (IX), (IXa), or (IXb).

25. 24. A pharmaceutical composition comprising a compound of claim 22 or 23 and an excipient, diluent, or carrier.

26. A compound according to claim 23 or 24, or a pharmaceutical composition according to claim 25, for use in therapy, particularly as a pKAL inhibitor.

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