Process and intermediates for preparing d1 PAM i

Abstract

The present invention provides processes and intermediates 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] ethanone (D1 PAM I) of formula (I). # imgabs0 #

Description

[0001] This application is a divisional application of the international application filed on June 11, 2020, with application number PCT / US2020 / 037186 and invention title "Methods and Intermediates 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]Ethanone", which entered the Chinese national stage on December 17, 2021, with application number 202080044854.3. Technical Field

[0002] Embodiments of the present invention relate to the fields of medicinal chemistry and organic synthetic chemistry, and provide methods and key intermediates for the synthesis of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, D1 receptor positive allosteric modulators (D1 PAMs), and their compositions. Background Art

[0003] 2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone 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-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone (CAS registration number 1638667-79-4) will be referred to herein as D1 PAM I in some cases and can be structurally represented as:

[0004]

[0005] Useful forms of D1 PAM I include crystalline forms (see WO 2017 / 070068) and co-crystalline 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 (CAS Registry Number 1638669-32-5) (see WO2014 / 193781). As a positive allosteric modulator, also known as a "potentiator" of the dopamine D1 receptor subtype, D1 PAM I is highly selective for D1. D1 PAM I shows very weak direct agonistic action on the D1 receptor and is only active in the presence of dopamine and is believed to be dependent on the endogenous tone and subject to normal feedback control. Thus, D1 PAM I represents an innovative pharmacological agent and method for modulating the D1 signaling pathway in Parkinson's disease, Alzheimer's disease, and other dopaminergic CNS disorders where D1 signaling may be defective.

[0006] Methods for preparing D1 PAM I are described in WO 2014 / 193781, for example in Examples 1 and 2. The 11-step synthetic route for preparing D1 PAM I was previously disclosed in US 8,962,654, as shown in Scheme 1 below. The overall yield of D1 PAM I in all 11 steps starting from commercially available 2-bromo-D-phenylalanine via the route described in Scheme 1 below is approximately 17%. Thus, improvements in the synthesis of D1 PAM I can provide substantial and diverse benefits.

[0007] Scheme 1

[0008]

[0009] Synthetic chemical process routes can be redesigned or revised in order to achieve various advantages, including for example: increasing the yield, obtaining crystalline products, reducing the impurity profile, utilizing commercially available intermediates, enhancing or improving enantioselectivity and / or stereoselectivity and / or diastereoselectivity, minimizing the number of synthetic steps required, reducing the inputs required and / or the by-products generated, or any useful combination of such improvements, in order to achieve important real-world outcomes, including reducing costs, providing less resource-intensive processes, and facilitating efficient production. There is a need to improve the method for preparing D1 PAM I in order to achieve one or more of these goals. Summary of the Invention

[0010] Embodiments of the present invention provide methods for preparing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and / or its compositions, as well as particularly useful intermediates for these methods.

[0011] In one embodiment, the present invention provides a method for preparing a compound having the following formula:

[0012]

[0013] The method comprises the following steps:

[0014] i.) Treating (R)-2-bromophenylalanine successively with a reducing agent and iodine; and subsequently treating with a weak mineral base and an alkyl carbonate to obtain (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one;

[0015] ii.) Treating (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one with an arylsulfinic acid sodium salt and acetaldehyde to obtain (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one;

[0016] iii.) Optionally crystallizing the (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one;

[0017] 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;

[0018] v.) Subjecting (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one to Pictet-Spengler cyclization using 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;

[0019] vi.) Optionally crystallizing the (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one;

[0020] vii.) Optionally verify 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;

[0021] viii.) Subject (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one to Heck coupling 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;

[0022] ix.) Optionally crystallize the said (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol;

[0023] x.) Reduce (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;

[0024] xi.) Optionally crystallize 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol;

[0025] xii.) Couple 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;

[0026] xiii.) Optionally crystallize 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; and

[0027] xiv.) Treat 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 and 4-hydroxybenzoic acid.

[0028] Preferably, the reaction in this method is carried out using a flow reaction method.

[0029] In another embodiment, the present invention provides a method for preparing a compound having the following formula:

[0030]

[0031] The method comprises the following steps:

[0032] i.) Treat (S)-(+)-benzyl glycidyl ether and 1,3-dibromobenzene with a metal base to obtain (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol;

[0033] ii.) Treat (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol with an arylsulfonyl chloride in the presence of an organic base to obtain [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] arylsulfonate;

[0034] iii.) Treat [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] arylsulfonate with (S,E)-N-ethylidene-2-methylpropan-2-sulfinamide in the presence of an organometallic base; and then treat with p-toluenesulfonic acid monohydrate to obtain (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate;

[0035] iv.) Optionally crystallize (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate;

[0036] v.) Free base (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate with a non-nucleophilic mineral base and then debenzylate to obtain [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol;

[0037] vi.) Subject [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol to Heck coupling 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-methylbut-3-en-2-ol;

[0038] vii.) Reduce (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;

[0039] viii.) Optionally crystallize 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol;

[0040] ix.) Couple 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-methylbutyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;

[0041] x.) Optionally crystallize 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; and

[0042] xi.) Treat 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-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-methylbutyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone and 4-hydroxybenzoic acid.

[0043] Preferably in this method, the coupling agent for amide synthesis is 2-chloro-4,6-dimethoxy-1,3,5-triazine. Preferably, the reactions in this method are carried out using a flow reaction method.

[0044] In another embodiment, the present invention provides a method for preparing a compound The method comprises:

[0045] i.) treating (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one with sodium benzenesulfinate, HCO 2 H and acetaldehyde; and

[0046] ii.) optionally crystallizing the single diastereomer to obtain (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

[0047] In another embodiment, the present invention provides a method for preparing the following compound

[0048]

[0049] The method comprises using ZrCl 4 to effect a diastereoselective Pictet-Spengler cyclization of (4R)-3-[(1S)-1-(benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one to obtain (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

[0050] Preferably, the above method for preparing the following compound

[0051]

[0052] achieves a diastereomeric ratio of greater than 50:1.

[0053] In another embodiment, the present invention provides a method for preparing the following compound

[0054]

[0055] The method comprises:

[0056] i.) treating [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl]4-methylbenzenesulfonate with n-butyllithium under continuous flow conditions and at low temperature to obtain [2-[(2S)-3-benzyloxy-2-(p-toluenesulfonyloxy)propyl]-3-bromo-phenyl]lithium

[0057] ii.) Treating [[2-[(2S)-3-benzyloxy-2-(p-toluenesulfonyloxy)propyl]-3-bromo-phenyl]lithium] with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide under continuous flow conditions;

[0058] iii.) Cleaving the chiral sulfonamide auxiliary with HCl under continuous flow conditions;

[0059] iv.) Treating the cleavage product with an inorganic base to afford (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline; and

[0060] v.) Treating (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline with 4-toluenesulfonic acid to afford (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-toluenesulfonate.

[0061] In other embodiments, the present invention provides compounds useful for the synthesis of D1 PAM I.

[0062] In another embodiment, the present invention provides a compound

[0063]

[0064] which may be named (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one. Preferably, the compound is crystalline.

[0065] In another embodiment, the present invention provides

[0066]

[0067] which 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.

[0068] In another embodiment, the present invention provides

[0069]

[0070] which 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.

[0071] In another embodiment, the present invention provides

[0072]

[0073] It can be named as [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate. Preferably, the compound is crystalline.

[0074] In another embodiment, the present invention provides

[0075]

[0076] It can be named as (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate. Preferably, the compound is crystalline.

[0077] In another embodiment, the present invention provides

[0078]

[0079] It can be named as [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol. Preferably, the compound is crystalline.

[0080] In another embodiment, the present invention provides

[0081]

[0082] It can be named as (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

[0083] The reactions described herein can be carried out using standard techniques known to those skilled in the art using conventional glassware, or can be carried out on a pilot and / or production scale in equipment designed for such transformations. In addition, each of the described reactions can be carried out by a batch process or a flow reaction method. As used herein, the term "batch process" refers to a process in which the raw materials are combined in a reactor or vessel and the product is removed at the end of the reaction. As used herein, the term "continuous processing" or "flow reaction" refers to a process in which the raw materials flow in continuously and the product flows out continuously. Such continuous processing provides a platform in which the final product can be synthesized from the initial starting materials through a series of completely continuous operations.

[0084] One of ordinary skill in the art can separate or resolve the various individual isomers, enantiomers, and diastereomers at any convenient point in the synthesis of the compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (see, e.g., 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).

[0085] In addition, some of the intermediates described in the preparations below may contain one or more nitrogen protecting groups. Depending on the specific reaction conditions and the specific transformation to be carried out, the variable protecting groups may be the same or different each time they appear. The protecting and deprotecting conditions are well known to those skilled in the art and are described in the literature (see, e.g., “Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, edited by Peter G. M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0086] The abbreviations listed below are defined as follows when used herein: Means one angstrom or a few angstroms. “AcOH” means acetic acid. “Bn” means benzyl; “nBuLi” means n-butyllithium. “CAS number” means Chemical Abstracts Registry Number. “CDI” means carbonyldiimidazole. As used herein, “D1 PAM I” may include co-crystalline forms that comprise 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 dimethyl sulfoxide (if used for NMR, deuterated [d 6)。"dr" means diastereomeric ratio. "esd" means estimated standard deviation. "EtOAc" means ethyl acetate. "EtOH" means ethanol (ethanol or ethyl alcohol). "HPLC" means high performance liquid chromatography. "h" represents one hour or several 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 (methanol or methyl alcohol). "min" means minute. "MS" means mass spectrometry or mass spectrum. "NCS" means N-chlorosuccinimide. "NMR" means nuclear magnetic resonance. "OAc" means acetate. In terms of pipeline materials, "PFA" means perfluoroalkoxy. "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 one second or several seconds, as a unit of time. "TBAF" means tetrabutylammonium fluoride. "TBS-Cl" means tert-butyldimethylchlorosilane. "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.

[0087] Improved routes for preparing D1 PAM I are provided below as Routes I and II, and other additional methods are provided as follows.

[0088] I. Epoxide route for preparing D1 PAM I.

[0089] Method 1

[0090]

[0091] Method 1 describes the synthesis of compound D1 PAM I. Treatment of dibromobenzene with a strong base (such as LDA) under low temperature conditions (usually below -40 °C) 1 , resulting in deprotonation of the aromatic proton at the 2-position, and subsequent reaction with a commercially available epoxide 1a can provide an alcohol 2 . It can be achieved by gradually generating an aryllithium species and then exposing it to 1a , or by adding an LDA solution to 1 and 1aThe transformation is achieved in a mixture of [substances]. The reaction can be carried out in batch mode or using continuous processing. It can be effected by treating with tosyl chloride at a temperature between 20 °C and 80 °C in the presence of a suitable base such as pyridine 2 to form a tosylate 3 . Adding EtOH and water to the reaction mixture causes the solid 3 to crystallize directly from the reaction mixture. Treating the tosylate 3 with an alkyllithium reagent (e.g., nBuLi in an ether solvent such as THF or 2-Me-THF) under cryogenic conditions such as -70 °C causes lithium-halogen exchange and forms an aryllithium species. This transformation can be achieved on a production scale in small batches or in continuous flow mode. The aryllithium species can be exposed to an imine 3a , resulting in the formation of a benzylamine intermediate. Treating the crude solution of the benzylamine with an acid such as aqueous HCl causes cleavage of the chiral sulfinyl auxiliary and forms the amine hydrochloride. Other strong acids can be used to effect this cleavage. Treating the crude solution with a suitable inorganic base such as aqueous sodium carbonate to raise the pH, so that the free amine can perform a nucleophilic attack on the tosylate, resulting in the formation of 4 the 6-membered ring present in [compound]. Aqueous work-up can then remove various impurities and by-products, and a solvent exchange with a solvent such as isopropyl acetate can be used. Exposing the crude solution to an acid such as TsOH monohydrate forms a crystal 4 . Other acids such as HCl or naphthalene-1,5-disulfonic acid can be used instead of TsOH and the crystalline solid can be isolated. These crystals 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 accomplished by treating a solution of [compound] in DCM with BCl 3 using a co-solvent such as toluene or xylene 4 . The product 5 can then be isolated by extraction into acidic water, discarding the organic phase, and forming a crystal 5 by adjusting the pH of the aqueous phase with a base such as aqueous NaOH. Subsequent Heck coupling under well-known conditions can give the compound 6 . Reduction under hydrogenation conditions to 7 and finally amide coupling with 2,6-dichlorophenylacetic acid can give compound D1 PAM I

[0092] In addition, (S)-(-)-tert-butylsulfinamide can be treated with acetaldehyde in the presence of an acidic catalyst such as PPTS or Amberlyst-15, with or without a dehydrating agent such as MgSO 4 , to form an imine 3a . This can be achieved by removing the acidic catalyst via filtration or solvent exchange, precipitation, and filtration3a Purification. Further purification can be achieved by vacuum distillation, maintaining the temperature of the distillation flask below about 80 °C to avoid decomposition of the crude material 3a decomposition.

[0093] The method described in Method 1 provides a route to D1 PAM I that is independent of D-2-Br-phenylalanine, which is difficult to obtain and expensive. The starting materials are inexpensive and readily available. This method route has fewer steps than the Scheme 1 route, the overall yield of producing D1 PAM I is significantly higher than the method disclosed in US 8,962,654, and there is less waste. It is expected that this route is much cheaper than the Scheme 1 route, can produce large quantities of D1 PAM I, and can be carried out in a shorter time. This route utilizes many crystallization control points along the way, allowing for effective purification and separation of intermediates and the final compound.

[0094] A key step in this method route is described in Step C. Due to the instability of the aryllithium intermediate and the challenge of adequately removing heat from a large-scale reactor, this step is preferably carried out in a continuous flow mode at a scale of more than 50 g. The aryllithium intermediate has two bromine atoms that can be lithiated, but the method described in Method 1 stops at monolithiation; the intermediate has an electrophile built into the sulfonate ester, but unwanted reactions with this functional group can be avoided. The resulting chiral aryllithium species is then reacted with a chiral sulfinylimine in batch or flow mode, thereby setting the second stereocenter. This method of forming tetrahydroisoquinoline is considered unprecedented in the literature and allows for independent control of the two stereocenters adjacent to the nitrogen. After the reaction with the imine, the method stream can be immediately treated with acid to effect cleavage of the chiral auxiliary, which can also be done in flow mode in the same stream as the lithium-halogen exchange and imine addition.

[0095] Details of the intermediate in Step C of Method I:

[0096]

[0097] Another embodiment of the present invention is a method in which compound 3 is lithiated using n-BuLi (or n-HexLi, etc.) in a continuous flow under low-temperature conditions to obtain an intermediate aryllithium species.

[0098] Another embodiment of the present invention is a method in which the intermediate aryllithium species is reacted with imine 3a in a continuous flow under low-temperature conditions.

[0099] Another embodiment of the present invention is a method in which the reaction product between the aryllithium and 3a is treated with an acid such as HCl to effect cleavage of the sulfinamido auxiliary.

[0100] Another embodiment of the present invention is a method in which 4 is isolated in its TsOH or 1,5-naphthalenedisulfonate form. II.D1 PAM I's diastereoselective Pictet-Spengler (PS) pathway.

[0101] Method 2

[0102]

[0103] The present invention described in Method 2 is a synthetic method based on a highly diastereoselective Pictet-Spengler, which starts from R-2-bromophenylalanine 8 and produces compound D1 PAM I in about 8 steps, with excellent control of the necessary stereochemistry and good to excellent yields for individual steps. All intermediates in Method 2 can be isolated as crystalline solids, which helps to control chemical and stereochemical purity. R-2-bromophenylalanine 8 can be converted into a novel oxazolidinone in two steps 9 . Preparation of N-(phenylsulfonyl)alkyl oxazolidinone 10 in Method 2 step C is driven by the preferential crystallization of a single diastereoisomer of the novel compound 10 for dynamic kinetic resolution (DKR) (see, for example, Pearson, W.H.; Lindbeck, A.C.; Kampf, J.W. J. Am. Chem. Soc. 1993, 115, 2622). Method 2 step C is considered to be the first example of DKR using chiral oxazolidinone formation to form N-(phenylsulfonyl)alkyl oxazolidinone as a single diastereoisomer. The absolute stereochemistry of 10 can be determined by single crystal X-ray analysis. Method 2 step D is a highly diastereoselective and high-yield Pictet-Spengler cyclization to provide a novel chiral tetrahydroisoquinoline (THIQ) 11 , which establishes the core structure of D1 PAM I. The absolute stereochemistry of 11 can be determined by single crystal X-ray analysis. The Pictet-Spengler cyclization reaction is usually catalyzed by titanium(IV) chloride and other Lewis acids. After screening Lewis acids to promote the reaction in Method 2 step D, several acids were found to be useful for this purpose (Table 1). In particular, since the desired product 11The diastereoselectivity and yield are very high, the reaction curve is clean, the relatively low equivalents required for high conversion, the lack of color imparted to the reaction and the product, and the relatively non-toxic and easily removable by-product zirconium oxide and its hydrates, so zirconium(IV) chloride can be used to promote the Pictet-Spengler cyclization. Generally, higher dilution and lower temperature result in increased diastereoselectivity in the Pictet-Spengler cyclization.

[0104] Some of the benefits of Method 2 relative to the route described in Scheme 1 and previously disclosed in US 8,962,654 include: (a) Starting from R-2-bromophenylalanine, the Pictet-Spengler (PS) route requires 8 synthetic steps to prepare D1 PAMI, compared to the existing route which involves approximately 11 synthetic steps. The overall yield of the Method 2 route is approximately 56%, representing a significant improvement relative to the previously disclosed route as in Scheme 1. Relative to the route 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. The synthetic route disclosed in Scheme 1 is expected to take approximately 1.5 to 2 years to prepare D1 PAM I on a large scale, while 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 low-temperature chemistry and has several intermediates that were not isolated due to poor physical or unstable properties, while the Method 2 route does not have these unattractive features. The protecting groups and salt forms of the advanced starting materials in the route disclosed in Scheme 1 add a large amount of mass that is effectively wasted, such that only approximately one-third of the advanced starting material contains atoms that will become part of D1 PAM I. In contrast, the Method 2 route has a similar advanced intermediate (PS product) that does not have the above problems, and approximately two-thirds of the atoms are present in the desired compound D1 PAM I, which represents a significant highly efficient increase relative to the number of kilograms of the process to produce D1 PAM I. In summary, the route disclosed in US 8,962,654 and shown in Scheme 1 has such a low level of efficiency and cost that it may not provide a viable commercial production route for D1 PAM I, while the efficiency and relatively low cost of the Method 2 route are considered capable of enabling the commercial production of D1 PAM I.

[0105] Table 1

[0106] Promote the Pictet-Spengler cyclization to produce 11 a Lewis acid.

[0107] Standard conditions: Lewis acid (2.5 equivalents) / DCM (20 mL / g intermediate 8) / 2 h.

[0108]

[0109] Lewis acid 0℃ RT Conversion <![CDATA[TiCl 4 Group 4]]> 100.5 to 1 dr 26.2 to 1 dr >99.5％ <![CDATA[ZrCl 4 Group 4]]> 73.3 to 1 dr 57.9 - 124 to 1 dr >99.5％ <![CDATA[HfCl 4 Group 4]]> 64.1 to 1 dr 56.3 to 1 dr >99.5％ <![CDATA[AlCl 3 Group 13]]> 11.5 to 1 dr 9.7 to 1 dr >99.5％ <![CDATA[GaCl 3 Group 13]]> 28.5 to 1 dr 22 to 1 dr >99.5％

[0110] In steps E and F of Method 2, the installation of the gem-dimethyl-tert-alcohol side chain by Heck coupling can be achieved by directly telescoping into the hydrolysis of the oxazolidinone to produce an amino-alcohol. 12 . The hydrolysis of the oxazolidinone can be facilitated by the removal of phosphine through the selective extraction and purification of the product via crystallization. 12 . Step G of Method 2 describes the mild and nearly quantitative hydrogenation of the double bond, and step H of Method 2 is a selective amide coupling to provide D1 PAM I.

[0111] Preparation

[0112] The following preparation of method intermediates further illustrates the invention and represents typical syntheses of various compounds. The reagents and starting materials are readily available or can be easily synthesized by those of ordinary skill in the art. It should be understood that the preparations and examples are set forth by way of illustration and not limitation, and various modifications can be made by those of ordinary skill in the art.

[0113] LC-ES / MS was performed on an HP1100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and / or negative mode) were performed on a mass selective detector quadrupole mass spectrometer interfaced with an HP1100 HPLC. LC-MS conditions (low pH): Column: NX C18 2.1 mm × 50 mm, 3.0 μm; Gradient: 5 - 100% B in 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 containing 0.1% HCOOH; Solvent B: ACN containing 0.1% formic acid; Wavelength 214 nm. Alternative LC-MS conditions (high pH): Column: MS C18 column, 2.1 × 50 mm, 3.5 μm; Gradient: 5% Solvent A for 0.25 min, gradient from 5% to 100% Solvent B in 3 min and 100% Solvent B for 0.5 min or from 10% to 100% Solvent B in 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: Acetonitrile; Wavelength: 214 nm.

[0114] NMR spectra were recorded on a Bruker AVIII HD 400 MHz NMR spectrometer using residual solvent [CDCl 3，7.26 ppm; (CD 3 ) 2 SO, 2.05 ppm] as the reference standard to obtain CDCl reported in ppm 3 or (CD 3 ) 2 SO solution. When reporting the multiplicity of peaks, the following abbreviations can be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant (J) is reported in hertz (Hz) when reporting. For Q-NMR, maleic acid is used as the internal standard.

[0115] Chiral HPLC is performed on an Agilent 1260 HPLC system equipped with LUX-cellulose-1 column: 4.6 x 250 mm, flow rate of 1 mL / min, column temperature of 35 °C, detection at 222 nm, mobile phase: 40% (by volume) 20 mM NH 4 HCO 3 : 60% (by volume) ACN, isocratic elution, run time of at least 15 min, unless otherwise specified. t R is reported in min.

[0116] The chiral HPLC method is performed on an Agilent 1260 HPLC system equipped with C18 column 3 mm x 75 mm, 2,5 2.5 μ; mobile phase: 5 mM NH 4 CO 3 , adjusted to pH 9 with NH 4 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.

[0117] High-resolution mass spectrometry (HRMS) is measured in the electrospray ionization mode (ESI+) on a Thermo Scientific LTQ-ORBITRAP DISCOVERY TM system with a mass accuracy of less than 2 ppm and an applied mass range of 75 to 1500 Da.

[0118] Method Intermediate 1

[0119] (2S)-1-Benzyloxy-3-(2,6-dibromophenyl)propan-2-ol

[0120]

[0121] Method 1 Step A: Charge a nitrogen-inert flask with (S)-(+)-benzyl glycidyl ether (CAS# 16495-13-9, Oakwood Chemical; 10.0 g, 61 mmol), 1,3-dibromobenzene (18.7 g, 79 mmol) and THF (60 mL) with stirring. Cool the mixture in a bath of acetone and dry ice to an internal temperature below -70 °C. Charge a separate nitrogen-inert flask with THF (40 mL) and DIPEA (11.1 mL) with stirring. Cool the solution in a bath of a mixture of acetone and dry ice to an internal temperature below 0 °C. Gradually add a 2.5 M solution of nBuLi in hexanes (30.5 mL, 76.3 mmol), maintaining the internal temperature below 0 °C. Approximately 10 min after the addition of nBuLi is complete, gradually transfer the resulting LDA solution to the flask containing the epoxide and dibromide using a double-headed needle / cannula, keeping the flask in an acetone / dry ice mixture below -70 °C during the addition, during which a tan slurry may form. Keep the flask at below -70 °C for approximately 12 h. Allow the solution to warm to approximately 0 °C and quench with water (50 mL). Pour the mixture into a separate flask and partially concentrate it under reduced pressure to a total volume of approximately 100 mL. Add toluene (50 mL) and transfer the mixture to a separatory funnel. Dilute 5 M aqueous HCl (12.2 mL) with water (50 mL) and add it to the toluene mixture to pH approximately 1. Remove the yellow aqueous layer and wash the organic phase successively with water and saturated aqueous NaCl. Dry the organic phase over Na 2 SO 4 dry, filter and concentrate under reduced pressure to obtain the crude title compound as a yellow oil (Method 1, Compound 2 )(30.36 g, Q-NMR determination = 75.5% w / w, corrected yield = 22.92 g, 94% yield). MS (m / z): 418 (M + NH 4 ).

[0122] Method Intermediate 2

[0123] [(1S)-1-(Benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate

[0124]

[0125] Method 1, Step B: In a flask under nitrogen, dissolve the crude (2S)-1-benzyloxy-3-(2,6-dibromophenyl)propan-2-ol (211.6 g, 530 mmol) in pyridine (424 mL) and add p-toluenesulfonyl chloride (121 g, 636 mmol) in two portions. Heat the mixture to 75 °C and stir for 18 h. Add additional p-toluenesulfonyl chloride (25 g, 131 mmol) and continue heating at 75 °C for 24 h. Cool the reaction mixture to below 40 °C and transfer it to a larger flask. Add water (500 mL) and stir the mixture for 5 min. Add EtOH (1 L), then seed with [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate (1 g) at 20 °C. Stir the mixture and solids begin to form in the flask. Add additional EtOH (500 mL) and stir the mixture for 20 h. Add water (500 mL) and cool the resulting slurry to below 5 °C in an ice-water bath for 4 h. Isolate the resulting solid by filtration, wash it with 1:1 (v / v) EtOH / water (400 mL) and cold EtOH (200 mL) to give a white solid. Dry the collected solid in vacuo at 40 °C to give the title compound as an off-white solid (Method 1, Compound 3 )(258.8 g, 88% yield). MS (m / z): 572 (M + NH 4 ).

[0126] Method Intermediate 3

[0127] (S,E)-N-Ethylidene-2-methylpropan-2-sulfinamide

[0128]

[0129] Add (S)-2-methylpropan-2-sulfinamide (50.0 g, 404 mmol) to a flask containing powdered MgSO 4(97 g, 809 mmol) and DCM (500 mL) in a flask. The resulting mixture was stirred at RT, and acetaldehyde (45 mL, 809 mmol) and PPTS (3.1 g, 12.1 mmol) were added. The mixture was stirred at RT for 24 h. Celite (25 g) was added to the slurry, and the solid was removed by filtration through a fritted glass filter filled with Celite; the filter cake was washed with additional DCM (3 x 100 mL). The filtrate was concentrated to approximately 50% volume under reduced pressure, hexane (250 mL) was added, and the solution was concentrated to approximately 50% volume under reduced pressure. Hexane was added again to the resulting concentrate and the solution was concentrated to near dryness under reduced pressure, thereby forming a yellow solid. Hexane (250 mL) was added to the mixture, the solid was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluting with 4:1 hexane:EtOAc, and after evaporation of the desired compound fractions, the title compound (Method 1, Compound 3a , 53.5 g, yield 90% as determined by Q-NMR) was obtained. Further purification was possible by vacuum distillation (5 Torr, pot temperature 75 °C) to give the title compound. MS (m / z): 148 (M+H).

[0130] Method Intermediate 4

[0131] (1S,3R)-3-(Benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate

[0132]

[0133] Method 1 Step C: Charge a flask 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). Heat the solution to 50 °C and apply a vacuum (230 Torr) to distill off approximately 50 mL of solvent. Then cool the flask to RT and further cool to an internal temperature of approximately -80 °C using a bath containing a combination of dry ice, acetone, and liquid nitrogen. Charge the flask with (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (14.6 g, 99.2 mmol) dissolved in 2-Me-THF (100 mL) using the stir bar and cool the resulting solution to below -70 °C using an acetone / dry ice bath. Add a 2.5 M solution of nBuLi in hexanes (37.2 mL, 92.9 mmol) dropwise with stirring over approximately 150 sec. Age the solution for approximately 3 min and add the imine solution over 90 sec using a 1 / 8-inch PFA tube and nitrogen pressure. Stir the solution for 15 min, quench by adding a solution of AcOH (7.8 mL, 135 mmol) in MeOH (100 mL), and warm to -15 °C. Add 12 M aqueous HCl (14.8 mL, 180 mmol) and warm the mixture to 30 °C while stirring for 2 h. Prepare a solution of Na 2 CO 3 (28.7 g, 271 mmol) in water (400 mL) and add to the reaction mixture with stirring, warm to 45 °C, and heat at this temperature for 17 h. Cool the resulting mixture to RT, dilute with EtOAc (ca. 50 mL), and separate the resulting layers. Wash the organic layer with saturated aqueous NaCl (40 mL) and concentrate under reduced pressure. Dissolve the resulting residue in isopropyl acetate (368 mL) and EtOH (23 mL). Heat the resulting solution to approximately 30 °C with stirring and add methanesulfonic acid monohydrate (14.9 g, 85.7 mmol). Heat the resulting mixture to 50 °C until all components are dissolved. Cool the solution to 40 °C, add a seed crystal of (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate (100 mg), and a slurry begins to form. After 20 min, lower the temperature setting to 35 °C. After 2 h, heat the resulting slurry to 50 °C for 4 h. Lower the slurry temperature to 35 °C and hold for 2 h. Cool the resulting slurry mixture to RT while stirring for 15 h. Cool the resulting slurry to 3 °C using an ice / water bath and collect the solid by filtration. Press the filter cake dry 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 as a white solid (Method 1, Compound 4, 33.0 g, the yield of the E-isomer obtained by NMR plus 3% of the cis-isomer obtained by NMR was 68%). MS (m / z): 346 (M+H).

[0134] Method Intermediate 5

[0135] [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol

[0136]

[0137] Method 1 Step D: Add (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate (30.0 g, 58 mmol) to a flask containing a solution of K 2 CO 3 (9.78 g, 70 mmol), water (120 mL) and toluene (120 mL). Stir the mixture until the solid dissolves. Separate the resulting layers, and extract the aqueous layer with toluene (2 × 50 mL). Combine the organic extracts, wash with saturated aqueous NaCl solution (10 mL), and concentrate to a volume of approximately 120 mL under reduced pressure. Inert the resulting concentrate with nitrogen under stirring and cool in an ice / water bath. Add a 1M solution of BCl 3 (96 mL, 96 mmol), then add chlorobenzene (100 mL). Heat the resulting mixture to 35 °C and add DCM (100 mL) under stirring. Cool the mixture to RT, add MeOH (50 mL) and water (150 mL), and separate the resulting layers. Extract the organic phase with water (2 x 50 mL). Wash the combined aqueous extracts with toluene (50 mL), and gradually add 50% aqueous NaOH solution under stirring while forming a white solid and the pH reaches approximately 10. Stir the resulting mixture at RT for 22 h. Separate the resulting precipitate by filtration, wash with water (25 mL) and heptane (2 × 25 mL), and dry the collected solid in a vacuum oven at 40 °C to give the title compound (Method 1, Compound 5 )(14.4 g, 97% yield). MS (m / z): 256 (M+H).

[0138] Alternative Procedure for Method Intermediate 5

[0139] Method 1 Step D: Add (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) Dissolved in EtOH (35.6 mL). 50 wt% aqueous NaOH solution (15.9 mL, 79.4 mmol) was added to the mixture, and then heated to 70 °C for 17 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure until a slurry began to form. The slurry was heated to gentle boiling and EtOH was added until the mixture became homogeneous. The resulting mixture was cooled to RT with stirring for 2 h. The resulting solid was collected by filtration and washed with a 1:1 mixture of EtOH and water. A second batch of solid formed in the filtrate, the solid was collected by filtration, washed with water, and combined with the initial crop in a 45 °C vacuum oven to give the title compound (Method 1, Compound 5 , 1.88 g, 92% yield). MS (m / z): 256 (M+H).

[0140] Method Intermediate 6

[0141] (E)-4-[(1S,3R)-3-(Hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol

[0142]

[0143] A 3-necked 250 mL round-bottom flask equipped with a magnetic stir bar, Claisen adapter, nitrogen inlet, thermocouple, heating mantle, air-cooled condenser, and rubber septum was evacuated and backfilled with nitrogen twice. Charged with [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol (13.9 g, 54.3 mmol) and toluene (120 mL). The mixture was bubbled with nitrogen for 5 min, and 2-methyl-but-3-en-2-ol (Alfa Aesar, 28.4 mL, 271.3 mmol) was added, then TEA (18.9 mL, 135.7 mmol). The resulting mixture was bubbled with nitrogen for 5 min. Added Pd(OAc) 2(244 mg, 1.1 mmol) and tris(2-methylphenyl)phosphine (661 mg, 2.2 mmol), and nitrogen was bubbled through for an additional 5 min. The resulting mixture was heated at 86 °C for 17.5 h. The reaction mixture was cooled to RT. The resulting solid was removed by filtration through a pad of Celite. The filtrate was concentrated to 1 / 2 volume under reduced pressure. The resulting residue was extracted with a solution of citric acid (13 g) in water (100 mL). The aqueous layer was washed with toluene (25 mL) and neutralized to pH 10 with 50% aqueous NaOH. The resulting mixture was extracted with EtOAc (250 mL), the organic extract was washed with saturated aqueous NaCl, and the organic extract was concentrated under reduced pressure. The resulting oil was dissolved in isopropyl acetate (56 mL) and heated to 35 °C, during which a slurry formed. Heptane (70 mL) was added and the slurry was cooled to RT and additionally cooled in ice water. The resulting solid was collected by filtration, washed with a 3:1 mixture of heptane / isopropyl acetate (30 mL), and dried in vacuo to afford the title compound as a pale yellow solid (Method 1, Compound 6 ; 10.8 g, 77% yield). MS (m / z): 262 (M+H).

[0144] Method Intermediate 7

[0145] 4-[(1S,3R)-3-(Hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol

[0146]

[0147] 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) was added to a 300 mL hydrogenation vessel containing 5% Pd / C catalyst (Johnson-Matthey, 505 mg, 59% water wet). The system was pressurized with nitrogen, vented, and then with H 2The gas was pressurized to 50 psig and stirred at RT for 1 h. The reaction mixture was evacuated and the system was inerted with nitrogen. The solid was removed by filtration and the resulting filtrate was concentrated under reduced pressure to less than 50 mL. Isopropyl acetate (100 mL) was added and the solution was concentrated under reduced pressure to less than 50 mL. Isopropyl acetate (100 mL) was added and the resulting mixture was concentrated under reduced pressure to less than 50 mL; additional isopropyl acetate (100 mL) was added and the resulting mixture was heated to 40 °C for several minutes. The mixture was concentrated under reduced pressure and the resulting slurry was cooled to RT. The solid was collected by filtration and washed with a 1:1 mixture of heptane / isopropyl acetate (30 mL). The solid was dried under vacuum to afford the title compound as a white solid (Method 1, Compound 7; 9.8 g, 94% yield). MS (m / z): 264 (M+H).

[0148] Method Intermediate 8

[0149] (4R)-4-[(2-Bromophenyl)methyl]oxazolidin-2-one

[0150]

[0151] Method 2 Steps A and B: A 60% dispersion of NaH in mineral oil (63 mg, 1.59 mmol) was added to a solution of (R)-(1-(2-bromophenyl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (CAS# 944470-60-4, see for example Journal of Medicinal Chemistry (2007), 50(13), 2990-3003; 0.5 g, 1.51 mmol) in THF (7.5 mL) and stirred at RT for 16.5 h. The reaction mixture was warmed to 55 °C for 45 min and cooled back to RT. The resulting solid was filtered and washed with heptane, then the solid was dissolved in a mixture of DCM and aqueous NH 4 Cl. The layers were separated, the organic phase was collected, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over Na 2 SO 4 and concentrated under reduced pressure to afford the title compound as a white solid (Method 2, Compound 9 , 356 mg; 91%), 94.4% ee by chiral HPLC (Daicel IC, 4.6 mm x 150 mm, 5u; mobile phase: 80 / 20 hexane / ethanol; injection volume: 2 μL; column temperature: 35 °C; wavelength: 220 nm; flow rate: 1.0 mL / min). 1 1H NMR (600 MHz, DMSO-d 6): δ 2.86 (dd, J = 13.7, 7.5 Hz, 1H), 2.98 (dd, J = 13.7, 5.8 Hz, 1H), 4.12 - 4.04 (m, 1H), 4.02 (dd, J = 8.4, 5.2 Hz, 1H), 4.27 (t, J = 8.2 Hz, 1H), 7.18 (td, J = 7.6, 1.8 Hz, 1H), 7.32 (td, J = 7.4, 1.3 Hz, 1H), 7.37 (dd, J = 7.6, 1.8 Hz, 1H), 7.59 (dd, J = 8.0, 1.3 Hz, 1H), 7.83 (s, 1H). 13 C{1H} NMR (151 MHz, DMSO-d 6 ): δ 40.82, 51.79, 68.48, 124.64, 128.36, 123.20, 133.12, 136.42, 158.99. C 10 H 11 BrNO 2 The calculated value of HRMS (ESI+) for

[0152] Alternative Procedure for Method Intermediate 8

[0153] Method 2, Steps A and B: Combine (R)-2-bromophenylalanine (170.1 g, 0.7 mol) and THF (1.7 L), cool to about 5 °C, and add NaBH 4 (63.3 g, 1.7 mol) portionwise to keep the temperature below 5 °C. Slowly add a solution of I 2 (176.9 g, 0.7 mol) in THF (510 mL) to the mixture, keeping the internal reaction temperature below 10 °C. Warm the reaction mixture to RT and heat to 45 °C while stirring for 30 min. Add MeOH (134.0 g, 4.2 mol) dropwise to the reaction mixture. Concentrate the resulting mixture by distillation until the internal temperature reaches 68 °C at 700 Torr. Add THF (238 mL), aqueous KOH solution (85% KOH: 46.0 g, 0.7 mol and water: 150 mL), and toluene (1.7 L) to the reaction mixture. Stir the two-phase mixture at 83 °C for 4 h and wash the resulting mixture with 20% aqueous NaCl solution (3 x 400 mL). Concentrate the organic phase at 90 °C and 200 Torr.

[0154] Add K 2 CO 3(9.7 g, 69.7 mmol) and diethyl carbonate (30.8 g, 2.8 mol). Stir the resulting mixture and distill EtOH at reflux temperature (bath temperature 145 °C, internal temperature 124 °C) and atmospheric pressure for 3.5 h. Dilute the mixture with isopropyl acetate (850 mL), wash with water (3 × 350 mL), and concentrate at 120 °C and 50 Torr to obtain a slurry of a white solid. Add isopropyl acetate (340 mL) to the slurry at 70 °C to obtain a homogeneous mixture, and slowly add heptane (510 mL) to the clarified solution to crystallize the product. Cool the resulting slurry to -10 °C, stir for 1 h, and collect the resulting solid by filtration. Dry the solid at 50 °C and 20 Torr to obtain the title compound (Method 2, Compound 9 ; 151.8 g, 85% yield), with 94.4% ee by chiral HPLC (Daicel IC, 4.6 mm x 150 mm, 5u; mobile phase: 80 / 20 hexane / ethanol; injection volume: 2 μL; column temperature: 35 °C; wavelength: 220 nm. Flow rate: 1.0 mL / min). t R = 10.12.

[0155] Method Intermediate 9

[0156] (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one

[0157]

[0158] Method 2 Step C: Combine (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one (17.5 g, 64.9 mmol) 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) in a reactor vessel. Seal the vessel and heat the reaction mixture with stirring to 75 °C. After 40 h, cool the reaction mixture with stirring to RT in 2.5 h. Open the reactor and collect the resulting crystalline white solid by filtration, wash successively with water (2 x 50 mL) and hexane (2 x 50 mL), and dry in a vacuum oven at 50 °C for 48 h to obtain the title compound (Method 2, Compound 10 , 26.3 g, 95% yield), with >99% ee by chiral HPLC (Daicel IC-3, 4.6 mm x 150 mm, 3μ, mobile phase: 3:2 H 2O: ACN; Injection volume: 2 μL; Column temperature: 25 °C; Wavelength: 220 nm; Flow rate: 1.5 mL / min). t R = 17.85 min. Achiral HPLC t R = 7.7 min. The absolute stereochemistry of (R)-4-(2-bromobenzyl)-3-((S)-1-(phenylsulfonyl)ethyl)oxazolidin-2-one was confirmed by single-crystal X-ray analysis. 1 H NMR (600 MHz, DMSO-d 6 ): δ 1.77 (d, J = 7.3 Hz, 3H), 2.81 (dd, J = 13.5, 10.7 Hz, 1H), 3.22 (dd, J = 13.5, 3.8 Hz, 1H), 4.00 (dd, J = 8.9, 2.5 Hz, 1H), 4.05 (m, 1H), 4.45 (m, 1H), 5.24 (q, J = 7.2 Hz, 1H), 7.22 (td, J = 7.7, 1.7 Hz, 1H), 7.36 (td, J = 7.5, 1.3 Hz, 1H), 7.43 (dd, J = 7.6, 1.7 Hz, 1H), 7.77 (t, J = 7.3 Hz, 1H), 7.63 (td, J = 8.0, 1.4 Hz, 3H), 7.90 (d, J = 8.5 Hz, 2H). 13 C{1H}NMR (151 MHz, DMSO-d 6 ): δ 12.30, 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. C 18 H 19 BrNO 4 S HRMS (ESI+) calcd for 424.0213, found 424.0211.

[0159] Single-crystal X-ray analysis: C 18 H 18 BrNO 4 S transparent colorless rod-shaped sample, dimensions of approximately 0.010 mm x 0.010 mm x 0.150 mm, grown by dissolving in hot toluene and then using slow cooling crystallization technique for X-ray crystallographic analysis. Measuring X-ray intensity data A total of 5711 frames were collected. The total exposure time was 15.9 h. These frames were integrated using the narrow frame algorithm using the Bruker SAINT software package. The data was integrated using a monoclinic unit cell, giving a total of 11348 reflections, with a maximum θ angle of 72.47°( Resolution), of which 3314 times were independent (average redundancy 3.424, completeness = 97.3%, R int = 5.77%, R sig = 5.18%) and 3067 times (92.55%) were greater than 2σ (F 2 ). The final cell constant β = 110.348 (esd = 5)°, was refined based on the XYZ centroids of 8561 reflections with I > 20σ, where 6.484° < 2θ < 144.5°. The data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmittance was 0.716. The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.5610 and 0.9580.

[0160] Using the Bruker SHELXTL software package, the structure was solved and refined in the space group P1 2 1 1, where for the formula unit C 18 H 18 BrNO 4 S, Z = 2. The final anisotropic full-matrix least-squares refinement on F 2 converged to R1 = 7.83% for the observed data and wR2 = 22.06% for all data. The goodness of fit was 1.142. The largest peak in the final difference electron density synthesis was and the largest hole was where the RMS deviation was Based on the final model, the calculated density was 1.553 g / cm 3 and F(000), 432e-. The observed flack parameter was -0.03(5), which indicates that the stereocenters were correctly assigned. The results of the single-crystal X-ray analysis confirmed the stereochemistry shown above for the method intermediate 9 (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

[0161] Alternative Procedure for Method Intermediate 9

[0162] (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) were charged into a 1 L autoclave. The resulting mixture was heated to 60 °C and stirred for 24 h. The resulting slurry was cooled to 35 °C, and the resulting solid was collected by filtration. The collected solid was washed with water (100 mL) and dried at 50 °C and 20 Torr to give the title compound as a single enantiomer and diastereomer (157.5 g, 95% yield).

[0163] Method Intermediate 10

[0164] (5S,10aR)-9-Bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one

[0165]

[0166] Method 2 Step D: (4R)-3-[(1S)-1-(Benzenesulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one (10.0 g, 23.5 mmol) was slurried in DCM (100 mL) and the resulting mixture was cooled to 2 °C. Zirconium(IV) chloride (9.6 g, 41.1 mmol) was added to the mixture. After stirring for 1.5 h at 2 °C, the reaction mixture was warmed to about 10 °C. Water (50 mL) was added, and 50 wt% aqueous NaOH was added to pH about 13, where the temperature rose to about 20 °C. Celite (20 g) was added to the resulting slurry under rapid mixing. The slurry was filtered through Celite with water and DCM, and the resulting cake was rinsed with DCM. The resulting filtrate mixture was separated, the organic phase was washed twice with water (2 × 50 mL), the organic phase was dried over Na 2 SO 4 dried, filtered, and concentrated under reduced pressure to give the title compound as a white crystalline solid (Method 2, Compound 11 , 6.4 g, 93% yield; 54:1 dr), >99% ee by chiral HPLC (Daicel IC-3, 4.6 mm x 150 mm, 3 μ, 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). t R = 19.38 min. The absolute stereochemistry of the title compound was confirmed by single crystal X-ray analysis. 1 H NMR (600 MHz, DMSO-d 6) δ 1.41 (d, J = 6.8 Hz, 3H), 2.57 (dd, J = 16.6, 10.4 Hz, 1H), 3.11 (dd, J = 16.6, 4.6 Hz, 1H), 4.14 (ddt, J = 10.4, 8.1, 4.6 Hz, 1H), 4.19 (dd, J = 8.4, 5.3 Hz, 1H), 4.53 (t, J = 8.1 Hz, 1H), 4.84 (q, J = 6.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H). 13 C{1H} NMR (151 MHz, DMSO-d 6 ): δ 22.14, 34.43, 47.27, 48.21, 68.75, 125.26, 127.10, 128.52, 131.19, 131.88, 140.34, 156.25. C 12 H 13 BrNO 2 The calculated value of HRMS (ESI+) for C

[0167] Single crystal X-ray analysis: C 12 H 12 BrNO 2 A transparent colorless rod-shaped sample with dimensions of approximately 0.100 mm x 0.400 mm x 0.700 mm was grown from a mixture of toluene and heptane using the vapor diffusion crystallization technique for X-ray crystallographic analysis. X-ray intensity data were measured A total of 9218 frames were collected. The total exposure time was 25.61 h. These frames were integrated using the narrow frame algorithm with the Bruker SAINT software package. The data were integrated using a monoclinic unit cell, yielding a total of 84492 reflections with a maximum θ angle of 66.99° ( resolution), of which 8122 were independent (average redundancy 10.403, completeness = 100.0%, R int = 5.93%, R sig = 2.77%) and 7897 (97.23%) were greater than 2σ(F 2 ). The final unit cell constants β = 112.7990 (esd = 10)°, It is a refinement of the XYZ centroid based on 9449 reflections greater than 20σ(I), where 4.912° < 2θ < 156.3°. The data corrected for absorption effects using the multi-scan method (SADABS). The ratio of the minimum to the maximum apparent transmittance is 0.503. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.138 and 0.651.

[0168] Using the Bruker SHELXTL software package, the structure was solved and refined using the space group P1 2 1 1, where for the formula unit C 12 H 12 BrNO 2 , Z = 8. The final anisotropic full-matrix least-squares refinement on F 2 converged to R1 = 5.54% for the observed data and wR2 = 18.74% for all data. The goodness of fit was 1.641. The largest peak in the final difference electron density synthesis was and the largest hole was where the RMS deviation was Based on the final model, the calculated density was 1.609 g / cm 3 and F(000), 1136e-. The observed flack parameter was 0.116 (esd = 5), which indicates that the stereocenter was correctly assigned. The results of the single-crystal X-ray analysis confirmed the stereochemistry shown above for the method intermediate 10 (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

[0169] Alternative Procedure for Method Intermediate 10

[0170] (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one (144.2 g; 339.9 mmol) was combined with DCM (4325 mL) and the resulting mixture was cooled to -10 °C. Zirconium(IV) chloride (154.0 g; 660.8 mmol) was added in four portions (each 38.5 g) at -10 °C and the resulting mixture was stirred for 2 h. Water (721 mL) and 28% NH 3 aqueous solution (721 mL) were slowly added to the reaction mixture. The aqueous phase was separated and the organic phase was washed with water (721 mL). The organic phase was dried over Na 2 SO 4 (306.9 g) and filtered. The filtrate was concentrated at 50 °C under 50 Torr and the resulting white solid was dried at 50 °C under 20 Torr to afford the title compound (91.6 g, 95.5% yield, 124:1 dr).

[0171] Method Intermediate 11

[0172] (E)-4-((1S,3R)-3-(Hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol

[0173]

[0174] Method 2, Steps E and F: Combine (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), 2-methylbut-3-en-2-ol (9.75 mL, 93.0 mmol), and TEA (4.32 mL; 31.0 mmol) at RT, and degas the resulting white slurry by bubbling nitrogen beneath the surface for 10 min. Add tris-o-tolylphosphine (786 mg, 2.58 mmol) and Pd(OAc) 2 (232 mg; 1.03 mmol) to the reaction mixture and continue degassing for 3 min. Switch the nitrogen from degassing to positive pressure in the headspace, and heat the resulting mixture to 75 °C and hold for 6.0 h. At 75 °C, add EtOH (30 mL) and 50 wt% NaOH (10.9 mL, 207 mmol) to the reaction mixture, and stir the resulting mixture at 75 °C for 2.5 h. Cool the reaction mixture to RT, filter the solid and wash with EtOH, and combine the washings with the filtrate. Concentrate the resulting filtrate mixture under reduced pressure. Add toluene, water, and saturated aqueous citric acid to the resulting residue. Separate the aqueous phase and wash with toluene. Adjust the aqueous phase to pH ~13 with 50 wt% NaOH and extract with DCM. Dry the organic phase over Na 2 SO 4 and concentrate under reduced pressure. Dissolve the resulting residue in hot isopropyl acetate (6 mL) and heptane (6 mL) and seed with some (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. Slowly add heptane (24 mL) to the slurry while cooling to RT and stir for 48 h. Filter the resulting slurry, wash the collected solid with heptane, and dry in a 60 °C vacuum oven to obtain the title compound as a white solid (Method 2, Compound 12 , 5.0 g; 89% yield). 1 1H NMR (600 MHz, DMSO-d 6): δ 1.25 (s, 6H), 1.31 (d, J = 6.8 Hz, 3H), 2.13 (br, 1H), 2.24 (dd, J = 16.4, 10.1 Hz, 1H), 2.67 (dd, J = 16.4, 4.2 Hz, 1H), 3.06 (m, 1H), 3.39 (dd, J = 10.3, 6.6 Hz, 1H), 3.46 (dd, J = 10.3, 5.1 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 4.62 (br, 1H), 4.69 (s, 1H), 6.17 (d, J = 15.8 Hz, 1H), 6.66 (d, J = 15.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1Hz), 7.05 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H). 13 C{1H} NMR (151 MHz, DMSO-d 6 ): δ 24.25, 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. C 16 H 24 NO 2 The calculated value of HRMS (ESI+) for

[0175] Alternative Procedure for Method Intermediate 11

[0176] Deoxygenated 2-methyl-3-buten-2-ol (109.9 g, 1.3 mol), Pd(OAc) 2(318.3 mg, 1.4 mmol) and tris(o -tolyl)phosphine (2.2 g, 7.2 mmol) were combined and the mixture was stirred at 16 °C for 30 min. (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 degassed TEA (43 g, 424.9 mmol) were added to the mixture. The resulting mixture was heated to reflux for 5 h. The reaction mixture was cooled to RT. Ethanol (400 mL) and 50 wt% aqueous NaOH solution (226.8 g, 2.8 mol) were added to the reaction mixture. The resulting mixture was heated to 75 °C and stirred for 3 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated at 50 °C and 80 Torr. Toluene (400 mL), water (400 mL) and saturated aqueous citric acid solution (640 mL) were added to the concentrated residue. The organic phase was separated and the aqueous phase was washed with toluene (400 mL). 50 wt% aqueous NaOH solution (400 mL) was slowly added to the aqueous phase. The basified aqueous mixture was extracted with isopropyl acetate (2 × 800) and the combined organic phases were dried over Na 2 SO 4 (160.0 g), filtered. The filtrate was concentrated at 50 Torr at 50 °C and the resulting residue was dissolved in isopropyl acetate (320 mL) at 60 °C. The resulting mixture was cooled to 37 °C. Heptane (1040 mL) was added to the resulting slurry at RT. The slurry was cooled to -10 °C, stirred for 1 h and the resulting solid was collected by filtration. The collected solid was washed with heptane (160 mL) and dried at 50 °C and 20 Torr to afford the title compound (68.6 g, 92% yield).

[0177] Method Intermediate 12

[0178] 4-[(1S,3R)-3-(Hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol

[0179]

[0180] Method 2 Step G: Under nitrogen, (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) were combined in an autoclave, purged with nitrogen, and the system was replaced with hydrogen at 145 psig. The resulting mixture was stirred at RT and 145 psig hydrogen for 4 h. The reaction mixture was filtered through a bed of diatomaceous earth and concentrated at 50 °C and 50 Torr. The resulting solid was collected by filtration and suspended and stirred in isopropyl acetate (200 mL) at RT for 1 h. Heptane (200 mL) was added dropwise, and the resulting slurry was cooled to -10 °C and stirred for 1 h. The resulting solid was collected by filtration, washed with heptane (100 mL), and dried at 50 °C and 20 Torr to obtain the title compound as a white solid (Method 2, Compound 13， 46.2 g, 92% yield), >99% ee by chiral HPLC (Daicel AD-H, 4.6 mm x 250 mm; 5 μm; mobile phase: 0.1% ethanolamine in ACN; injection volume: 2 μL; column temperature: 35 °C; wavelength: 220 nm; flow rate: 1.5 mL / min). t R = 4.43 min. 1 HNMR (600 MHz, DMSO-d 6 ): δ 1.13 (s, 6H), 1.31 (d, J = 6.8 Hz, 3H), 1.57 - 1.45 (m, 2H), 2.08 (s, 1H), 2.21 (dd, J = 16.3, 10.1 Hz, 1H), 2.52 (t, J = 8.7 Hz, 2H), 2.64 (dd, J = 16.3, 4.1 Hz, 1H), 3.06 (tt, J = 10.4, 4.6 Hz, 1H), 3.37 (dd, J = 10.3, 6.8 Hz, 1H), 3.46 (dd, J = 10.5, 4.9 Hz, 1H), 4.07 (q, J = 6.7 Hz, 1H), 4.21 (s, 1H), 4.63 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H). 13 C{1H}NMR (151 MHz, DMSO-d 6 ): δ 24.36, 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. C16 H 26 NO 2 The calculated HRMS(ESI+) value of HNO is 264.1958, and the measured value is 264.1956.

[0181] D1 PAM I

[0182] 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

[0183]

[0184] Step H of Method 2: Combine 2-chloro-4,6-dimethoxy-1,3,5-triazine (14.7 g, 83.7 mmol) and ACN (400 mL), and add 4-methylmorpholine (17.7 g, 175.0 mmol) at 0 °C. Stir the resulting mixture for 30 min, add 2,6-dichlorophenylacetic acid (20.8 g, 101.4 mmol), and stir the mixture at 0 °C for 1 h. Add a mixture of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol (20 g, 75.9 mmol) and 2 CO 3 (11.5 g, 83.7 mmol) in water (100 mL) to the mixture and stir at 0 °C for 4 h. Separate the resulting layers, and dilute the organic phase with isopropyl acetate (100 mL) and saturated NH 4 Cl aqueous solution (100 mL). Separate the resulting layers, wash the organic phase with water (100 mL), dry with Na 2 SO 4 (133.1 g) and filter. Concentrate the filtrate at 50 °C under 80 Torr, and dissolve the resulting mixture in isopropyl acetate (80 mL). Cool the resulting mixture to RT, add heptane (80 mL) dropwise, and cool the resulting slurry to -10 °C while stirring for 1 h. Collect the resulting solid by filtration, wash it with heptane (40 mL), and dry it at 50 °C under 20 Torr to obtain the title compound (29.2 g, 85% yield), with >99% ee obtained by chiral HPLC (Daicel AD-H, 4.6 mm x 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). t R= 14.03. MS (m / z): 451 (M+H).

[0185] Additional Procedure for D1 PAM I

[0186] Method 1 Step G: Charge 2-chloro-4,6-dimethoxy-1,3,5-triazine (6.36 g, 36.2 mmol) and ACN (94 mL) into a nitrogen inert reactor. Cool the mixture to 0 °C and add N-methylmorpholine (9.02 mL, 81.7 mmol). After 20 min, add 2-(2,6-dichlorophenyl)acetic acid (7.43 g, 36.2 mmol), and stir the resulting mixture at 0 °C for 60 min. Add 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). Stir the resulting mixture at 0 °C for 22 h. Filter the reaction mixture and wash the filter cake with isopropyl acetate (100 mL). Concentrate the resulting filtrate under reduced pressure to less than 150 mL. Dilute the resulting mixture with isopropyl acetate (200 mL) and wash with a 1:1 mixture of water / saturated NH 4 Cl aqueous solution (3 × 50 mL). Wash the combined organic extracts successively with water (50 mL), saturated NaHCO 3 aqueous solution (50 mL), saturated NaCl aqueous solution, and dry over Na 2 SO 4 Filter the resulting mixture and concentrate the filtrate under reduced pressure to about 100 mL. Remove the solvent by vacuum distillation at 60 °C to a volume of about 50 mL, and add 50 mL of isopropyl acetate. Repeat the distillation and solvent exchange two more times. Seed with 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 (50 mg), stir the resulting slurry at RT for 21 h, and cool to 0 °C in an ice-water bath for 2 h. Collect the resulting solid by filtration. Wash the filter cake with a 1:1 mixture of heptane / isopropyl acetate (15 mL) and dry under vacuum to obtain the title compound as a white solid (12.5 g, 78% yield). MS (m / z): 450 (M+H). Chiral HPLCt R = 8.48 min (<99% ee).

[0187] Procedure for the Formation of the Cocrystal of D1 PAM I with 4-Hydroxybenzoic Acid

[0188] D1 PAM I (11.5 g, 25.5 mmol) and 4-hydroxybenzoic acid (Aldrich, 3.6 g, 26.0 mmol) were combined in THF (28.8 mL) in a 100 mL round-bottom flask under magnetic stirring. The resulting mixture was heated at 50 °C until all materials were dissolved. The solution was filtered through a 0.45 μm syringe filter into a 250 mL three-neck round-bottom flask equipped with top stirring, a nitrogen inlet, a thermocouple, and an addition port. Transfer and filtration were completed by rinsing with additional THF (4.6 mL). The filtered solution was heated to 50 °C until all components were dissolved, and heptane (18.4 mL) was added immediately. Seeds of the eutectic (75 mg) were added and the mixture was stirred at 50 °C for 30 min. Additional heptane (48.3 mL) was added via a syringe pump over 8 h. The resulting slurry was cooled to RT and stirred for 12 h. The resulting solid was 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 was dried under vacuum to afford the title compound as a white solid (13.5 g, 90% yield). MS (m / z): 450 (M+H).

[0189] X-ray powder diffraction (XRPD)

[0190] Equipped with a CuKa source XRPD patterns of crystalline solids were obtained on a Bruker D4 Endeavor X-ray powder diffractometer operating at 35 kV and 45 mA, with a Vantec detector. The sample was scanned at 2θ between 4° and 40°, with a step size of 0.03° in 2θ, a scan rate of 0.5 seconds / step, a divergence angle of 0.6 mm, a fixed anti-scatterer of 5.28, and a detector slit of 9.5 mm. The dry powder was packed in a zero-background quartz sample holder, and a smooth surface was obtained using a glass slide. The crystalline diffraction patterns were 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 caused by factors such as crystal morphology and habit. In the presence of the effect of preferred orientation, the peak intensities change, but the characteristic peak positions of the polymorphs remain unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843 - 1844, 1995. Additionally, it is also well known in the field of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, due to changes in temperature or humidity during analysis of the sample, sample displacement, or the presence or absence of an internal standard, the peak positions may shift. In the present case, peak position differences of ±0.2 in 2θ will account for these potential variations without preventing the clear identification of the indicated crystalline form. Confirmation of the crystalline form can be made based on any unique combination of distinguishing peaks (in degrees 2θ), typically the more prominent peaks. The crystalline diffraction patterns collected at ambient temperature and relative humidity were adjusted based on the NIST 675 standard peaks at 8.853 degrees and 26.774 degrees 2θ.

[0191] The co-crystal sample of D1 PAM I with 4-hydroxybenzoic acid was characterized by XRD patterns using CuKa radiation as having diffraction peaks (2θ values) as described in Table 2 below, and specifically having a combination of a peak at 7.0° with one or more peaks selected from 15.0°, 16.1°, and 21.0°; where the tolerance of the diffraction angle is 0.2 degrees.

[0192] Table 2: X-ray powder diffraction peaks of the co-crystalline compound of D1 PAM I with 4-hydroxybenzoic acid

[0193] Peak Angle (°θ) + / - 0.2° Relative Intensity (% of the Strongest Peak) 1 7.0 100％ 2 15.0 31.8％ 3 16.1 35.3％ 4 17.4 20.3％ 5 18.2 29.9％ 6 19.8 17.2％ 7 20.3 17.6％ 8 21.0 33.1％ 9 21.3 23.3％ 10 25.2 20.9％ 11 25.5 21.4％

Claims

1. The compound (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

2. The compound according to claim 1, wherein the compound is crystalline.

3. The compound (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

4. The compound according to claim 3, wherein the compound is crystalline.

5. The compound [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate.

6. The compound according to claim 5, wherein the compound is crystalline.

7. The compound (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline 4-methylbenzenesulfonate.

8. The compound according to claim 7, wherein the compound is crystalline.

9. The compound [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol.

10. The compound according to claim 9, wherein the compound is crystalline.

11. The compound (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol.

12. The compound according to claim 11, wherein the compound is crystalline.

13. A method for preparing the compound according to claim 1, the method comprising: i.) Treat (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one with sodium benzenesulfinate, HCO 2 H and acetaldehyde; and ii.) Optionally crystallizing the single diastereoisomer to obtain (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one.

14. A method for preparing the compound according to claim 3, the method comprising using ZrCl 4 subjecting (4R)-3-[(1S)-1-(phenylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl]oxazolidin-2-one to diastereoselective Pictet-Spengler cyclization to obtain (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one.

15. The method according to claim 14, wherein the diastereomeric ratio achieved is greater than 50:

1.

16. A method for preparing the compound according to claim 7, the method comprising: i.) Treating [(1S)-1-(benzyloxymethyl)-2-(2,6-dibromophenyl)ethyl] 4-methylbenzenesulfonate with n-butyllithium under continuous flow conditions and at low temperature to obtain [2-[(2S)-3-benzyloxy-2-(p-toluenesulfonyloxy)propyl]-3-bromo-phenyl]lithium ii.) Treating [2-[(2S)-3-benzyloxy-2-(p-toluenesulfonyloxy)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 cleavage product with an inorganic base to provide (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline; and v.) Treat (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline with p-toluenesulfonic acid to afford (1S,3R)-3-(benzyloxymethyl)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline p-toluenesulfonate.

17. The method according to any one of claims 13-16, wherein the reaction is carried out using a flow reaction method.

18. The method according to any one of claims 13-16, wherein the reaction is carried out using a batch processing method.

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