Process for preparing a cis-1,2-diaryltetralin derivative

Abstract

The present invention relates to a process for preparing a cis-1,2-diaryltetralin derivative, a key chiral intermediate in the synthesis of Compound 1.

Description

[0001]PC073152A - 1 - Process for Preparing a Cis-1,2-Diaryltetralin Derivative Background of the Invention 5 The present invention relates to a process for preparing a cis-1,2-diaryltetralin derivative, a key chiral intermediate in the synthesis of (S)-3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or (3S)-3-[1,3- dihydro-1-oxo-5-[4-[[1-[4-[(1R,2S)-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-10 naphthalenylphenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2H-isoindol-2-yl]-2,6- piperidinedione (referred to herein as “Compound 1”) which has the molecular formula of C45H49N5O4 and the following structure: . 15 Compound 1 is in clinical development as a PROTAC®protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway. Compound 1 is in phase 3 clinical trials for the treatment of patients with estrogen receptor positive / human epidermal growth factor 20 receptor 2 negative (ER+ / HER2-) metastatic breast cancer. The ability to synthesize complex molecules with high levels of stereochemical control remains of paramount importance in organic chemistry. Stereoisomers often have variable biological activity, necessitating synthetic access to all stereochemical configurations of a chiral molecule of interest. In the pharmaceutical industry, control of 25 absolute stereochemistry has major implications in commercial route design of active pharmaceutical ingredients (API) due to cost and scaling limitations. Though asymmetric catalysis offers the most desirable solution, complex architectures, time constraints, and synthetic limitations often necessitate the use of chromatographic or classical resolution methods. These latter alternatives are frequently not practical on a large scale, suffering from lengthy lead times and material losses. Compound 1 and its synthesis have been described in the PCT international patent applications published as WO 2018 / 102725 and WO 2023 / 009521, the contents of which are incorporated herein by reference in their entirety. Crystalline forms of Compound 1 are also described in the PCT international patent application published as WO 2022 / 056368, the content of which is incorporated herein by reference in its entirety. These synthetic routes to Compound 1 are however not adapted for large scale preparation. There is thus a need for a manufacturing process enabling the preparation of large quantities of Compound 1 in a safe and cost-effective way. Synthesis of Compound 1 proceeds through a racemic intermediate, wherein enantiopure access to the challenging cis-1,2-diaryl motif occurs in a late-stage classical resolution, resulting in >50 % material loss of the main API cost contributor, a cis-1,2-diaryltetralin derivative. Reliance on a resolution strategy is unattractive from both a throughput and cost perspective, demonstrating the need for a concise, scalable, asymmetric process. Accordingly, the development of a synthetic route enabling an enantioselective synthesis of a cis-1,2-diaryltetralin derivative, a key chiral intermediate in the synthesis of Compound 1 at large scale is particularly desirable. Summary of the Invention The present invention provides an asymmetric route, including intermediates and synthetic steps, to a key intermediate in the process of preparing Compound 1. Chirality is introduced via a catalytic enantioselective intramolecular Corey-Chaykovsky epoxidation, with the challenging cis-1,2-diaryl motif subsequentially installed via diastereoselective hydrogenation. The route is depicted below in Scheme 1: Scheme 1 The process of the present invention contains several differences compared to previously disclosed processes for preparing Compound 1, which are described in detail below. Also, the process of the present invention is particularly advantageous at least because it enables an enantioselective synthesis of a key chiral intermediate in the synthesis of Compound 1 at large scale. Detailed Description of the Invention The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art. The following embodiments, E1 to E28 are representative embodiments of the present invention. According to a first embodiment E1, the present invention relates to a process for preparing compound Int-2 (Int-2) comprising the step of reacting compound Int-23 and a hydrogen source and, optionally a catalyst, in a solvent. E2 The process of embodiment E1, wherein the catalyst is palladium on carbon. E3 The process of embodiment 1 or embodiment 2, wherein the solvent is methanol or ethyl acetate. E4 The process of embodiment 1 or embodiment 2, wherein the solvent is methanol. E5 The process of any one of embodiments 1 to 3, wherein the hydrogen source is hydrogen. According to E6, the present invention relates to a process for preparing compound Int-23 comprising the step of reacting compound Int-20 and piperidine fragment with a palladium catalyst and a base, in a solvent. E7 The process of embodiment E6, wherein the palladium catalyst is Pd2(dba)3 / RuPhos. E8 The process of embodiment 6 or embodiment 7, wherein the base is sodium tert- butoxide. E9 The process of any one of embodiments 6 to 8, wherein the solvent is toluene. According to E10, the present invention relates to a process for preparing compound Int-20 comprising the step of reacting compound Int-19 with an acid in a solvent. E11 The process of embodiment 10, wherein the acid is sulfuric acid, p- toluenesulfonic acid, or polyphosphoric acid. E12 The process of embodiment 10, wherein the acid is sulfuric acid. E13 The process of any one of embodiments 10 to 12, wherein the solvent is 2- methyltetrahydrofuran. According to E14, the present invention relates to a process for preparing compound Int-19 comprising the step of reacting compound Int-13 with a Grignard reagent in a solvent. E15 A process of embodiment 14, wherein the Grignard reagent is 4-chlorophenyl- magnesium bromide. E16 A process of embodiment 14 or embodiment 15, wherein the solvent is 2- methyltetrahydrofuran. According to E17, the present invention relates to a process for preparing compound Int-20 comprising the steps of: 1) reacting compound Int-19 with an acid in a solvent; and 2) reacting compound Int-13 with a Grignard reagent in a solvent, and not isolating compound Int-19. E18 The process of embodiment 17, wherein the acid is sulfuric acid, p- toluenesulfonic acid, or polyphosphoric acid. E19 The process of embodiment 17, wherein the acid is sulfuric acid. E20 The process of any one of embodiments 17 to 19, wherein the solvent is 2- methyltetrahydrofuran. E21 The process of any one of embodiments 17 to 20, wherein the Grignard reagent is 4-chlorophenyl-magnesium bromide. According to E22, the present invention relates to a process for preparing compound of Int-13 comprising the step of reacting compound of Int-16 and isothiocineole: (Int-16), lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water. According to E23, the present invention relates to a process for preparing compound Int-16 with phosphorous tribromide or hydrogen bromide in a solvent. E24 The process of embodiment 23, wherein the solvent is dichloromethane. According to E25, the present invention relates to a process for preparing compound Int-12 comprising the step of reacting compound Int-10 and allylic alcohol: with a palladium source, a ligand and a base, in a solvent. E26 The process of embodiment 25, wherein the palladium source is Pd(OAc)2. E27 The process of embodiment 25, wherein the ligand is catacxium A. According to E28, the present invention relates to a process for preparing compound Int-2 comprising the steps of: 1) reacting compound Int-10 and allylic alcohol with a Pd(OAc)2and catacxium A in a solvent; 2) reacting compound Int-12 with phosphorous tribromide in a dichloromethane; 3) reacting compound Int-16 and isothiocineole (Int-16), lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water; 4) reacting compound Int-13 with 4-chlorophenyl-magnesium bromide in 2-methyltetrahydrofuran; 5) reacting compound Int-19 with sulfuric acid in 2-methyltetrahydrofuran; 6) reacting compound Int-20 and a piperidine fragment with Pd2(dba)3 / RuPhos and sodium tert-butoxide, in toluene; and 7) reacting compound Int-23 and a hydrogen source and, optionally palladium on carbon, in methanol. For convenience, many chemical moieties and compounds are represented using well known abbreviations, including: Ac (acetyl), Bn (benzyl), BOC (tert- butyloxycarbonyl), catacxium®A (di-adamantylalkylphosphine), CN (cyano), MeOH (methanol), DIPEA (N,N-diisopropylethylamine), DCM (dichloromethane or methylene chloride), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), ETOAc (ethyl acetate), iPr (isopropyl), LiOTf (lithium triflate), LiOTf (lithium triflate), Me (methyl), MTBE (methyl tert-butyl ether), Pd / C (palladium on carbon, Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)), RuPhos (2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl), SNAr (nucleophilic aromatic substitution), TBAI (tetrabutylammonium iodide), TEBAC (benzyltriethylammonium chloride), t-Bu or tBu (tert-butyl), Ts (tosyl), and THF (tetrahydrofuran). Other abbreviations used herein: ee (enantiomeric excess), e.r. (enantiomeric ratio), eq. or equiv. (equivalent or equivalents), g (gram or grams), HPLC (high- performance liquid chromatography-mass spectrometry), min (minute or minutes), mL (milliliter or millititers) MP (melting point), MPA (megapascal), h (hour or hours), L (liter or liters), s (second or seconds), aq. (aqueous) and V (volume or volumes). As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter (± 10%). For example, a temperature of about 10 °C means 10 °C ± 10% i.e., it may vary between 9 °C and 11 °C. The term, "solvate," as used herein, refers to a crystal form of a substance which contains solvent. The term "hydrate" refers to a solvate wherein the solvent is water. The compound of formula Int-4 may be obtained as a hydrate or may convert to an hydrate, depending on storage conditions, specifically temperature and humidity conditions. Grignard compounds are popular reagents in organic synthesis for creating new carbon–carbon bonds. Generally, Grignard reagents or Grignard compounds are chemical compounds with the general formula R−Mg−X, where X is a halogen and R is an organic group, normally an alkyl or aryl. Unless indicated otherwise, all references herein to Compound 1 and intermediates used in its preparation include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof. Previously known synthetic routes for preparing Compound 1 proceed through a racemic intermediate followed by a classical resolution as depicted below in Scheme 2: 2. The synthetic steps described in Scheme 1 present several advantages compared to previously known synthetic routes for preparing Compound 1 as shown in Scheme 2. The route of the present invention introduces chirality via a catalytic, intramolecular Corey-Chaykovksy epoxidation, avoiding the classical resolution process currently used to prepare (Int-2). The unprecedented enantioselective intramolecular epoxidation not only installs a key stereocenter but completes assembly of the tetralin. The challenging cis-1,2-diaryl motif is installed via stereochemical relay using hydrogenation. The present invention controls stereochemistry earlier in the route providing more opportunities for control of chirality as well as conventional process related impurities, while intercepting a common intermediate with the existing convergent route. As shown in Scheme 3, the synthesis commences with the SNAr reaction of benzyl alcohol with fluoro-substituted aldehyde (8) and provides (9) in 77 % yield (2.5 kg scale). The subsequent reduction of (9) in the presence of NaBH4delivers benzylic alcohol (10) in 90 % isolated yield after crystallization (2.75 kg scale). Next, (10) is subjected to a palladium-catalyzed Heck reaction with allylic alcohol or vinyl-benzyl alcohol (11), which may be prepared in one step via addition of vinyl Grignard to benzaldehyde. Several effective ligands may be used in the Heck reaction, with catacxium®A proving to be the most effective ligand. Selection of the palladium source proves important to reduce palladium loading to <1%. When Pd2(dba)3 was utilized as the palladium source, reaction progress often stalled when employed at <0.5%, likely due to the inhibitory effect the dibenzylideneacetone olefin ligand can have in Heck reactions. Pd(OAc)2 enables the use of 0.5 % loading, affording (Int-12) in 66 % yield on 600 g scale. The Heck reaction not only generates the desired C-C sp2-sp3linkage, but also delivers the saturated ketone following tautomerization of the enol product. This feature is advantageous from a process chemistry perspective as it avoids any oxidation step to access desired ketone (Int-12). Scheme 3. Preparation of Corey-Chaykovsky Epoxidation Precursor 2 An asymmetric variant is investigated by reacting either benzylic alcohol (Int-12) or benzyl bromide (Int-16) with a diverse series of chiral sulfides under precedented conditions (Scheme 4). The crude sulfonium salts are subjected to aqueous potassium hydroxide to generate (Int-13), with enantioselectivity being measured via HPLC. Reactions with a diverse series of chiral sulfides with enantiomeric ratio (e.r.) of epoxide product formed (Scheme 5) demonstrates that isothiocineole (17), a hindered chiral sulfide well-established for intermolecular asymmetric variants delivers (Int-13) with >90 % ee, albeit with very sluggish overall reactivity – only 10% of the corresponding sulfonium salt forms prior to epoxidation. While less hindered sulfides often produce higher levels of intermediate sulfonium salts, enantioselectivities in the subsequent epoxidation are low to moderate due to distal chiral information. Scheme 4. Development of an Asymmetric Corey-Chaykovsky Epoxidation - Sulfonium Formation and Subsequent Epoxidation Scheme 5. Analysis of Chiral Sulfides To evaluate a one-pot approach, (Int-12) is treated with phosphorous tribromide in DCM solution to prepare benzyl bromide (Int-16) (Scheme 6). (Int-16) is then evaluated in a one-pot sulfonium formation / epoxidation procedure. A 95% ee results when (Int-16) is subjected to established biphasic reaction conditions (DCM:tBuOH:water) in the presence of (17), lithium triflate, and potassium hydroxide (Table 1, Entry 1). Having now demonstrated that no prior sulfonium preformation is necessary, the one-pot reaction is optimized. Scheme 6. Preparation of benzyl bromide (Int-16), and reaction scheme for one-pot sulfonium salt formation-epoxidation procedure Table 1. Optimization of Corey-Chaykovsky epoxidation 17 LiOTf Additive DCM / H2O Base % % e.r. (Int- Entry (eq.) (eq.) tBuOH (V) (3 eq.) Int- Int- 13) (V) 12 13 1 1.5 5 n / a 10 / 10 2.2 KOH 20 55 97.5:2.5 2 1.5 1.5 n / a 10 / 10 2.2 KOH 10 58 97.5:2.5 3 1.5 0.2 n / a 10 / 10 2.2 KOH 9 56 75.5:25.5 4 1.5 0 n / a 10 / 10 2.2 KOH 0 11 67.5:33.5 5 1.5 0 LiBr (5 10 / 10 2.2 KOH 16 18 95:5 eq.) 6 1.5 1.5 n / a 10 / 10 2.2 Na2CO385 <1 n / a 7 1.5 1.5 n / a 10 / 10 2.2 K2CO3 79 <1 n / a 8 1.5 1.5 n / a 5 / 5 1.1 KOH 9 75 97:3 9 0.5 1.5 n / a 5 / 5 1.1 KOH 27 63 97:3 10 0.5 1.5 TBAI 5 / 5 1.1 KOH 12 84 97:3 (0.2 eq.) 11 0.25 1.5 TBAI 5 / 5 1.1 KOH 16 79 97:3 (0.2 eq.) 12 0.1 1.5 TBAI 4 / 1 0.55 KOH 18 77 96.5:3.5 (0.2 eq.) V 13a0.1 1.5 TBAI 4.45 / 0.58 KOH n / a 67 98:2 (0.2 eq.) 0.55 VaReaction run on 120g scale, 0-15°C, 72 hr, isolated yield and enantiomeric ratio of Int- 13 after crystallization. Percentage of Int-13 and Int-12 determined via HPLC. Enantiomeric ratio (e.r.) of (Int-13) determined via chiral HPLC. Equivalents of LiOTf are reduced from 5 to 1.5 eq with no effect on ee or reaction yield (Entry 2). The importance of lithium salt for successful reaction is demonstrated as further reduction in loading results in decreased ee, and complete omission of LiOTf results in dramatic loss of both yield and ee (Entry 3-4). The exact role of lithium is not fully understood, however Entry 5 demonstrates that an alternative lithium source may be employed, yielding similar enantioselectivities of (Int-13). It was discovered that hydroxide is necessary in order to promote epoxidation, while weaker carbonate- derived bases fail to deliver more than trace epoxide (Entry 6-7). Next, we discovered that by concentrating the biphasic solvent system conversion to (Int-13) is increased (Entry 8). Next, we discovered that when catalytic quantities of (Int-17) are employed, epoxide (Int-13) is obtained with conversion and enantioselectivity matching the stoichiometric studies (Entry 10-12). A phase transfer reagent, tetrabutyl ammonium iodide (TBAI) is also utilized, due to the biphasic nature of the reaction system. TBAI provides a slight enhancement in overall reactivity (Entry 9-10). The common enantioselectivities when using either super-stoichiometric or catalytic chiral sulfide (Int- 17) is due to the lack of competing racemic background reaction. Since (Int-13) cannot form without prior formation of 17-derived chiral sulfonium ylide, regardless of catalyst loading, a common reactive intermediate is shared in all scenarios. Analysis of the reaction mixture indicates that the two main impurities generated are derived from competing hydrolysis of (Int-16) via water or tert-butanol to generate (Int-12) and (Int- 18), both of which are unreactive species in the epoxidation (Scheme 7). Non- nucleophilic solvent combinations do not suppress impurity formation and deliver worsened reaction profiles. Concentrating the reaction system and minimizing the amount of both water and tert-butanol present, suppresses hydrolysis rates to achieve conversions reaching 85 % (Entry 12). Optimal reaction conditions (Entry 13) afford a 67 % isolated yield of (Int-13) with 98.4:1.6 e.r. after crystallization from a isopropanol:acetonitrile blend. Development of crystallization conditions following epoxidation is beneficial from both an impurity purge perspective, and upgrading the enantiopurity of (Int-13). Scheme 7. Major impurities generated during epoxidation Treatment of a 2-methyltetrahydrofuran solution of (Int-13) with 1.2 equiv.4- chlorophenyl-magneisum bromide results in epoxide ring opening at the less substituted carbon, installing the second aryl group to yield tertiary alcohol (Int-19) (Scheme 8). Selection of a Grignard reagent is important to include an aryl chloride cross coupling handle for later manipulations. Use of 4-bromophenylmagnesium bromide is plagued with transmetallation which results in side reactions and dehalogenation. Regioselective dehydration of (Int-19) provides the desired trisubstituted olefin (Int-20). An E1 elimination mechanism via carbocation intermediate may produce a mixture of both undesired (21), and desired (Int-20). Formation of (21) erodes all introduced chirality, yielding an intermediate already shown to be unproductive in asymmetric hydrogenation. However, an E2 mechanism, requiring anti-periplanar geometry provides entirely the desired regioisomer (Int-20). Reaction conditions may influence the regiochemistry of acid-catalyzed alcohol dehydration (Hejtmánková, L., et al, Research on Chemical Intermediates, 2009, 35, 615-623). Numerous combinations of various acids in various solvents deliver the desired regioisomer (Int-20) in high conversion. In general, sulfuric acid provides the fastest rate of elimination, followed by p-toluenesulfonic acid, and polyphosphoric acid. Sulfuric acid performs similarly across multiple solvents. Preferably, 2-methyltetrahydrofuran is the solvent for the dehydration step to facilitate a telescoped process with the prior Grignard step. The dehydration product (20) is more crystalline than alcohol (19), a telescoped process avoids any isolation following Grignard addition (Scheme 8). Utilization of the two distinct crystallizations, one following the asymmetric Corey-Chaykovksy epoxidation, and a second after the Grignard-dehydration process, enables dual chirality upgrade and overall impurity control. Scheme 8. alcohol (Int-23) is provided through amination with (22), for installation of the piperidine acetal fragment. Several viable combinations of solvent, base, and palladium catalysts are available for the carbon-nitrogen coupling (Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem. Rev.2016, 116, 12564-12649). An important factor is the ability of the double benzylic chiral center to survive the alkaline conditions at elevated temperature without any erosion of enantiopurity. Preferably, a Pd2(dba)3 / RuPhos system with sodium tert-butoxide in toluene at 85°C is used. (Scheme 9). Scheme 9. Installation of Piperidine (Int-2) is provided by diastereoselective hydrogenation of (Int-23) along with benzyl group removal. 10 % Pd / C may be utilized in variable solvents, such as methanol and ethyl acetate, with each reaction run at 2 atmosphere hydrogen and 60oC. Olefin reduction occurs prior to debenzylation, but both may be fully converted to (Int-2) within 24 hours. Methanol provides a better overall impurity profile than ethyl acetate. Lower temperatures and higher pressures provide even better impurity control, though reaction times are extended. (Scheme 10). Scheme 10. Diastereoselective Hydrogenation / Debenzylation to access the cis-1,2- Diaryl Motif EXAMPLES The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. Although some of the examples below have been provided at the mL and g scale, it has been assessed that they are all scalable. General Experimental Details All reactions were carried out in dry reaction vessels under an atmosphere of nitrogen unless otherwise specified. All reagents and solvents were used as received unless otherwise specified. For most steps, reactions were monitored, and purity was assessed by UPLC. Chemical shifts were measured relative to the residual solvent resonance for1H and13C NMR (CDCl3= 7.26 ppm for1H and 77.2 ppm for13C, DMSO- d6= 2.50 ppm for1H and 39.5 ppm for13C, and CD3OD = 3.31 ppm for1H and 49.0 ppm for13C). Coupling constants J are reported in Hertz (Hz). Unless otherwise stated the following generalizations apply. All NMR spectra were recorded on a Bruker AVANCE Neo (400 MHz).1H and13C NMR spectral data are reported as chemical shifts (δ) in parts per million (ppm) indirectly referenced to TMS at 0.00 ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, sept = septet, br = broad, m = multiplet), coupling constants J (Hz) and integration. Exchangeable protons are not always observed. (Int-8) (Int-9)Under nitrogen protection, dimethyl sulfoxide (8.6 L, 3.45 V) and benzyl alcohol (Int-7) (4 kg, 3.00 equiv.) were charged to the reactor in one portion at 20-25°C. Potassium phosphate (3.98 kg, 1.50 equiv.) was charged to the reactor in one portion at 20-25°C. Heated reaction mixture to 77-82°C. Charged (Int-8) (2.50 kg, 1.00 equiv.) and dimethyl sulfoxide (3.4 L, 1.35 V) to a flask and stirred until (Int-8) dissolved. Charged solution into the reactor and held for 7-13 h. The reaction mixture was then cooled to 30-40°C and charged methanol (10 L, 4 V). Reaction mixture was heated to 35-45°C and charged water (20 L, 8 V). Reaction mixture was cooled to 0-10°C at a rate of about 10°C per hour. The reaction mixture was held for 2-3 h. The reaction mixture was filtered, and the filter cake was washed once with water (5 L, 2 V) and methanol (2.5 L, 1 V) before drying on filter for at least 8 h. (Int-9) was isolated as a white solid (2.75 kg, 78% yield) in 91.8% purity. MP 44.8°C – 48.7°C;1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.81 (d, J = 8.76 Hz, 1H), 7.47 – 7.33 (m, 6H), 7.17 (dd, J = 8.93, 2.46 Hz, 1H), 5.23 (s, 2H);13C NMR (100 MHz, DMSO-d6) 189.8, 163.3, 135.8, 131.5, 128.5, 128.1, 127.8, 127.5, 126.5, 119.3, 115.2, 70.1. Charged toluene (9.27 L, 3.37 V) and (Int-9) (2.75 kg, 1.00 equiv.) under nitrogen protection. Charged NaBH4(0.43 kg, 1.20 equiv.) and cooled reaction mixture to 0-10°C. Afterwards, charged MeOH (1.66 L, 0.605 V) and toluene (6 L, 2.18 V) ensuring reaction temperature did not exceed 10°C. Reaction mixture was heated to 15-25°C and held for 1 h. The reaction mixture was cooled to -5-10°C before 20% ammonium chloride solution (10.9 L, 3.95 V) was charged dropwise. Then, the reaction mixture was held for 20-30 min. Charged ethyl acetate (9.16 L, 3.33 V) and stirred for 20-30 min before the upper organic layer was collected. Ethyl acetate (4.59 L, 1.67 V) was used to back-extract the lower aqueous phase. Organic phases were combined and washed with 20% sodium chloride aqueous solution (6.46 L, 2.35 V). Aqueous phase was separated, and organic phase was concentrated to 1.0 V-1.5 V at 40-50°C. n-Heptane (14.9 L, 5.4 V) was added dropwise at 40-50°C, and the reaction temperature was then lowered to 0-10°C. Reaction mixture was allowed to stir for 2-3 h. The mixture was filtered and washed with n-Heptane (2.70 L, 0.98 V). Filter cake was dried at 40-50°C under vacuum. (Int-10) was isolated as a white solid (2.53 kg, 90% yield) in 90% assay and 98.8% purity. MP 72.6°C – 73.2°C;1H NMR (400 MHz, DMSO- d6) δ 7.46 – 7.31 (m, 6H), 7.25 (d, J = 2.54 Hz, 1H), 7.06 (dd, J = 8.61, 2.59 Hz, 1H), 5.32 – 5.29 (m, 1H), 5.11 (s, 2H), 4.49 (s, 2H);13C NMR (100 MHz, DMSO-d6) δ 157.7, 136.7, 133.1, 129.1, 128.4, 127.8, 127.6, 121.5, 118.1, 114.3, 69.5, 62.2. Charged Pd(OAc)2(2.28 g, 0.005 equiv.) into reactor. Charged catacxium®A (7.49 g, 0.01 equiv.) into reactor. Charged DMF (3 L, 5 V) into reactor. Charged purified water (60 mL, 0.1 V) into reactor 1 and stirred the reaction mixture at 20-30°C for 0.5-1 h under N2. Charge (Int-11) vinylbenzylalcohol (282.4 mL, 1.05 equiv.) into reactor. Charged (Int-10) (600 g, 1.0 equiv.) into reactor. Charged DIPEA (446 mL, 1.25 equiv.) into reactor. Charged TEBAC (2.33 g, 0.005 equiv.) into reactor. The reaction mixture was heated to 95-105°C held for 3-6 h under N2. Reaction mixture was cooled down to 20-40°C. The reaction liquid was filtered through filter paper to remove the black heavy metals. Charged n-Heptane (2.4 L, 4 V) into reactor and stirred for 0.5 h. Allowed reaction mixture to stand for 0.5 h at 20-40°C to allow layers to separate (the n-Heptane phase was abandoned). Extraction operation was repeated 2 more times. Charged water (6 L, 10 V) and ethyl acetate (3 L, 5 V) into reactor. Stirred the mixture at 20-30°C for 30 min and let stand for 30 min. The ethyl acetate phase was collected. Charged ethyl acetate (3 L, 5 V) into reactor. The water phase was added back into reactor and the mixture was stirred at 20-30°C for 30 min. Reaction mixture was allowed to stand for 30 min. The ethyl acetate phase was collected and combined with the first ethyl acetate layer. Charged 15% sodium chloride solution (3 L, 5 V) into reactor and stirred the mixture at 20-30°C for 30 min. Reaction mixture was allowed to rest for 30 min. The ethyl acetate phase was collected before 15% sodium chloride solution (3 L, 5 V) was charged into reactor. The mixture was stirred at 20-30°C for 30 min and stand for 30 min before the ethyl acetate phase was collected. Concentrated the organic phase under reduced pressure at 45-55°C to 1-1.5V. Charged Isopropyl alcohol (2.4 L, 4 V) into reactor and the reaction mixture was heated to 55-65°C. The solution was dissolved. The reaction mixture was then cooled to -5-5°C and stirred for 1-2 h. Reaction mixture was filtered, and the cake was washed with cold isopropyl alcohol (1.2 L, 2 V). (Int-12) was dried at 50°C under vacuum for 16 h. (Int-12) was isolated as a white solid (476.5 g, 67% yield) in 98.5% purity. MP 97.6°C – 100.0°C;1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.68 Hz, 2H), 7.63 (t, J = 14.78 Hz, 1H), 7.54 – 7.26 (m, 8H), 6.95 (d, J = 2.65 Hz, 1H), 6.84 (dd, J = 8.33, 2.67 Hz, 1H), 5.08 (s, 2H), 5.00 (t, J = 10.58 Hz, 1H), 4.53 (d, J = 5.26 Hz, 2H), 3.42 – 3.34 (m, 2H), 2.98 (t, J = 15.28 Hz, 2H);13C NMR (100 MHz, DMSO-d6) δ 199.2, 157.2, 140.7, 137.2, 136.6, 133.1, 132.3, 129.5, 128.6, 128.3, 127.9, 127.7, 127.6, 115.6, 111.6, 69.1, 60.8, 39.5, 26.2. Example 4: Formation of 3-(5-(benzyloxy)-2-(bromomethyl)phenyl)-1- phenylpropan-1-one (Int-16) (Int-12) (Int-16)Charged (Int-12) (440 g, 1.0 equiv.) into reactor. Charged DCM (2.2 L, 5 V) into reactor. The reaction mixture was cooled to -5-0°C and stirred for 0.5-1 h with N2. Charged PBr3 (206.1 g, 0.6 equiv.) slowly into reactor to keep the temperature at -5- 0°C. Stirred the reaction mixture at -5-0°C for 4-16 h with N2. Reaction mixture was cooled down to 0-10°C. Charged 5% sodium bicarbonate aqueous solution (4.4 L-5.3 L, 10-12 V) into reactor to adjust pH=7-8. Stirred the mixture at 0-10°C for 1 h. Reaction mixture was allowed to stand for 0.5 hours at 20-40°C to allow the layers to be separated (Product in Organic phase). Charged DCM (2.2 L, 5 V) into reactor and stirred for 0.5 hours. Reaction mixture was allowed to stand for 0.5 hours at 20-40°C to allow the layers to be separated (Product in Organic phase). Organic phases were charged back into reactor. Charged water (2.2 L, 5 V) into reactor and stirred for 0.5 hours. Reaction mixture was allowed to stand for 0.5 hours at 20-40°C to allow the layers to be separated (Product in Organic phase). Concentrated the organic phase under reduced pressure at 30-40°C to 2-3 V. Charged MTBE (2.6 L, 6 V) into reactor and concentrated the organic phase under reduced pressure at 30-40°C to 2-3 V. Charged n-Heptane (3.96 L, 9 V) into reactor and stirred mixture at 5-15°C for 1-2 h. Reaction mixture was filtered and the cake was washed with n-Heptane (880 ml, 2 V). (Int-16) was dried at 45°C under vacuum for 16-20 h. (Int-16) was isolated as an off- white solid (469.2 g, 90% yield) in 97.1% purity. MP 86.2°C – 88.0°C;1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.09 Hz, 2H), 7.58 (t, J = 14.74 Hz, 1H), 7.50 – 7.29 (m, 8H), 6.90 (d, J = 2.61 Hz, 1H), 6.83 (dd, J = 8.64, 2.68 Hz, 1H), 5.06 (s, 2H), 4.64 (s, 2H), 3.41 (t, J = 15.40 Hz, 2H), 3.18 (t, J = 15.42 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 198.9, 159.4, 142.1, 136.8, 136.7, 133.2, 132.2, 128.7, 128.6, 128.2, 128.1, 128.1, 127.5, 116.3, 112.9, 70.0, 39.4, 32.4, 26.6. Example 5: Formation of (1aR,7bR)-5-(benzyloxy)-1a-phenyl-1a,2,3,7b- tetrahydronaphtho[1,2-b]oxirene (Int-13) (Int-16) (Int-17) (Int-13)Charged (Int-16) (120 g, 1.0 equiv.) into reactor. Charged LiOTf (68.6 g, 1.5 equiv.) into reactor. Charged (Int-17) isothiocineole (5.1 g, 0.1 equiv.) into reactor. Charged TBAI (21.6 g, 0.2 equiv.) into reactor. Charged DCM (534 mL, 4.45 V) and t- BuOH (66 mL, 0.55 V) into reactor. Reaction mixture was cooled to -15-5°C and stirred for 2-4 h. Charged KOH (49.3 g, 3.0 equiv.) in water (69.6 mL, 0.58 V) to reaction dropwise at -15-5°C. Stirred reaction solution at 5-15°C for 48 h. Charged DCM (408 mL, 3.4 V) into reactor. Charged water (300 mL, 2.5 V) into reactor and stirred the mixture at 5-15°C for 20-30 min. Allowed reaction mixture to settle for 30-40 min. Separated the layers and collected the organic layer. Charged aqueous layer into reactor and charged DCM (60 mL, 0.5 V) into reactor. Stirred mixture at 20-30°C for 5- 10 min. Allowed reaction mixture to settle for 10-20 min. Separated the layers and collected the organic layer. Combined the two organic layers and charge organic layer into reactor. Charged water (360 mL, 3 V) into reactor and stirred mixture at 20-30°C for 20-30 min. Allowed reaction mixture to settle for 20-30 min. Separated the layers and collected the organic layer. Charged aqueous layer into reactor and charged 15% NaCl aqueous layer (300 mL, 2.5 V) into reactor. Stirred the mixture at 20-30°C for 5-10 min. Allowed reaction mixture to settle for 10~20 min. Separated the layers and collected the organic layer. Concentrated the organic layer under reduced pressure at 28-38°C to 1.3-1.8 V. Charged acetonitrile (120 mL, 1.0 V) into reactor and charged iPrOH (600 mL, 5.0 V) into reactor. Stirred the mixture at -10-0°C for 3 h. Reaction mixture was filtered, and the cake was washed with iPrOH (120 mL, 1.0 V). (Int-13) was dried at 30- 40°C under vacuum for 24 h. (Int-13) was isolated as a light-yellow solid (59.2 g, 68% yield) in 99.1% purity, 98.4% chiral purity, and 67.9% assay. MP 117.4°C – 118.8°C;1H NMR (400 MHz, DMSO-d6) δ 7.47 – 7.31 (m, 11H), 6.88 (t, J =17.16 Hz, 2H), 5.11 (s, 2H), 3.88 (s, 1H), 2.83 – 2.74 (m, 1H), 2.67 – 2.63 (m, 1H), 2.42 – 2.35 (m, 2H);13C NMR (100 MHz, DMSO-d6) δ 158.6, 140.4, 138.0, 137.0, 130.4, 128.4, 128.3, 127.8, 127.6, 127.5, 125.1, 124.9, 114.8, 112.1, 69.1, 62.7, 61.2, 25.3, 24.8. Alternate Examples 4 and 5: Development of (1aR,7bR)-5-(benzyloxy)-1a-phenyl- 1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene (Int-13) Treatment of (Int-12) with phosphorous tribromide in DCM solution provided benzyl bromide (Int-16) in 90 % yield on 440 g scale. (Int-16) was subjected to established biphasic reaction conditions (DCM:tBuOH:Water) in the presence of 1.5 equiv. (17), 5 equiv. lithium triflate (LiOTf), and 3 equiv. potassium hydroxide to provide 55 % (Int-13) with 95% ee (Table 2, Entry 1). Table 2. Optimization of Corey-Chaykovsky epoxidation 17 LiOTf Additive DCM / H2O Base % % e.r. (Int- Entry (eq.) (eq.) tBuOH (V) (3 eq.) Int- Int- 13) (V) 12 13 1 1.5 5 n / a 10 / 10 2.2 KOH 20 55 97.5:2.5 2 1.5 1.5 n / a 10 / 10 2.2 KOH 10 58 97.5:2.5 3 1.5 0.2 n / a 10 / 10 2.2 KOH 9 56 75.5:25.5 4 1.5 0 n / a 10 / 10 2.2 KOH 0 11 67.5:33.5 5 1.5 0 LiBr (5 10 / 10 2.2 KOH 16 18 95:5 eq.) 6 1.5 1.5 n / a 10 / 10 2.2 Na2CO385 <1 n / a 7 1.5 1.5 n / a 10 / 10 2.2 K2CO379 <1 n / a 8 1.5 1.5 n / a 5 / 5 1.1 KOH 9 75 97:3 9 0.5 1.5 n / a 5 / 5 1.1 KOH 27 63 97:3 10 0.5 1.5 TBAI 5 / 5 1.1 KOH 12 84 97:3 (0.2 eq.) 11 0.25 1.5 TBAI 5 / 5 1.1 KOH 16 79 97:3 (0.2 eq.) 12 0.1 1.5 TBAI 4 / 1 0.55 KOH 18 77 96.5:3.5 (0.2 eq.) V 13a0.1 1.5 TBAI 4.45 / 0.58 KOH n / a 67 98:2 (0.2 eq.) 0.55 VaReaction run on 120g scale, 0-15°C, 72 hr, isolated yield and enantiomeric ratio of Int- 13 after crystallization. Percentage of Int-13 and Int-12 determined via HPLC. Enantiomeric ratio (e.r.) of (Int-13) determined via chiral HPLC. The equivalents of LiOTf were reduced from 5 to 1.5 equiv. with no effect on ee or reaction yield (Entry 2). The importance of lithium salt for successful reaction was demonstrated as further reduction in loading resulted in decreased ee, and complete omission of LiOTf resulted in dramatic loss of both yield and ee (Entry 3-4). Entry 5 demonstrated that an alternative lithium source may be employed and yielded similar enantioselectivities of (Int-13). Hydroxide was necessary in order to promote epoxidation, while weaker carbonate-derived bases failed to deliver more than trace epoxide (Entry 6-7). Conversion to (Int-13) increased to 75% by concentrating the biphasic solvent system conversion (Entry 8). Catalytic quantities of (17) were employed to obtain epoxide (Int-13) with conversion and enantioselectivity matching the stoichiometric studies (Entry 10-12). Phase transfer reagent, TBAI was also used due to the biphasic nature of the reaction system. TBAI provided a slight enhancement in overall reactivity (Entry 9-10). The reaction mixture indicated that the two main impurities generated were derived from competing hydrolysis of (Int-16) via water or tert-butanol to generate (Int-12) and (Int- 18), both of which were unreactive species in the epoxidation (Scheme 11). Further concentrating the reaction system and minimizing the amount of both water and tert- butanol present, hydrolysis rates were be suppressed enough to achieve conversions reaching 85 % (Entry 12). Epoxidation on 120 g scale with optimal reaction conditions (Entry 13), afforded 67 % isolated yield of (Int-13) with 98.4:1.6 e.r. after crystallization from a isopropanol:acetonitrile blend. Development of crystallization conditions following epoxidation was beneficial from both an impurity purge perspective, and upgrading the enantiopurity of (Int-13). Scheme 11. Major impurities generated during epoxidation Example 6: Formation of (1R)-6-(benzyloxy)-1-(4-chlorophenyl)-2-phenyl-1,4- dihydronaphthalene (Int-20) Charged (Int-13) (80 g, 1.00 equiv.) and 2-MeTHF (160 mL, 2 V) into reactor. Stirred mixture for 5-10 min. Charged Grignard reagent as a 1 M solution in 2-MeTHF (731 mL, 0.731 mol, 3 equiv.) at 20-40°C. Stirred the mixture at 45-55°C for 2-3 h. Cooled reaction mixture to -10-0°C. Charged 20% NH4Cl aqueous solution (560 mL, 7 V) to reactor at 0-10°C. Charged ethyl acetate (320 mL, 4 V) to reactor and stirred the mixture for 20-30 min. Allowed reaction mixture to settle for 20-30 min. Separated the layers and collected the organic layer. Charged aqueous layer and ethyl acetate (160 mL, 2 V) to reactor and stirred the mixture for 20-30 min. Allowed reaction mixture to settle for 20-30 min. Separated the layers and combined two organic layers. Charged organic layer and activated carbon (12 g, 4.11 equiv.) to reactor. Stirred the mixture for 30-40 min. Charged celite (24 g, 0.3 w / w) into Brinell funnel. Filtered reaction mixture and collected filtered liquor. Concentrated organic layer under reduced pressure at 45- 55°C to 2.0-2.5V. The residue used directly to next step. Charged (Int-9) (148 g, Crude) into reactor. Charged 2-MeTHF (400 mL, 5 V relative to epoxide (Int-13)) into reactor and stirred mixture for 5-10 min. Cooled reaction mixture to -10-0°C. Charged H2SO4 (concentrated 95%~98%, 67 mL, 5 equiv.) at -10-0°C dropwise. Stirred the mixture at 45-55°C for 1-2 h. Charged ice water (400 mL, 5 V relative to epoxide (Int-13)) to reactor at 0-10°C and stirred the mixture for 20 min. Allowed reaction mixture to settle for 10-20 min. Separated the layers and collected the organic layer. Charged organic layer to reactor and charged 6% NaHCO3aqueous solution (320 mL, 4 V relative to epoxide (Int-13)) to reactor. Stirred the mixture for 20-30 min. Allowed reaction mixture to settle for 20-30 min. Separated the layers and collected organic layers. Charged celite (16 g, 0.2 w / w relative to epoxide (Int-13)). Filtered reaction mixture and collected filtered liquor. Concentrated filtered liquor under reduced pressure at 45-55°C to 1.8- 2.3V (relative to epoxide (Int-13)). Charged acetonitrile (136 mL, 1.7 V relative to epoxide (Int-13)) and isopropanol (704 mL, 8.8 V relative to epoxide (Int-13)) to reactor. Stirred the mixture at -5-5°C for 4-5 h. Reaction mixture was filtered, and the filter cake was collected. (Int-20) was dried under vacuum at 45-55°C for 48 h. (Int-20) was isolated as an off-white solid (73.2g, 71% yield) in 97.8% purity, 99.4% chiral purity, and 94.3% assay. MP 127.9°C – 128.1°C;1H NMR (400 MHz, CDCl3) δ 7.52 -7.27 (m, 11H), 7.23 – 7.19 (m, 5H), 6.89 (t, J =11.52 Hz, 2H), 5.14 (t, J = 6.52 Hz, 1H), 5.11 (s, 2H), 3.83 – 3.77 (m, 1H), 3.69 – 3.63 (m, 1H);13C NMR (100 MHz, CDCl3) δ 157.3, 143.7, 141.1, 139.7, 137.2, 134.4, 131.9, 131.2, 129.8, 129.1, 128.8, 128.7, 128.3, 128.0, 127.5, 127.1, 126.4, 123.8, 113.8, 113.7, 70.1, 48.0, 31.5. Charged (22), TsOH (56.4 g, 1.2 equiv.) and toluene (600 mL, 10 V) into reactor. Charged tBuONa (59 g, 4.2 equiv.) into reactor and stirred the reaction mixture at 20- 30°C for 0.5-1 h with N2. Charged (Int-20) (60 g, 1 equiv.) into reactor. Charged Pd2(dba)3(1.34 g, 0.01 equiv.) into reactor. Charged RuPhos (4.73 g, 0.04 equiv.) into reactor and stirred the reaction mixture at 85-90°C for 1-2 h with N2. Reaction mixture was cooled to 20-40°C. Charged DCM (600 mL, 10 V) and charged water (600 mL, 10 V) into reactor. Stirred the mixture at 20-30°C for 10-30 min. Reaction mixture was filtered with diatomite. The filter cake was washed with DCM (120 mL-180 mL, 2-3 V). Separated the filtrate and collected the organic layer. Stirred and dried with MgSO4 while adding activated carbon (type 767) for 30-60 min. Filtered with diatomite and washed the filter cake with DCM (120 mL-180 mL, 2-3V). Concentrated the filtrate under reduced pressure at 40-50°C to 3-5 V. Charged ethyl acetate (60 mL, 1 V) into reactor along with Heptane (300 mL, 5 V). Charged MeOH (60 mL, 1 V) into reactor and stirred mixture at 20-30°C for 16-24 h. Reaction mixture was filtered, and the cake was washed with 1:5:1 EtOAc:Heptane:MeOH (120 mL-180 mL, 2-3 V). (Int-23) was dried at 40°C under vacuum for 6 h. (Int-23) was isolated as a light-yellow solid (56.8 g, 73% yield) in 99.3% assay and 99.1% chiral purity. MP 164.4°C – 166.0°C;1H NMR (400 MHz, CDCl3) δ 7.45 – 7.31 (m, 7H), 7.27 – 7.17 (m, 4H), 7.10 (d, J = 8.66 Hz, 2H), 6.81 (t, J = 8.02 Hz, 4H), 6.42 (q, J = 2.49 Hz, 1H), 5.04 (s, 2H), 5.00 (s, 1H), 4.07 (d, J = 7.35 Hz, 1H), 3.71 (s, 1H), 3.61 – 3.54 (m, 3H), 3.37 (s, 6H), 2.59 (t, J = 12.24 Hz, 2H), 1.82 (d, J = 13.44 Hz, 2H), 1.73 – 1.67 (m, 1H), 1.51 – 1.40 (m, 2H);13C NMR (100 MHz, CDCl3) δ 157.0, 141.6, 140.3, 137.3, 134.5, 132.5, 129.7, 129.1, 128.6, 128.3, 128.2, 128.0, 127.5, 126.9, 126.5, 123.3, 117.0, 113.6, 113.5, 107.9, 77.3, 70.1, 53.7, 49.8, 47.9, 38.3, 31.6, 27.4. Example 8: Formation (5R,6S)-5-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (Int-2) Charged (Int-23) (50 g, 1.0 equiv.) into reactor along with MeOH (750 mL, 15 V). Charged 5% Pd / C (7.5 g, 15% w / w) into reactor. The reactor was degassed with N2 three times and then with H2three times. Stirred the mixture at 40-45°C for 2 days with 2 MPa H2. Reaction mixture was cooled to 20-30°C. Charged ethyl acetate (500 mL, 10V) into reactor. Reaction mixture was filtered, and the cake was washed with ethyl acetate (100 mL, 2 V). Concentrated the filtrate under reduced pressure at 40°C to 3 V in a new reactor. Charge MeOH (500 mL, 10 V) into reactor and concentrated at 40°C to 3 V. Charged MeOH (500 mL, 10 V) into reactor and concentrated at 40°C to 3 V. Charged MeOH (450 mL, 9 V) into reactor and stirred mixture at 40°C for 4 h. Reaction mixture was cooled to 20°C over 2 h. Stirred mixture at 20°C for 12-20 h. Reaction mixture was filtered and the cake was washed with ice MeOH (100 mL, 2 V). (Int-2) was dried at 40°C under vacuum for 6 h. Charged the solid (Int-2) into reactor. Charged 1-propanol (400 mL, 8 V) into reactor. Reaction mixture was stirred and heated to 40°C. Once the solids dissolved, charged water (50 mL, 1 V) into reactor along with (Int-2) seed (0.42 g, 0.01 equiv.). Stirred mixture at 40°C for 1 h. Charged water (350 mL, 7 V) into reactor over 6 h and stirred mixture at 40°C for 2 h. Reaction mixture was cooled to 20°C over 2 h. Stirred mixture at 20°C for 12-20 h. Reaction mixture was filtered, and the cake was washed with 1-propanol / water (100 mL, 2 V). (Int-2) was dried at 40°C under vacuum for 6 h. (Int-2) was isolated as a white solid (30 g, 72% yield) in 98% purity. MP 169.4°C – 170.0°C;1H (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.12 (s, 3H), 6.82 (d, J = 6.55 Hz, 2H), 6.65 – 6.47 (m, 5H), 6.19 (d, J = 7.66 Hz, 2H), 4.12 (s, 1H), 4.04 (d, J = 6.48 Hz, 1H), 3.51 (d, J =11.31 Hz, 2H), 3.24 (s, 6H), 3.17 (d, J = 5.23 Hz, 1H), 2.94 (s, 2H), 2.42 (t, J = 12.12 Hz, 2H), 2.09 (s, 1H), 1.70 – 1.63 (m, 4H), 1.25 (d, J = 11.95 Hz, 2H);13C NMR (100 MHz, DMSO-d6) δ 155.2, 149.0, 144.3, 137.0, 132.7, 131.0, 130.4, 130.3, 127.8, 127.5, 125.7, 114.2, 113.5, 107.1, 53.3, 49.4, 48.4, 48.3, 44.5, 37.8, 29.3, 26.7, 21.6.

Claims

Claims We claim:

1. A process for preparing compound Int-2comprising the step of reacting compound Int-23and a hydrogen source and, optionally a catalyst, in a solvent.

2. The process of claim 1, wherein the catalyst is palladium on carbon.

3. The process of claim 1 or claim 2, wherein the solvent is methanol or ethyl acetate and the hydrogen source is hydrogen.

4. A process for preparing compound Int-23comprising the step of reacting compound Int-20 and piperidine fragment (Int-20) OONand H TsOH with a palladium catalyst and a base, in a solvent.

5. The process of claim 4, wherein the palladium catalyst is Pd2(dba)3 / RuPhos.

6. The process of claim 4 or claim 5, wherein the base is sodium tert-butoxide.

7. The process of any one of claims 4 to 6, wherein the solvent is toluene.

8. A process for preparing compound Int-20comprising the step of reacting compound Int-19with an acid in a solvent.

9. The process of claim 8, wherein the acid is sulfuric acid, p-toluenesulfonic acid, or polyphosphoric acid.

10. The process of claim 8 or claim 9, wherein the solvent is 2-methyltetrahydrofuran.

11. A process for preparing compound Int-19comprising the step of reacting compound Int-13with a Grignard reagent in a solvent.

12. A process of claim 11, wherein the Grignard reagent is 4-chlorophenyl-magnesium bromide and the solvent is 2-methyltetrahydrofuran.

13. A process for preparing compound Int-20comprising the steps of:3) reacting compound Int-19with an acid in a solvent; and 4) reacting compound Int-13with a Grignard reagent in a solvent, and not isolating compound Int-19.

14. The process of claim 13, wherein the acid is sulfuric acid, p-toluenesulfonic acid, or polyphosphoric acid.

15. The process of claim 13 or claim 14, wherein the solvent is 2- methyltetrahydrofuran.

16. The process of any one of claims 13 to 15, wherein the Grignard reagent is 4- chlorophenyl-magnesium bromide.

17. A process for preparing compound of Int-13comprising the step of reacting compound of Int-16 and isothiocineole:(Int-16), lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water.

18. A process for preparing compound Int-12comprising the step of reacting compound Int-10 and allylic alcohol:with a palladium source, a ligand and a base, in a solvent.

19. The process of claim 18, wherein the palladium source is Pd(OAc)2and the ligand is catacxium A.

20. A process for preparing compound Int-2comprising the steps of: 1) reacting compound Int-10 and allylic alcoholwith a Pd(OAc)2and catacxium A in a solvent; 2) reacting compound Int-12with phosphorous tribromide in a dichloromethane; 3) reacting compound Int-16 and isothiocineole(Int-16), lithium triflate, and potassium hydroxide in a solution of dichloromethane, tert-butyl alcohol, and water; 4) reacting compound Int-13with 4-chlorophenyl-magnesium bromide in 2-methyltetrahydrofuran; 5) reacting compound Int-19with sulfuric acid in 2-methyltetrahydrofuran; 6) reacting compound Int-20 and a piperidine fragmentwith Pd2(dba)3 / RuPhos and sodium tert-butoxide, in toluene; and 7) reacting compound Int-23and a hydrogen source and, optionally palladium on carbon, in methanol.

Images