Processes and intermediates for preparation of 2-(2,6-dichlorophenyl)-1-[(1s,3r)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone

Abstract

To provide processes and intermediates for the preparation of D1 PAM I.SOLUTION: Embodiments of the present invention provide processes and intermediates for the preparation of D1 PAM I represented by the following formula. The process for the preparation comprises i.) sequential treatment of (R)-2-bromophenyl alanine with a reducing agent and iodine; and subsequent treatment with a mild mineral base and an alkyl carbonate to obtain (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one.SELECTED DRAWING: None

Description

[Technical field]

[0001] Embodiments of the present invention relate to the fields of pharmaceutical chemistry and synthetic organic chemistry and provide methods and key intermediates for the synthesis of the D1 receptor positive allosteric modulator (D1 PAM), 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone, and compositions thereof. [Background technology]

[0002] 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone is a dopamine D1 receptor positive allosteric modulator (D1 PAM) and represents a potential first-in-class treatment for dementia and other dopaminergic CNS disorders. 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone (CAS Registry Number 1638667-79-4), sometimes referred to herein as D1 PAM I, can be structurally represented as follows: [ka]

[0003] Useful forms of D1 PAM I include crystalline forms (see WO2017 / 070068) and co-crystalline forms (see WO2014 / 193781) containing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and 4-hydroxybenzoic acid (CAS Registry Number 1638669-32-5). As a positive allosteric modulator, D1 PAM I, also called a "potentiator" of the dopamine D1 receptor subtype, is highly selective for D1. D1 PAM I exhibits very weak direct agonism of the D1 receptor, is active only in the presence of dopamine, is believed to be endogenous tone dependent, and has normal feedback control in the subject. Thus, D1 PAM I represents an innovative pharmacological agent and approach for modulating the D1 signaling pathway in Parkinson's disease, Alzheimer's disease, and other dopaminergic CNS disorders in which D1 signaling may be deficient.

[0004] The method of making D1 PAM I is described in WO2014 / 193781, for example, in Examples 1 and 2. As shown in Scheme 1 below, an 11-step synthetic route for preparing D1 PAM I has been previously disclosed in U.S. Patent No. 8,962,654. The overall yield of D1 PAM I starting from commercially available 2-bromo-D-phenylalanine via the route described in Scheme 1 below is about 17% over all 11 steps. Therefore, an improvement in the synthesis of D1 PAM I would provide substantial and diverse advantages.

[0005] [ka]

[0006] Synthetic chemistry process routes can be redesigned or revised with the goal of achieving various advantages, such as, for example, increased yields, obtaining crystalline products, reducing impurity profiles, utilizing commercially available intermediates, increasing or improving enantioselectivity and / or stereoselectivity and / or diastereoselectivity, minimizing the number of synthetic steps required, reducing inputs required and / or by-products produced, or a useful combination of such improvements to achieve practical and important outcomes, such as reducing costs, providing less resource intensive processes, and facilitating efficient production. Improved methods for making D1 PAM I that may achieve one or more of these objectives are needed. Summary of the Invention

[0007] Embodiments of the present invention provide processes for the preparation of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone and / or compositions thereof, and particularly useful intermediates for use in these processes.

[0008] In one embodiment, the present invention provides a compound of the formula: [ka] i.) sequential treatment of (R)-2-bromophenylalanine with a reducing agent and iodine; and subsequent treatment with a mild mineral base and alkyl carbonate to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one; ii.) treating (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one with sodium arylsulfinate and acetaldehyde to obtain (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one; iii.) optionally crystallizing the (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one; iv.) optionally verifying the stereochemistry of the (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one by single crystal X-ray analysis; v.) Pictet-Spengler cyclization of (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one with a transition metal halide to obtain (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one; vi.) optionally crystallizing the (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one; vii.) optionally verifying the stereochemistry of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one by single crystal X-ray analysis; viii.) Heck coupling of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one with 2-methyl-3-buten-2-ol to obtain (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol; ix.) optionally crystallizing the (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol; x.) reducing (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-ene under hydrogenation conditions to obtain 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; xi.) optionally crystallizing 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; xii.) coupling of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol with 2,6-dichlorophenylacetic acid in the presence of a coupling agent for amide synthesis and a non-nucleophilic organic base to obtain 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xiii.) optionally crystallizing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xiv.) treating 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid to obtain a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid.

[0009] Preferably, the reaction in this process is carried out using flow reaction methodology.

[0010] In another embodiment, the present invention provides a method for preparing a compound of the formula: [ka] i.) treating (S)-(+)-benzyl glycidyl ether and 1,3-dibromobenzene with a metal base to obtain (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol; ii.) treating (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol with arylsulfonyl chloride in the presence of an organic base to give [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl]arylsulfonate; iii.) treatment of [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl]arylsulfonate with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide in the presence of an organometallic base; and subsequent treatment with toluenesulfonic acid monohydrate to give (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid; iv.) optionally crystallizing (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid; v.) (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline free basing of 4-methylbenzenesulfonic acid with a non-nucleophilic mineral base followed by debenzylation to give (1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; vi.) Heck coupling of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol with 2-methylbut-3-en-2-ol to obtain (E)-4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol; vii.) reduction of (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol under hydrogenation conditions to obtain 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; viii.) optionally crystallizing 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-oe; ix.) coupling of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol with 2,6-dichlorophenylacetic acid in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine and a non-nucleophilic organic base to obtain 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; x.) optionally crystallizing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xi.) treating 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid to obtain a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid.

[0011] Preferably, in this method, the coupling agent for the amide synthesis is 2-chloro-4,6-dimethoxy-1,3,5-triazine. Preferably, the reaction in this method is carried out using a flow reaction method.

[0012] In another embodiment, the present invention provides the compound [ka] A method for preparing i.) (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one was reacted with sodium benzenesulfinate, HCO 2 H, and acetaldehyde; ii.) optionally crystallizing the single diastereomer to obtain (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

[0013] In another embodiment, the present invention provides a method for preparing a compound comprising the steps of: [ka] (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one was reacted with ZrCl 4to give (5S,10AR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

[0014] Preferably, the above process for preparing a compound comprises: [ka] A diastereomeric ratio of greater than 50:1 is achieved.

[0015] In another embodiment, the present invention provides a method for preparing a compound comprising the steps of: [ka] i.) treating [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate and n-butyllithium under continuous flow and cryogenic conditions to obtain [2-[(2S)-3-benzyloxy-2-(p-tolylsulfonyloxy)propyl]-3-bromo-phenyl]lithium; ii.) treating [2-[(2S)-3-benzyloxy-2-(p-tolylsulfonyloxy)propyl]-3-bromo-phenyl]lithium with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide under continuous flow conditions; iii.) cleaving the chiral sulfonamide auxiliary with HCl under continuous flow conditions; iv.) treating the cleaved product with an inorganic base to provide (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline; v.) treating (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline with 4-toluenesulfonic acid to obtain (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-toluenesulfonic acid.

[0016] In another embodiment, the present invention provides compounds useful for the synthesis of D1 PAM I.

[0017] In another embodiment, the present invention provides the compound [ka] Provide It may be named (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one. Preferably, the compound is crystalline.

[0018] In another embodiment, the present invention provides a compound: [ka] Provide This may be named (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one. Preferably, the compound is crystalline.

[0019] In another embodiment, the present invention provides a compound: [ka] Provide It may be named (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol. Preferably, the compound is crystalline.

[0020] In another embodiment, the present invention provides a compound: [ka] Provide It may be named [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate. Preferably, the compound is crystalline.

[0021] In another embodiment, the present invention provides a compound: [ka] Provide It may be named (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid. Preferably, the compound is crystalline.

[0022] In another embodiment, the present invention provides a compound: [ka] Provide It may be named [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol. Preferably, the compound is crystalline.

[0023] In another embodiment, the present invention provides a compound: [ka] Provide It may be named (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol. Preferably, the compound is crystalline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The reactions described herein can be carried out by standard techniques known to those skilled in the art by using conventional glassware, or can be carried out at pilot and / or production scale in equipment designed for such conversions. Furthermore, each of these reactions described can be carried out by either batch process or flow reaction methods. The term "batch process" as used herein refers to a method in which raw materials are combined in a reactor or vessel and the product is removed at the end of the reaction. The term "continuous processing" or "flow reaction" as used herein refers to a method in which there is a continuous inflow of raw materials and an outflow of products. Such continuous processing allows a platform that can synthesize the final product by a completely continuous series of operations starting from the initial starting material.

[0025] The individual isomers, enantiomers, and diastereomers can be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of the compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994).

[0026] In addition, certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. Variable protecting groups may be the same or different from one occurrence to another, depending on the specific reaction conditions and the specific transformation carried out. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0027] The abbreviations listed below as used herein are defined as follows: "Å" means angstrom or angstroms; "AcOH" means acetic acid; "Bn" means benzyl; "nBuLi" means n-butyl lithium; "CAS Number" means Chemical Abstracts Registry Number; "CDI" means carbonyldiimidazole; "D1 PAM I" as used herein may include co-crystal forms that include 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and 4-hydroxybenzoic acid; "DCM" means dichloromethane; "DIPEA" means diisopropylethylamine; "DMSO" means dimethylsulfoxide (when used for NMR, perdeuterated [d 6]). "dr" means diastereomeric ratio. "esd" means estimated standard deviation. "EtOAc" means ethyl acetate. "EtOH" means ethanol or ethyl alcohol. "HPLC" means high performance liquid chromatography. "h" means hours. "HRMS(ESI+)" means high resolution electrospray ionization mass spectrometry in positive ionization mode. "LAH" means lithium aluminum hydride. "LCMS" means liquid chromatography mass spectrometry. "LDA" means lithium diisopropylamide. "MeOH" means methanol or methyl alcohol. "min" means minutes. "MS" means mass spectrometry or mass spectrum. "NCS" means N-chlorosuccinimide. "NMR" means nuclear magnetic resonance. "OAc" means acetate. "PFA" means perfluoroalkoxy with respect to tubing material. "PPTS" means pyridinium p-toluenesulfonate. "psig" means pounds per square inch gauge. "Q-NMR" means quantitative nuclear magnetic resonance. "RMS" means root mean square. "RT" means room temperature / ambient temperature. "Sec" means second(s) as a unit of time. "TBAF" means tert-butylammonium fluoride. "TBS-Cl" means tert-butyldimethylsilyl chloride. "TEA" means triethylamine. "THF" means tetrahydrofuran. "tR" means retention time. "Ts" means 4-toluenesulfonate. "v / v" means volume to volume ratio. "w / w" means weight to weight ratio.

[0028] Improved routes for preparing D1 PAM I are provided below as Routes I and II, and other additional methods are provided below.

[0029] I.D1 Epoxide route for preparing PAM I. [ka]

[0030] Method 1 illustrates the synthesis of compound D1 PAM I. Treatment of dibromobenzene 1 with a strong base such as LDA under cryogenic conditions (typically below -40 °C) deprotonates the aromatic proton at the 2-position, and subsequent reaction with commercially available epoxide 1a can provide alcohol 2. Conversion can be accomplished by stepwise generation of the aryllithium species followed by exposure to 1a or by adding a solution of LDA to a mixture of 1 and 1a. The reaction can be accomplished in batch mode or using continuous processing. Formation of tosylate 3 can be achieved by treating 2 with tosyl chloride in the presence of a suitable base such as pyridine at temperatures between 20 and 80 °C. Addition of EtOH and water to the reaction mixture results in direct crystallization of solid 3 from the reaction mixture. Treatment of tosylate 3 with an alkyllithium reagent such as nBuLi in an ethereal solvent such as THF or 2-Me-THF under cryogenic conditions such as -70 °C results in lithium-halogen exchange and formation of the aryllithium species. This transformation can be carried out in small batch or continuous flow mode on a production scale. The aryllithium species can be exposed to the imine 3a, resulting in the formation of the benzylamine intermediate. The crude solution of benzylamine is treated with an acid such as aqueous HCl to cleave the chiral sulfoxyl auxiliary to form the amine hydrochloride salt. Other strong acids can be used to achieve this cleavage. The crude solution can be treated with a suitable inorganic base such as aqueous sodium carbonate to increase the pH and allow nucleophilic attack of the tosyl ester by the free amine to form the six-membered ring present in 4. An aqueous workup can then be used to remove various impurities and by-products, or a solvent exchange to a solvent such as isopropyl acetate can be used. The crude solution is exposed to an acid such as TsOH monohydrate to form crystalline 4. Other acids such as HCl or naphthalene-1,5-disulfonic acid can be used in place of TsOH to allow for the isolation of a crystalline solid. These crystallizations can reduce the amount of the cis stereoisomer, which is typically present at about 10%, as shown in Scheme 1 (see, for example, US 8,962,654). Debenzylation can be carried out by using a co-solvent such as toluene or xylene in the presence of BCl 3The reaction can be accomplished by treatment of a solution of 4 in DCM with 1,2-dichlorophenylacetic acid. The product 5 can then be isolated by extraction into acidic water, discarding the organic phase, and producing crystalline 5 by adjusting the pH of the aqueous phase with a base such as aqueous NaOH. Subsequent Heck coupling under well-known conditions can afford compound 6. Reduction to 7 under hydrogenation conditions and final amide coupling with 2,6-dichlorophenylacetic acid can afford compound D1 PAM I.

[0031] Additionally, (S)-(-)-tert-butylsulfinamide can be catalyzed with MgSO in the presence of an acidic catalyst such as PPTS or Amberlyst-15. 4 The imine 3a can be formed by treatment with acetaldehyde, with or without a dehydrating reagent such as 2-(2-methyl-1,2-diphenyl-2-propanediol). Purification of 3a can be achieved by filtration or solvent exchange, precipitation, and removal of the acid catalyst by filtration. Further purification can be achieved by vacuum distillation, keeping the distillation pot temperature below about 80° C. to avoid decomposition of crude 3a.

[0032] The method illustrated in Method 1 provides a route to D1 PAM I that does not rely on D-2-Br-phenylalanine, which can be difficult and expensive to source. The starting materials are inexpensive and readily available. This method route has fewer steps than the Scheme 1 route and produces D1 PAM I in a significantly higher overall yield and with less waste than the method disclosed in US 8,962,654. This route is predicted to be significantly cheaper than the Scheme 1 route for producing large quantities of D1 PAM I and can be carried out in less time. This route utilizes many crystallization control points along the way, allowing for efficient purification and separation of intermediates and final compounds.

[0033] The key step of this process route is illustrated in step C, however, for scales above about 50 g, this step is best carried out in a continuous flow mode, due to the instability of the aryllithium intermediate and the difficulty in achieving adequate heat removal from large batch reactors. The aryllithium intermediate has two bromine atoms that may be lithiated, but the process illustrated in method 1 stops at monolithiation. The intermediate has an electrophile incorporated in the sulfonate ester, but undesired reactivity with this functional group may be avoided. The resulting chiral aryllithium species is then reacted in batch or flow mode with a chiral sulfimide to set up the second stereocenter. This method of tetrahydroisoquinoline formation is believed to be unprecedented in the literature, and provides independent control of both stereocenters adjacent to the nitrogen. After reaction with the imine, the process stream may be immediately treated with acid to affect cleavage of the chiral auxiliary, although this may also be accomplished in flow mode, in the same stream as the lithium halogen exchange and imine addition.

[0034] Intermediate Details for Method I, Step C: [ka]

[0035] Another embodiment of the present invention is a method for the continuous flow lithiation of compound 3 using n-BuLi (or n-HexLi, etc.) under cryogenic conditions to provide intermediate aryllithium species.

[0036] Another embodiment of the present invention is a method for reacting an intermediate aryllithium species with imine 3a in a continuous flow under cryogenic conditions.

[0037] Another embodiment of the present invention is a method to achieve cleavage of the sulfinamide auxiliary by treating the product of the reaction between an aryllithium and 3a with an acid such as HCl.

[0038] Another embodiment of the present invention is a process whereby 4 is isolated as its TsOH or 1,5-naphthalenedisulfonic acid salt.

[0039] II.D1 Diastereoselective Pictet-Spengler (PS) route to PAM I. [ka]

[0040] The invention illustrated in Method 2 is a highly diastereoselective Pictet-Spengler based synthetic method starting from R-2-bromophenylalanine 8 to produce compound D1 PAM I in approximately eight steps with excellent control of the required stereochemistry and excellent yields of the individual steps. All intermediates in Method 2 can be isolated as crystalline solids facilitating control of chemical and stereochemical purity. R-2-bromophenylalanine 8 can be converted to novel oxazolidinone 9 in two steps. The preparation of N-(phenylsulfonyl)alkyloxazolidinone 10 in Method 2, Step C is a dynamic kinetic resolution (DKR) driven by preferential crystallization of a single diastereomer of novel compound 10 (e.g., Pearson, WH; Lindbeck, AC; Kampf, JWJ Am. Chem. Soc. 1993, 115, 2622). Method 2, step C is believed to be the first example of DKR using a chiral oxazolidinone to form an N-(phenylsulfonyl)alkyloxazolidinone as a single diastereomer. The absolute stereochemistry of 10 can be determined by single crystal X-ray analysis. Method 2, step D is a highly diastereoselective and productive Pictet-Spengler cyclization to generate novel chiral tetrahydroisoquinoline (THIQ) 11, establishing the core structure of D1 PAM I. The absolute stereochemistry of 11 can be determined by single crystal X-ray analysis. Pictet-Spengler cyclization type reactions are typically catalyzed by titanium(IV) chloride and other Lewis acids. After screening Lewis acids to promote the reaction of Method 2, step D, several were found to be useful for this purpose (Table 1). In particular, zirconium(IV) chloride is desirable to facilitate the Pictet-Spengler cyclization due to its very high diastereoselectivity and yield of the desired product 11, its clean reaction profile, the relatively low equivalent weight required for high conversion, the lack of color imparted to the reaction and products, and the relative non-toxicity and ease of removing its by-products, zirconium oxide, and hydrate. In general, higher dilution and lower temperature lead to increased diastereoselectivity in the Pictet-Spengler cyclization.

[0041] Some advantages of Method 2 compared to the route illustrated in Scheme 1 and previously disclosed in U.S. Patent No. 8,962,654 include: (a) compared to the existing route, which includes approximately 11 synthetic steps, the Pictet-Spengler (PS) route requires 8 steps, starting from R-2-bromophenylalanine, to prepare D1 PAM I. The Method 2 route produces an overall yield of approximately 56%, which is a significant improvement over the previously disclosed route as shown in Scheme 1. The Method 2 route is expected to reduce costs by approximately 75% and shorten the cycle time for preparing D1 PAM I by approximately one-third to one-half, compared to the Scheme 1 route. The synthetic route disclosed in Scheme 1 is expected to take approximately 1.5-2 years to prepare D1 PAM I on a large scale, whereas the Method 2 route is expected to take less than one year to prepare D1 PAM I on a large scale. The route disclosed in Scheme 1 uses protecting groups and cryogenic chemistry and has several intermediates that are not isolated due to weak physical or unstable properties, whereas the route of Method 2 does not have these unattractive features. The protecting groups and salt forms of the advanced starting materials of the pathway disclosed in Scheme 1 add substantial mass that is effectively wasted, to the extent that only about one-third of the advanced starting materials are composed of atoms that become part of D1. Conversely, the route of Method 2 has similarly advanced intermediates (PS products) without the aforementioned problems, with about two-thirds of the atoms being present in the desired compound D1 PAM I, which corresponds to a very large efficiency in terms of the kilograms processed to produce D1 PAM I. In summary, the route disclosed in U.S. Pat. No. 8,962,654 and shown in Scheme 1 suffers from inefficiencies and costs that do not provide a viable commercial production route for D1 PAM, whereas the efficiency and relatively low cost of the route of Method 2 is believed to enable commercial production of D1 PAM I.

[0042] [Table 1]

[0043] In Method 2, Steps E and F, introduction of a gem-dimethyl-tertiary alcohol side chain via Heck coupling can be achieved by direct sequential insertion into oxazolidinone hydrolysis to generate amino alcohol 12. Oxazolidinone hydrolysis facilitates removal of the phosphine by allowing selective extraction and purification of product 12 by crystallization. Method 2, Step G illustrates the mild and nearly quantitative hydrogenation of the double bond, and Method 2, Step H is the selective amide coupling to generate D1 PAM I.

[0044] preparation The preparation of the following process intermediates further illustrates the present invention and represents exemplary syntheses of various compounds. The reagents and starting materials are readily available or can be readily synthesized by one skilled in the art. It should be understood that the preparations and examples are given by way of illustration and not limitation, and that various modifications may be made by one skilled in the art.

[0045] LC-ES / MS is performed on an AGILENT® HP1100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and / or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to the HP1100 HPLC. LC-MS conditions (low pH): Column: PHENOMENEX® GEMINI® NX C18 2.1 mm×50 mm, 3.0μ, gradient: 5 to 100% B for 3 min, then 100% B for 0.75 min, column temperature: 50° C.±10° C., flow rate: 1.2 mL / min, solvent A: deionized water with 0.1% HCOOH, solvent B: ACN with 0.1% formic acid, wavelength 214 nm. Alternative LC-MS conditions (high pH): Column: XTERRA® MS C18 column 2.1×50 mm, 3.5 μm; Gradient: 5% solvent A for 0.25 min; Gradient: 5% to 100% solvent B for 3 min and 100% solvent B for 0.5 min or 10% to 100% solvent B for 3 min and 100% solvent B for 0.75 min; Column temperature: 50° C.±10° C.; Flow rate: 1.2 mL / min; Solvent A: 10 mM NH4HCO3 pH 9; Solvent B: ACN; Wavelength: 214 nm.

[0046] NMR spectra were performed on a Bruker AVIII HD 400 MHz NMR Spectrometer and the residual solvent [CDCl 3 , 7.26ppm, (C.D. 3 ) 2 SO, 2.05 ppm] as the reference standard. 3 Solution or (CD 3 ) 2 SO solution. When reporting peak multiplicities, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broadband singlet), dd (doublet of doublets), dt (doublet of triplets). When reporting coupling constants (J), they are reported in Hertz (Hz). For Q-NMR, maleic acid is used as the internal standard.

[0047] Chiral HPLC was performed on an Agilent 1260 HPLC system equipped with a PHENOMENEX® LUX--Cellulose-1 column: 4.6 × 250 mm, flow rate of 1 mL / min, column temperature of 35 °C, detection at 222 nm, mobile phase: 20 mM NH 3 with 0.1% diethylamine in 40% (volume) water. 4 HCO 3 : 60% (volume) ACN, isocratic elution, run time at least 15 minutes unless otherwise stated. R is reported in minutes.

[0048] The achiral HPLC method is performed on an Agilent 1260 HPLC system equipped with an X-BRIDGE® C18 column, 3 mm x 75 mm, 2.5 2.5μ. Mobile phase: 5 mM NH 4 CO 3 , N.H. 4 Adjust to pH 9 with OH(A) / ACN(B); Gradient (A / B) 0 min (95 / 5)-11.25 min (5 / 95)-13.50 min (5 / 95)-13.61 min (95 / 5)-15.75 min (95 / 5); Injection volume: 2 μL; Column temperature: 40 °C, Wavelength: 220 nm. Flow rate: 0.8 mL / min.

[0049] High-resolution mass spectra (HRMS) were measured on a Thermo Scientific LTQ-ORBITRAP DISCOVERY™ system using electrospray ionization mode (ESI+) with a mass accuracy of less than 2 ppm and an applicable mass range of 75–1500 Da.

[0050] Method Intermediate 1 [ka]

[0051] Method 1, Step A: With nitrogen inerting, a flask is charged with (S)-(+)-benzyl glycidyl ether (CAS number 16495-13-9, Oakwood Chemical; 10.0 g, 61 mmol), 1,3-dibromobenzene (18.7 g, 79 mmol) and THF (60 mL) with stirring. The mixture is cooled to an internal temperature below -70 °C in a bath of acetone and dry ice. In a separate nitrogen inert flask is charged with THF (40 mL) and DIPEA (11.1 mL) with stirring. The solution is cooled to an internal temperature below 0 °C in a bath of a mixture of acetone and dry ice. A 2.5 M solution of nBuLi in hexanes (30.5 mL, 76.3 mmol) is slowly added while maintaining the internal temperature below 0 °C. Approximately 10 minutes after the addition of nBuLi is complete, the resulting LDA solution is slowly transferred to the flask containing the epoxide and dibromide using a double-tipped needle / cannula. During the addition, the flask is kept in an acetone / dry ice mixture below -70°C for approximately 1 hour or more, during which time a tan slurry may form. The flask is maintained below -70°C for approximately 12 hours. The solution is warmed to approximately 0°C and quenched with water (50 mL). The mixture is poured into another flask and partially concentrated under reduced pressure to a total volume of approximately 100 mL. Toluene (50 mL) is added and the mixture is transferred to a separatory funnel. 5M aqueous HCl (12.2 mL) is diluted with water (50 mL) and added to the toluene mixture until the pH is approximately 1. The yellow aqueous layer is removed and the organic phase is washed successively with water and saturated aqueous NaCl. The organic phase is washed with NaCl. 2 SO 4 Dry at 40° C., filter and concentrate under reduced pressure to give the crude title compound (Method 1, Compound 2) as a yellow oil (30.36 g, Q-NMR analysis = 75.5% w / w, corrected yield = 22.92 g, 94% yield). MS (m / z): 418 (M+NH 4 ).

[0052] Method Intermediate 2 [ka]

[0053] Method 1, Step B: In a flask under nitrogen, crude (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol (211.6 g, 530 mmol) is dissolved in pyridine (424 mL) and 4-toluenesulfonyl chloride (121 g, 636 mmol) is added in two portions. The mixture is heated to 75° C. and stirred for 18 hours. Additional 4-toluenesulfonyl chloride (25 g, 131 mmol) is added and heating at 75° C. is continued for 24 hours. The reaction mixture is cooled to below 40° C. and transferred to a larger flask. Water (500 mL) is added and the mixture is stirred for 5 minutes. EtOH (1 L) is added followed by seed crystals of [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate (1 g) at 20° C. The mixture is stirred and a solid begins to form in the flask. Additional EtOH (500 mL) is added and the mixture is stirred for 20 h. Water (500 mL) is added and the resulting slurry is cooled to <5° C. in an ice-water bath for 4 h. The resulting solid is isolated by filtration and washed with 1:1 (v / v) EtOH / water (400 mL), and cold EtOH (200 mL) to give a white solid. The collected solid is dried under vacuum at 40° C. to give the title compound (Method 1, Compound 3) as an almost white solid (258.8 g, 88% yield). MS (m / z): 572 (M+NH 4 ).

[0054] Method Intermediate 3 [ka]

[0055] (S)-2-Methylpropane-2-sulfinamide (50.0 g, 404 mmol) was dissolved in powdered MgSO 4(97 g, 809 mmol) and DCM (500 mL). The resulting mixture is stirred at room temperature and acetaldehyde (45 mL, 809 mmol) and PPTS (3.1 g, 12.1 mmol) are added. The mixture is stirred at room temperature for 24 h. Diatomaceous earth (25 g) is added to the slurry and the solids are removed by filtration through a ceramic frit packed with diatomaceous earth, and the filter cake is washed with additional DCM (3x100 mL). The filtrate is concentrated under reduced pressure to about 50% by volume, hexanes (250 mL) are added, and the solution is concentrated under reduced pressure to about 50% by volume. Hexanes are added again to the resulting concentrate and the solution is concentrated under reduced pressure to near dryness to form a yellow solid. Hexanes (250 mL) is added to the mixture, the solids are removed by filtration, and the resulting filtrate is concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel eluting with 4:1 hexane:EtOAc to give, after evaporation of the desired product fractions, the title compound (Method 1, Compound 3a, 53.5 g, 90% yield as determined by Q-NMR), which can be further purified by vacuum distillation (5 torr, pot temperature 75° C.) to give the title compound. MS (m / z): 148 (M+H).

[0056] Method Intermediate 4 [ka]

[0057] Method 1, Step C: A flask is charged with a magnetic stir bar, [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate (50.0 g, 90.2 mmol) and 2-Me-THF (500 mL). The solution is heated to 50° C. and vacuum (230 torr) is applied to distill off approximately 50 mL of solvent. The flask is then cooled to room temperature and further cooled to an internal temperature of approximately −80° C. using a bath containing a combination of dry ice, acetone, and liquid nitrogen. A flask is charged with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (14.6 g, 99.2 mmol) dissolved in 2-Me-THF (100 mL) with a stir bar and the resulting solution is cooled to less than −70° C. using a bath of acetone / dry ice. A 2.5 M solution of nBuLi in hexanes (37.2 mL, 92.9 mmol) is added over approximately 150 seconds with stirring. The solution is aged for approximately 3 minutes and the imine solution is added over 90 seconds using 1 / 8 inch PFA tubing and nitrogen pressure. The solution is stirred for 15 minutes and quenched by adding a solution of AcOH (7.8 mL, 135 mmol) in MeOH (100 mL) and warmed to -15°C. A 12 M solution of aqueous HCl (14.8 mL, 180 mmol) is added and the mixture is warmed to 30°C with stirring for 2 hours. Na in water (400 mL) is added. 2 CO 3A solution of (28.7 g, 271 mmol) is prepared and added to the reaction mixture with stirring, warmed to 45° C., and heated at this temperature for 17 hours. The resulting mixture is cooled to room temperature, diluted with EtOAc (about 50 mL), and the resulting layers are separated. The organic layer is washed with saturated aqueous NaCl (40 mL) and concentrated under reduced pressure. The resulting residue is dissolved in isopropyl acetate (368 mL) and EtOH (23 mL). The resulting solution is heated to about 30° C. with stirring and toluenesulfonic acid monohydrate (14.9 g, 85.7 mmol) is added. The resulting mixture is heated to 50° C. until all components are dissolved. The solution is cooled to 40° C. and seed crystals of (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid (100 mg) are added and a slurry begins to form. After 20 minutes, reduce the temperature setting to 35°C. After 2 hours, heat the resulting slurry to 50°C for 4 hours. Reduce the slurry temperature to 35°C and hold for 2 hours. Cool the resulting slurry mixture to room temperature with stirring for 15 hours. Cool the resulting slurry to 3°C in an ice-water bath and collect the solid by filtration. Press dry the filter cake with a spatula, wash with 1:1 isopropyl acetate:n-heptane, and press dry again. Dry the filter cake under vacuum at 40°C to give the title compound (Method 1, Compound 4, 33.0 g, 68% yield of E-isomer by NMR and 3% cis-isomer by NMR) as a white solid. MS m / z 346 (M+H).

[0058] Method Intermediate 5 [ka]

[0059] Method 1, Step D: (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-Methylbenzenesulfonic acid (30.0 g, 58 mmol) was reacted with K 2 CO 3Add to a flask containing a solution of (9.78 g, 70 mmol), water (120 mL), and toluene (120 mL). Stir the mixture until the solids are dissolved. Separate the resulting layers and extract the aqueous layer with toluene (2x50 mL). Combine the organic extracts, wash with saturated aqueous NaCl (10 mL), and concentrate under reduced pressure to a volume of approximately 120 mL. Inertize the resulting concentrate with nitrogen while stirring and cooling with an ice / water bath. 3 (96 mL, 96 mmol) is added, followed by chlorobenzene (100 mL). The resulting mixture is heated to 35° C. and DCM (100 mL) is added with stirring. The mixture is cooled to room temperature, MeOH (50 mL) and water (150 mL) are added, and the resulting layers are separated. The organic phase is extracted with water (2×50 mL). The combined aqueous extracts are washed with toluene (50 mL) and a 50% aqueous solution of NaOH is slowly added with stirring to form a white solid and reach a pH of about 10. The resulting mixture is stirred at room temperature for 22 h. The resulting precipitate is isolated by filtration, washed with water (25 mL) and heptane (2×25 mL), and the collected solid is dried in a vacuum oven at 40° C. to give the title compound (Method 1, Compound 5) as a white solid (14.4 g, 97% yield). MS (m / z): 256 (M+H).

[0060] Alternative Procedure for Method Intermediate 5 Method 1, Step D: (5S,10aR)-9-Bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (2.2 g, 7.9 mmol, see Method Intermediate 8) is dissolved in EtOH (35.6 mL). A 50% by weight aqueous solution of NaOH (15.9 mL, 79.4 mmol) is added to the mixture, followed by heating to 70° C. for 17 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure until a slurry begins to form. The slurry is heated to a gentle boil and EtOH is added until the mixture is homogeneous. The resulting mixture is cooled to room temperature with stirring for 2 hours. The resulting solid is collected by filtration and washed with a 1:1 mixture of EtOH and water. A second crop of solids forms in the filtrate, which is collected by filtration, washed with water, and combined with the first crop in a vacuum oven at 45° C. to give the title compound (Method 1, Compound 5, 1.88 g, 92% yield). MS (m / z): 256 (M+H).

[0061] Method Intermediate 6 [ka]

[0062] Evacuate a three-necked 250 mL round-bottom flask equipped with a magnetic stirrer, Claisen adapter, nitrogen inlet, thermocouple, heating mantle, air-cooled condenser, and rubber septum and backfill with nitrogen twice. [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol (13.9 g, 54.3 mmol) is charged with toluene (120 mL). The mixture is sparged with nitrogen for 5 min and 2-methylbut-3-en-2-ol (Alfa Aesar, 28.4 mL, 271.3 mmol) is added, followed by TEA (18.9 mL, 135.7 mmol). The resulting mixture is sparged with nitrogen for 5 min and charged with Pd(OAc) 2(244 mg, 1.1 mmol) and triorthotolylphosphine (661 mg, 2.2 mmol) are added, nitrogen sparging is continued for an additional 5 min, and the resulting mixture is heated at 86° C. for 17.5 h. The reaction mixture is cooled to room temperature. The resulting solid is removed by filtration through a small pad of diatomaceous earth. The filtrate is concentrated to ½ volume under reduced pressure. The resulting residue is extracted with a solution of citric acid (13 g) in water (100 mL). The aqueous layer is washed with toluene (25 mL) and neutralized to pH 10 with 50% aqueous NaOH. The resulting mixture is extracted with EtOAc (250 mL), the organic extract is washed with saturated aqueous NaCl, and the organic extract is concentrated under reduced pressure. The resulting oil is dissolved in isopropyl acetate (56 mL) and heated to 35° C., during which a slurry is formed. Heptane (70 mL) is added, the slurry is cooled to room temperature, and further cooled with ice water. The resulting solid is collected by filtration, washed with a 3:1 mixture of heptane / isopropyl acetate (30 mL) and dried under vacuum to give the title compound (Method 1, Compound 6; 10.8 g, 77% yield) as a pale yellow solid. MS m / z 262 (M+H).

[0063] Method Intermediate 7 [ka]

[0064] A solution of (E)-4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol (10.3 g, 39.7 mmol) in EtOH (125 mL) is added to a 300 mL Parr® hydrogenation vessel containing 5% Pd / C catalyst (Johnson-Matthey, 505 mg, 59% wet). The system is pressurized with nitrogen, vented, and heated with H 2Pressurize with gas to 50 psig and stir at room temperature for 1 hour. Evacuate the reaction mixture and inertize the system with nitrogen. Remove the solids by filtration and concentrate the resulting filtrate under reduced pressure to less than 50 mL. Add isopropyl acetate (100 mL) and concentrate the solution under reduced pressure to less than 50 mL. Add isopropyl acetate (100 mL) and concentrate the resulting mixture under reduced pressure to less than 50 mL. Add additional isopropyl acetate (100 mL) and heat the resulting mixture to 40° C. for several minutes. Concentrate the mixture under reduced pressure and cool the resulting slurry to room temperature. Collect the solids by filtration and wash with a 1:1 mixture of heptane / isopropyl acetate (30 mL). Dry the solid under vacuum to give the title (Method 1, Compound 7; 9.8 g, 94% yield) as a white solid. MS m / z 264 (M+H).

[0065] Method Intermediate 8 [ka]

[0066] Method 2, Steps A and B: A 60% dispersion of NaH in mineral oil (63 mg, 1.59 mmol) is added to tert-butyl (R)-(1-(2-bromophenyl)-3-hydroxypropan-2-yl)carbamate (CAS#944470-60-4, e.g., Journal of Medicinal Chemistry (2007), 50(13), 2990-3003; 0.5 g, 1.51 mmol) in THF (7.5 mL) and stirred at room temperature for 16.5 min. The reaction mixture is warmed to 55° C. for 45 min and cooled back to room temperature. The resulting solid is filtered and washed with heptane, followed by distillation of the solid with DCM and aqueous NH 4 The layers are separated, the organic phase is collected and the aqueous phase is extracted with DCM. The organic phases are combined and dissolved in a mixture of Na 2 SO 4Dry at rt and concentrate under reduced pressure to obtain the title compound (Method 2, Compound 9, 356 mg; 91%) as a white solid in 94.4% ee by chiral HPLC (Daicel CHIRALPACK® IC, 4.6 mm x 150 mm, 5 u; Mobile phase: 80 / 20 Hexane / EtOH; Injection volume: 2 μL; Column temperature: 35° C.; Wavelength: 220 nm; Flow rate: 1.0 mL / min). 1 H NMR (600 MHz, DMSO-d 6 ): δ2.86(dd, J=13.7, 7.5Hz, 1H), 2.98(dd, J=13.7, 5.8Hz, 1H), 4.12~4.04(m, 1H), 4.02(dd, J=8.4, 5.2Hz, 1H), 4.27(t, J=8.2Hz, 1 H), 7.18 (td, J=7.6, 1.8Hz, 1H), 7.32 (td, J=7.4, 1.3Hz, 1H), 7.37 (dd, J=7.6, 1.8Hz, 1H), 7.59 (dd, J=8.0, 1.3Hz, 1H), 7.83 (s, 1H). 13 C{1H}NMR (151MHz, DMSO-d 6 ):δ40.82, 51.79, 68.48, 124.64, 128.36, 123.20, 133.12, 136.42, 158.99.HRMS(ESI+)C 10 H 11 BrNO 2 Calculated value: 255.9968, measured value: 255.9968.

[0067] Alternative Procedure for Method Intermediate 8 Method 2, Steps A and B: (R)-2-Bromophenylalanine (170.1 g, 0.7 mol) and THF (1.7 L) were combined, cooled to approximately 5° C., and diluted with NaBH 4 (63.3 g, 1.7 mol) is added in portions, maintaining the temperature below 5° C. I in THF (510 mL) 2A solution of (176.9 g, 0.7 mol) is slowly added to the mixture, maintaining the internal reaction temperature below 10 °C. The reaction mixture is warmed to room temperature and heated to 45 °C with stirring for 30 min. MeOH (134.0 g, 4.2 mol) is added dropwise to the reaction mixture. The resulting mixture is concentrated by distillation until the internal temperature reaches 68 °C at 700 torr. To the reaction mixture is added THF (238 mL), aqueous KOH (85% KOH: 46.0 g, 0.7 mol and water: 150 mL) and toluene (1.7 L). The biphasic mixture is stirred at 83 °C for 4 h and the resulting mixture is washed with 20% aqueous NaCl (3 x 400 mL). The organic phase is concentrated to 90 °C at 200 torr.

[0068] The resulting concentrated mixture was 2 CO 3 (9.7 g, 69.7 mmol) and diethyl carbonate (330.8 g, 2.8 mol) are added. The resulting mixture is stirred and EtOH is distilled at atmospheric pressure at reflux temperature (bath temperature 145 °C, internal temperature 124 °C) for 3.5 h. The mixture is diluted with isopropyl acetate (850 mL), washed with water (3x350 mL), and concentrated at 120 °C and 50 torr to give a slurry of white solids. Isopropyl acetate (340 mL) is added to the slurry at 70 °C to give a homogeneous mixture, and heptane (510 mL) is added slowly to the clear solution to crystallize the product. The resulting slurry is cooled to -10 °C, stirred for 1 h, and the resulting solid is collected by filtration. The solid is dried at 50° C. under 20 torr to give the title compound (Method 2, Compound 9; 151.8 g, 85% yield) in 94.4% ee by chiral HPLC (Daicel CHIRALPACK® IC, 4.6 mm×150 mm, 5 U; Mobile phase: 80 / 20 Hexane / EtOH; Injection volume: 2 μL; Column temperature: 35° C.; Wavelength: 220 nm; Flow rate: 1.0 mL / min). R =10.12.

[0069] Method Intermediate 9 [ka]

[0070] Method 2, Step C: (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one (17.5 g, 64.9 mmol) is combined in a reaction vessel with sodium benzenesulfinate (12.1 g, 71.4 mmol), water (87.5 mL), MeOH (8.75 mL), formic acid (20.1 mL) and acetaldehyde (18.5 mL, 325.0 mmol). The vessel is sealed and the reaction mixture is heated to 75° C. with stirring. After 40 h, the reaction mixture is cooled to room temperature over 2.5 h with stirring. The reactor was opened and the resulting crystalline white solid was collected by filtration, washed successively with water (2x50 mL) and hexanes (2x50 mL), dried in a vacuum oven at 50°C for 48 h, and purified by chiral HPLC (Daicel CHIRALPACK® IC-3, 4.6 mm x 150 mm, 3μ, mobile phase; 3:2 H 2 0ACN, injection volume: 2 μL; column temperature: 25° C.; wavelength: 220 nm; flow rate: 1.5 mL / min) to give the title compound (Method 2, Compound 10, 26.3 grams, 95% yield) in >99% ee. R = 17.85 min. Achiral HPLCt R = 7.7 min. The absolute stereochemistry of (R)-4-(2-bromobenzyl)-3-((S)-1-(phenylsulfonyl)ethyl)oxazolidin-2-one is confirmed by single crystal X-ray analysis. 1 H NMR (600 MHz, DMSO-d 6 ): δ1.77(d, J=7.3Hz, 3H), 2.81(dd, J=13.5, 10.7Hz, 1H), 3.22(dd, J=13.5, 3.8Hz , 1H), 4.00(dd, J=8.9, 2.5Hz, 1H), 4.05(m, 1H), 4.45(m, 1H), 5.24(q, J=7.2Hz, 1H ), 7.22(td, J=7.7, 1.7Hz, 1H), 7.36(td, J=7.5, 1.3Hz, 1H), 7.43(dd, J=7.6, 1.7H z, 1H), 7.77 (t, J=7.3Hz, 1H), 7.63 (td, J=8.0, 1.4Hz, 3H), 7.90 (d, J=8.5Hz, 2H), 13 C{1H}NMR (151MHz, DMSO-d 6):δ12.30, 39.70, 52.63, 66.83, 70.33, 124.66, 128.56, 129.36, 129.80, 130.06, 132.98, 133.33, 135.12, 135.66, 136.55, 156.80, HRMS(ESI+)C 18 H 19 BrNO 4 The calculated value for S was 424.0213, and the measured value was 424.0211.

[0071] Single crystal X-ray analysis: C 18 H 18 BrNO 4 A colorless, transparent rod-shaped sample of S with approximate dimensions of 0.010 mm x 0.010 mm x 0.150 mm is grown using slow-cooling crystallization techniques after dissolving in hot toluene. It is used for X-ray crystallography. X-ray intensity data is measured (λ = 1.54178 Å). A total of 5711 frames are collected. The total exposure time is 15.9 hours. The frames are integrated with the Bruker SAINT software package using a narrow frame algorithm. Integration of the data using a monoclinic unit cell results in a total of 11348 reflections with a maximum θ angle of 72.47° (0.81 Å resolution), of which 3314 are independent (average multiplicity 3.424, completeness = 97.3%, R int =5.77%, R sig =5.18%), 3067 (92.55%) is 2σ(F 2 ) is greater than a=11.5479(esd=16)Å, b=5.7655(esd=9)Å, c=14.537(esd=2)Å, β=110.348(esd=5)°, volume=907.5(esd=2)Å 3 The final lattice constants are based on a refinement of the XYZ centroids of 8561 reflections above 20σ(I) at 6.484°<2θ<144.5°. The data are corrected for absorption effects using a multiscan method (SADABS). The ratio of the minimum apparent transmittance to the maximum apparent transmittance is 0.716. The calculated minimum and maximum transmission coefficients (based on crystallite size) are 0.5610 and 0.9580.

[0072] Space group P12 using the Bruker SHELXTL software package 1 1, C 18 H 18 BrNO 4 For the chemical formula unit of S, the structure is analyzed and refined using Z=2. F with 252 variables 2 The final anisotropic full-matrix least-squares refinement of converges to R1=7.83% for the observed data and wR2=22.06% for all data. The goodness of fit is 1.142. The maximum peak in the final difference electron density synthesis is 0.738e- / Å. 3 and the maximum hole is -0.638e- / Å 3 and the RMS deviation is 0.078e- / Å 3 Based on the final model, the calculated density is 1.553 g / cm 3 and F(000), 432e-. The observed Flack parameter is -0.03(5), suggesting that the stereocenter is correctly assigned. Single crystal X-ray analysis results confirm the stereochemistry shown above for process intermediate 9, (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

[0073] Alternative Procedure for Method Intermediate 9 (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one (100 g, 0.5 mol), sodium benzenesulfinate (86 g, 0.5 mol), water (500 mL), formic acid (115 mL) and acetaldehyde (95.6 g, 2.2 mol) are placed in a 1 L autoclave. The resulting mixture is heated to 60° C. and stirred for 24 hours. The resulting slurry is cooled to 35° C. and the resulting solid is collected by filtration. The collected solid is washed with water (100 mL) and dried at 50° C. under 20 torr to give the title compound (157.5 g, 95% yield) as a single enantiomer and diastereomer.

[0074] Method Intermediate 10 [ka]

[0075] Method 2, Step D: (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one (10.0 g, 23.5 mmol) is slurried in DCM (100 mL) and the resulting mixture is cooled to 2° C. Zirconium(IV) oxide (9.6 g, 41.1 mmol) is added to the mixture. After stirring at 2° C. for 1.5 hours, the reaction mixture is warmed to about 10° C. Water (50 mL) is added and an aqueous solution of 50% by weight NaOH is added to the resulting slurry while increasing the temperature to about 20° C. until the pH is about 13. Diatomaceous earth (20 g) is added to the resulting slurry with rapid mixing. The slurry is filtered through diatomaceous earth with water and DCM and the resulting filter cake is rinsed with DCM. The resulting filtrate mixture is separated and the organic phase is washed twice with water (2×50 mL) and the organic phase is washed with Na 2 SO 4 The extract was dried at 40° C., filtered, concentrated under reduced pressure and purified by chiral HPLC (Daicel CHIRALPACK® IC-3, 4.6 mm×150 mm, 3μ, mobile phase: 3:2 H 2 O:ACN; injection volume: 2 μL; column temperature: 25 °C; wavelength: 220 nm; flow rate: 1.5 mL / min) to give the title compound (Method 2, Compound 11, 6.4 g, 93% yield; 54:1 dr) as a white crystalline solid in >99% ee. R = 19.38 min. The absolute stereochemistry of the title compound is confirmed by single crystal X-ray analysis. 1 H NMR (600 MHz, DMSO-d 6 )δ1.41(d, J=6.8Hz, 3H), 2.57(dd, J=16.6, 10.4Hz, 1H), 3.11(dd, J=16.6, 4.6Hz, 1H), 4.14(ddt, J=10.4, 8.1, 4.6Hz, 1H), 4.19(dd, J=8.4, 5.3Hz, 1H), 4.53(t, J=8.1Hz, 1H), 4.84(q, J=6.8Hz, 1H), 7.17(t, J=7.8Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.51(d, J=7.9Hz, 1H). 13C{1H}NMR (151MHz, DMSO-d 6 ): δ22.14, 34.43, 47.27, 48.21, 68.75, 125.26, 127.10, 128.52, 131.19, 131.88, 140.34, 156.25. HRMS(ESI+)C 12 H 13 BrNO 2 The calculated value was 282.0124 and the actual value was 282.0127.

[0076] Single crystal X-ray analysis: C 12 H 12 BrNO 2 A colorless, transparent rod-shaped sample of 1000 g of 1,000 g of 100% ... int =5.93%, R sig = 2.77%), and 7897 (97.23%) is 2σ(F 2 ) is larger than the original. a = 15.5606 (esd = 6) Å, b = 8.3186 (esd = 3) Å, c = 19.5153 (esd = 7) Å, β = 112.7990 (esd = 10) °, volume = 2328.74 (esd = 15 ) Å 3 is based on the refinement of the XYZ centroids of 9449 reflections above 20σ(I) at 4.912°<2θ<156.3°. The data are corrected for absorption effects using a multiscan method (SADABS). The ratio of the minimum apparent transmittance to the maximum apparent transmittance is 0.503. The calculated minimum and maximum transmission coefficients (based on crystallite size) are 0.138 and 0.651.

[0077] The structure was analyzed using the Bruker SHELXTL software package in space group P12 1 1, C 12 H 12 BrNO 2 Formula units are analyzed and refined using Z=8. F with 582 variables 2 The final anisotropic full-matrix least-squares refinement of converged to R1=5.54% for the observed data and wR2=18.74% for all data. The goodness of fit is 1.641. The maximum peak in the final difference electron density synthesis is 0.988e- / Å. 3 and the maximum hole is -1.512e- / Å 3 and the RMS deviation is 0.102e- / Å 3 Based on the final model, the calculated density is 1.609 g / cm 3 and F(000), 1136e-. The observed Flack parameter was 0.116 (esd=5), suggesting that the stereocenters were correctly assigned. Single crystal X-ray analysis results confirm the stereochemistry shown above for process intermediate 10, (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

[0078] Alternative Procedure for Method Intermediate 10 (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one (144.2 g; 339.9 mmol) is mixed with DCM (4325 mL) and the mixture is cooled to -10°C. Zirconium(IV) chloride (154.0 g; 660.8 mmol) is added in four portions (38.5 g each) at -10°C and the mixture is stirred for 2 h. Water (721 mL) and 28% NH 3 The aqueous solution (721 mL) is slowly added to the reaction mixture. The aqueous phase is separated and the organic phase is washed with water (721 mL). The organic phase is washed with Na 2 SO 4(306.9 grams), and filtered. The filtrate is concentrated at 50° C. under 50 torr, and the resulting white solid is dried at 50° C. under 20 torr to give the title compound (91.6 g, 95.5% yield, 124:1 dr).

[0079] Method Intermediate 11 [ka]

[0080] Method 2, Steps E and F: (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (6.0 g, 20.7 mmol) is combined with 2-methyl-3-buten-2-ol (9.75 mL, 93.0 mmol) and TEA (4.32 mL; 31.0 mmol) at room temperature, and the resulting white slurry is degassed with a nitrogen subsurface sparge for 10 minutes while stirring. Tris-o-tolylphosphine (786 mg, 2.58 mmol) and Pd(OAc) are added while continuing degassing for 3 minutes. 2 (232 mg; 1.03 mmol) is added to the reaction mixture. The headspace is switched from degassing to positive nitrogen pressure and the resulting mixture is heated to 75° C. for 6.0 h. At 75° C., EtOH (30 mL) and 50 wt % NaOH (10.9 mL, 207 mmol) are added to the reaction mixture and the resulting mixture is stirred at 75° C. for 2.5 h. The reaction mixture is cooled to room temperature, the solids are filtered and washed with EtOH and the washings are combined with the filtrate. The resulting filtrate mixture is concentrated under reduced pressure. Toluene, water, and aqueous saturated citric acid are added to the resulting residue. The aqueous phase is separated and washed with toluene. The aqueous phase is adjusted to pH 13 with 50 wt % NaOH and extracted with DCM. The organic phase is washed with Na 2 SO 4Dry on a kettle and concentrate under reduced pressure. Dissolve the resulting residue in hot isopropyl acetate (6 mL) and heptane (6 mL) and add a few seed crystals of (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol to obtain a thick slurry. Stir at room temperature for 48 hours and slowly add heptane (24 mL) to the slurry while cooling. Filter the resulting slurry and wash the collected solid with heptane and dry in a vacuum oven at 60° C. to obtain the title compound (Method 2, Compound 12, 5.0 g; 89% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 ):δ1.25(s, 6H), 1.31(d, J=6.8Hz, 3H), 2.13(br, 1H), 2.24(dd, J=16.4, 10.1Hz, 1H), 2.6 7(dd, J=16.4, 4.2Hz, 1H), 3.06(m, 1H), 3.39(dd, J=10.3, 6.6Hz, 1H), 3.46(dd, J=10.3, 5 .1Hz, 1H), 4.08(q, J=6.8Hz, 1H), 4.62(br, 1H), 4.69(s, 1H), 6.17(d, J=15.8Hz, 1H), 6.6 6(d, J=15.8Hz, 1H), 6.95(d, J=7.6Hz, 1Hz), 7.05(t, J=7.6Hz, 1H), 7.21(d, J=7.8Hz, 1H). 13 C{1H}NMR (151MHz, DMSO-d 6 ): δ24.25, 29.57, 125.59, 30.60, 30.63, 48.90, 50.52, 65.77, 69.91, 122.48, 123.25, 126.02, 131.95, 136.51, 141.21, 141.39. HRMS(ESI+)C 16 H 24 NO 2 The calculated value was 262.1802 and the actual value was 262.1799.

[0081] Alternative Procedure for Method Intermediate 11 Deoxygenated 2-methyl-3-buten-2-ol (109.9 g, 1.3 mol), Pd(OAc) 2(318.3 mg, 1.4 mmol) and tri-o-tolylphosphine (2.2 g, 7.2 mmol) are combined and the mixture is stirred at 16° C. for 30 minutes. (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (80 g, 283.6 mmol) and deoxygenated TEA (43 g, 424.9 mmol) are added to the mixture. The resulting mixture is heated to reflux for 5 hours. The reaction mixture is cooled to room temperature. Ethanol (400 mL) and 50 wt % aqueous NaOH (226.8 g, 2.8 mol) are added to the reaction mixture. The resulting mixture is heated to 75° C. and stirred for 3 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated at 50° C. under 80 torr. Toluene (400 mL), water (400 mL) and saturated aqueous citric acid (640 mL) are added to the concentrated residue. The organic phase is separated and the aqueous phase is washed with toluene (400 mL). 50 wt % aqueous NaOH (400 mL) is added slowly to the aqueous phase. The basified aqueous mixture is extracted with isopropyl acetate (2×800) and the combined organic phase is washed with Na 2 SO 4 (160.0 g) and filtered. The filtrate is concentrated at 50° C. under 50 torr and the resulting residue is dissolved in isopropyl acetate (320 mL) at 60° C. The resulting mixture is cooled to 37° C. To the resulting slurry is added heptane (1040 mL) at room temperature. The slurry is cooled to −10° C. and stirred for 1 hour and the resulting solid is collected by filtration. The collected solid is washed with heptane (160 mL) and dried at 50° C. under 20 torr to give the title compound (68.6 g, 92% yield).

[0082] Method Intermediate 12 [ka]

[0083] Method 2, Step G: Under nitrogen, combine (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol (50 g, 191.3 mmol), 5% Pd / C (1.1 g wet weight) and EtOH (250 mL) in an autoclave, purge with nitrogen and flush the system with hydrogen at 145 psig. The resulting mixture is stirred at room temperature under 145 psig of hydrogen for 4 hours. The reaction mixture is filtered through a bed of diatomaceous earth and concentrated at 50° C. under 50 torr. The resulting solid is collected by filtration and suspended and stirred in isopropyl acetate (200 mL) at room temperature for 1 hour. Heptane (200 mL) is added dropwise and the resulting slurry is cooled to −10° C. and stirred for 1 hour. The resulting solid is collected by filtration, washed with heptane (100 mL), and dried at 50° C. under 20 Torr to give the title compound (Method 2, Compound 13, 46.2 g, 92% yield) as a white solid in >99% purity by chiral HPLC (Daicel CHIRALPACK® AD-H, 4.6 mm×250 mm; 5 μ; mobile phase: 0.1% ethanolamine in ACN; injection volume: 2 μL; column temperature: 35° C.; wavelength: 220 nm; flow rate: 1.5 mL / min). R =4.43 minutes. 1 H NMR (600 MHz, DMSO-d 6 ):δ1.13(s, 6H), 1.31(d, J=6.8Hz, 3H), 1.57~1.45(m, 2H), 2.08(s, 1H), 2.21(dd, J=16.3, 10.1Hz, 1H), 2.52(t, J=8.7Hz, 2H), 2.64(dd, J=16.3, 4.1Hz, 1H), 3.06(tt, J=10.4, 4.6Hz, 1H), 3.37(dd, J=10.3, 6.8Hz, 1H), 3.46(dd, J=10.5, 4.9Hz, 1H), 4.07(q, J=6.7Hz, 1H), 4.2 1(s, 1H), 4.63(s, 1H), 6.89(d, J=7.5Hz, 1H), 6.91(d, J=7.4Hz, 1H), 7.00(t, J=7.5Hz, 1H). 13 C{1H}NMR (151MHz, DMSO-d 6): δ24.36, 27.40, 28.87, 29.62, 29.68, 44.73, 49.13, 50.59, 65.79, 69.18, 124.66, 125.44, 126.24, 132.57, 141.20, 141.28. HRMS(ESI+)C 16 H 26 NO 2 The calculated value was 264.1958 and the actual value was 264.1956.

[0084] D1 PAM I [ka]

[0085] Method 2, Step H: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (14.7 g, 83.7 mmol) and ACN (400 mL) are combined and 4-methylmorpholine (17.7 g, 175.0 mmol) is added at 0° C. The resulting mixture is stirred for 30 minutes, 2,6-dichlorophenylacetic acid (20.8 g, 101.4 mmol) is added, and the mixture is stirred for 1 hour at 0° C. 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol (20 g, 75.9 mmol) in water (100 mL) is added. 2 CO 3( Add a mixture of 11.5 g (83.7 mmol) of ethyl acetate (100 mL) to the mixture and stir at 0° C. for 4 h. The resulting layers are separated and the organic phase is diluted with isopropyl acetate (100 mL) and saturated NH 4 The resulting layers are separated and the organic phase is washed with water (100 mL) and diluted with Na 2 SO 4(133.1 g) and filtered. The filtrate is concentrated at 50° C. under 80 torr and the resulting mixture is dissolved in isopropyl acetate (80 mL). The resulting mixture is cooled to room temperature, heptane (80 mL) is added dropwise, and the resulting slurry is cooled to −10° C. with stirring for 1 h. The resulting solid is collected by filtration, washed with heptane (40 mL), dried at 50° C. under 20 torr, and purified by chiral HPLC (Daicel CHIRALPACK® AD-H, 4.6 mm×250 mm, 5 μ; mobile phase: 9:1 hexane:EtOH; injection volume: 2 μL, column temperature: 35° C.; wavelength: 220 nm; flow rate: 1.0 mL / min) to give the title compound (29.2 g, 85% yield) in >99% ee. R = 14.03. MS (m / z): 451 (M+H).

[0086] Additional steps for D1 PAM I Method 1, Step G: A nitrogen inerted reactor is charged with 2-chloro-4,6-dimethoxy-1,3,5-triazine (6.36 g, 36.2 mmol) and ACN (94 mL). The mixture is cooled to 0° C. and N-methylmorpholine (9.02 mL, 81.7 mmol) is added. After 20 min, 2-(2,6-dichlorophenyl)acetic acid (7.43 g, 36.2 mmol) is added, the resulting mixture is stirred at 0° C. for 60 min, and 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol (9.36 g, 35.5 mmol) slurried in ACN (81 mL) and THF (25 mL) are added. The resulting mixture is stirred at 0° C. for 22 h. The reaction mixture is filtered and the filter cake is washed with isopropyl acetate (100 mL). The resulting filtrate is concentrated under reduced pressure to less than 150 mL. The resulting mixture is diluted with isopropyl acetate (200 mL) and washed with water / saturated aqueous NH 4 The combined organic extracts were washed with a 1:1 mixture of water (50 mL), saturated NaHCO 3 The mixture was washed with aqueous solution (50 mL) and saturated aqueous solution of NaCl, and then with Na 2 SO 4The resulting mixture is filtered and the filtrate is concentrated under reduced pressure to about 100 mL. The solvent is removed by vacuum distillation at 60° C. to about 50 mL, and 50 mL of isopropyl acetate is added. The distillation and solvent exchange is repeated two more times. Seed crystals (50 mg) of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone are added, and the resulting slurry is stirred at room temperature for 21 hours and cooled to 0° C. in an ice-water bath for 2 hours. The resulting solid is collected by filtration. The filter cake is washed with a 1:1 mixture of heptane / isopropyl acetate (15 mL) and dried under vacuum to give the title compound (12.5 g, 78% yield) as a white solid. MS (m / z): 450 (M+H). Chiral HPLC R =8.48 min (<99% ee).

[0087] Co-crystal formation procedure D1 PAM I with 4-hydroxybenzoic acid D1 PAM I (11.5 g, 25.5 mmol) is mixed with 4-hydroxybenzoic acid (Aldrich, 3.6 g, 26.0 mmol) in THF (28.8 mL) in a 100 mL round bottom flask equipped with a magnetic stirrer. The resulting mixture is heated at 50 °C until all materials are dissolved. The solution is filtered through a 0.45 μm syringe filter into a 250 mL three-neck round bottom flask equipped with overhead stirring, nitrogen inlet, thermocouple, and addition port. The transfer and filtration are completed by rinsing with additional THF (4.6 mL). The filtered solution is heated to 50 °C until all components are dissolved, whereupon heptane (18.4 mL) is added. Co-crystal seed crystals (75 mg) are added and the mixture is stirred at 50 °C for 30 min. Additional heptane (48.3 mL) is added over 8 h via syringe pump. The resulting slurry is cooled to room temperature and stirred for 12 hours. The resulting solid is collected by filtration and washed successively with a 1:2 mixture of THF:heptane (23 mL) and a 5:95 mixture of THF / heptane (23 mL). The filtered solid is dried under vacuum to give the title compound as a white solid (13.5 g, 90% yield). MS (m / z): 450 (M+H).

[0088] X-ray Powder Diffraction (XRPD) XRPD patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source (λ=1.54060 Å) and a Vantec detector operating at 35 kV and 45 mA. Samples are scanned from 4 to 40° (2θ) with a step size of 0.03° (2θ) and a scan rate of 0.5 sec / step, as well as with a divergence slit of 0.6 mm, a fixed anti-scatter slit of 5.28, and a detector slit of 9.5 mm. Dry powders are loaded into a zero-background quartz sample holder and a glass slide is used to obtain a smooth surface. Diffraction patterns of crystalline forms are collected at ambient temperature and relative humidity. It is well known in the field of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When preferred orientation effects are present, the peak intensities change, but the characteristic peak positions of the polymorph do not. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is well known in the art of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, peak positions may vary due to variations in temperature or humidity at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, the variation in peak positions of ±0.2 (2θ) allows for these potential variations without precluding unambiguous identification of the indicated crystalline form. Confirmation of a crystalline form may be based on any unique combination of characteristic peaks (in units of °2θ), typically the more prominent peaks. The diffraction pattern of the crystalline form collected at ambient temperature and relative humidity is adjusted based on the NIST 675 standard peaks at 8.853 and 26.774 °2θ.

[0089] A sample of the crystalline compound of D1 PAM I with 4-hydroxybenzoic acid is characterized by an XRD pattern using Cu Ka radiation as having diffraction peaks (2θ values) as set forth in Table 2 below, in particular as having a peak at 7.0° in combination with one or more peaks selected from the group consisting of 15.0°, 16.1°, and 21.0°, with a diffraction angle tolerance of 0.2 degrees. [Table 2]

Claims

1. 1. A pharmaceutical composition comprising a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethenone with 4-hydroxybenzoic acid, wherein the co-crystal is a compound of the formula: 【Chemical 1】 and 4-hydroxybenzoic acid, said process comprising the steps of: i.) sequential treatment of (R)-2-bromophenylalanine with a reducing agent and iodine, followed by treatment with a mild mineral base and alkyl carbonate to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one; ii.) treating (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one with sodium arylsulfinate and acetaldehyde to obtain (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one; iii.) optionally crystallizing the (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one; iv.) optionally verifying the stereochemistry of (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one by single crystal X-ray analysis; v.) Pictet-Spengler cyclization of (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one with a transition metal halide to obtain (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one; vi.) optionally crystallizing the (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one; vii.) optionally verifying the stereochemistry of the (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one by single crystal X-ray analysis; viii.) Heck coupling of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one with 2-methyl-3-buten-2-ol to obtain (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol; ix.) optionally crystallizing the (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol; x.) (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol is reduced under hydrogenation conditions to give 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; xi.) optionally crystallizing 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; xii.) coupling 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol with 2,6-dichlorophenylacetic acid in the presence of a coupling agent for amide synthesis and 4-methylmorpholine to obtain 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xiii.) optionally crystallizing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xiv.) treating 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid to obtain a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid.

2. 1. A pharmaceutical composition comprising a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethenone with 4-hydroxybenzoic acid, wherein the co-crystal is a compound of the formula: 【Chemistry 2】 and 4-hydroxybenzoic acid, said process comprising the steps of: i.) treating (S)-(+)-benzyl glycidyl ether and 1,3-dibromobenzene with a metal base to obtain (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol; ii.) treating (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol with arylsulfonyl chloride in the presence of an organic base to give [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl]arylsulfonate; iii.) Treatment of [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl]arylsulfonate with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide in the presence of an organometallic base, followed by treatment with toluenesulfonic acid monohydrate to obtain (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid; iv.) optionally crystallizing (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid; v.) (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonic acid is free-based with mineral base followed by debenzylation to give [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; vi.) Heck coupling of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol with 2-methylbut-3-en-2-ol to obtain (E)-4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol; vii.) reducing (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol under hydrogenation conditions to obtain 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; viii.) optionally crystallizing 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol; ix.) coupling 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol with 2,6-dichlorophenylacetic acid in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine and 4-methylmorpholine to give 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; x.) optionally crystallizing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; xi.) treating 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid to obtain a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid.

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