Crystalline form of (2R,6R)-hydroxynorketamine hydrochloride

Abstract

The present disclosure provides methods for synthesizing the free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine. In certain embodiments, the synthesis of (2R,6R)-hydroxynorketamine (HNK) comprises preparing (R)-norketamine by chiral resolution from racemic norketamine via chiral resolution using L-pyroglutamic acid. The present disclosure also provides corresponding crystalline forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine hydrochloride.

Description

[Technical field]

[0001] The present invention relates to crystalline forms and methods of synthesis of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine.

[0002] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 313,309, filed in the U.S. Patent and Trademark Office on March 25, 2016, from which all benefit is obtained under 35 U.S.C. § 119, the contents of which are incorporated herein by reference in their entirety.

[0003] (Statement of government support) This invention was made with government support under Grant No. NH099345 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. [Background technology]

[0004] Ketamine, a drug currently used in human anesthesia and veterinary medicine, has been shown in clinical studies to be effective in treating several conditions, including pain, treatment-resistant bipolar depression, major depressive disorder, and other depression- and anxiety-related disorders.

[0005] However, routine use of the drug is hindered by undesirable central nervous system (CNS) effects. Approximately 30% of patients do not respond to ketamine treatment. Moreover, ketamine treatment is associated with severe side effects due to the drug's anesthetic properties and abuse potential.

[0006] Ketamine analogs have a potential advantage over standard antidepressants because the onset of action is rapid, occurring within hours or minutes, unlike the standard of care selective serotonin reuptake inhibitors (SSRIs), which require weeks to be effective. Additionally, there are patients who respond to the antidepressant effects of ketamine but not to SSRIs.

[0007] The compounds (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine are analogs of ketamine and may be useful in the treatment of pain, depression, anxiety, and related disorders. Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there is a need for practical and efficient synthetic methods for these compounds, and for stable polymorphs that have superior pharmaceutical properties. The present disclosure meets this need and provides additional advantages as demonstrated herein. [Means for solving the problem]

[0009] The present disclosure provides free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine, as well as the corresponding crystalline forms of the hydrochloride salt. The present disclosure also provides practical and efficient methods for producing (2R,6R)-HNK, (2S,6S)-HNK, (2S,6R)-HNK, and (2R,6S)-HNK. The present disclosure further provides methods for producing the crystalline forms of 2R,6R-HNK and 2S,6S-HNK, the corresponding crystalline forms of the hydrochloride salt, as well as methods for recrystallizing 2R,6R-HNK hydrochloride.

[0010] The present disclosure relates to a method for producing (2R,6R)-hydroxynorketamine or a salt thereof, and a method for producing (2S,6S)-hydroxynorketamine or a salt thereof, comprising: [ka] Formula Ia [ka] Formula Ib (i) treating a compound of formula Ia or formula Ib with a base, then with a trialkylsilyl chloride, then with a peroxy compound, and then optionally with an acid or a fluoride source to obtain a compound of formula IIa when treated with formula Ia, or a compound of formula IIb when treated with formula Ib, wherein the compound of formula IIa or formula IIb contains a carbamate linkage; [ka] Formula IIa [ka] Formula IIb and (ii) cleaving the carbamate bond of a compound of formula IIa or formula IIb to obtain (2R,6R)-hydroxynorketamine when the carbamate bond of a compound of formula IIa is cleaved, or to obtain (2S,6S)-hydroxynorketamine when the carbamate bond of a compound of formula IIb is cleaved. [ka] (2R,6R)-Hydroxynorketamine [ka] (2S,6S)-Hydroxynorketamine; (In the formula, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, benzyl, 4-methoxybenzyl, or 2-trimethylsilylethyl. The method includes the steps of: 1 Particularly good yields are achieved when is t-butyl. The use of chiral starting materials has the advantage that enantiomerically pure products are obtained.

[0011] The present disclosure includes crystalline forms of (2R,6R)-hydroxynorketamine hydrochloride and (2S,6S)-hydroxynorketamine hydrochloride.

[0012] The present disclosure includes a crystalline form of (2R,6R)-hydroxynorketamine hydrochloride characterized by single crystal parameters approximately equal to the following: a=7.3549(6)Å alpha=90° b=7.4932(5)Å beta=96.868(2)° c=11.3498(8)Å gamma=90° V=621.02(8)Å 3 The lattice dimensions, including Space group = P1211, crystal system = monoclinic, molecules per unit cell = 1, density (calculated) = 1.477 Mg / m 3 The numbers in parentheses indicate the last digit uncertainty for the crystals used to determine this crystal structure. However, when 2R,6R-HNK was crystallized multiple times, the variability in cell dimensions was slightly higher, but 2R,6R-HNK still crystallized in the same space group and system. When claiming a crystal form of 2R,6R-HNK by unit cell dimensions, the claim includes the unit cell dimensions a, b, and c as stated + / - 0.1 Å and the cell volume as stated + / - 2 Å of the same space group and system. 3 All crystalline forms of 2R,6R-HNK having the formula:

[0013] The present disclosure also includes a crystalline form of (2S,6S)-hydroxynorketamine hydrochloride characterized by single crystal parameters approximately equal to the following: a=7.3493(8)Å alpha=90° b=7.4846(8)Å beta=96.866(3)° c=11.3404(12)Å gamma=90° V=619.32(12)Å 3 The lattice dimensions, including Space group = P1211, crystal system = monoclinic, molecules per unit cell = 1, density (calculated) = 1.481 Mg / m 3When making a claim for a crystalline form of 2S,6S-HNK in terms of unit cell dimensions, the claim includes the unit cell dimensions a, b, and c as stated + / - 0.1 Å and the lattice volume as stated + / - 2 Å of the same space group and system. 3 All crystalline forms of 2S,6S-HNK having the formula:

[0014] The disclosure also includes crystalline forms of (2R,6R)-hydroxynorketamine hydrochloride that are free of detectable amounts of other crystalline forms of hydroxynorketamine or hydroxynorketamine salts as determined by x-ray powder diffraction, and crystalline forms of (2S,6S)-hydroxynorketamine hydrochloride that are free of detectable amounts of other crystalline forms of hydroxynorketamine or hydroxynorketamine salts as determined by x-ray powder diffraction. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the single crystal x-ray structure of (2S,6S)-hydroxynorketamine hydrochloride. [Diagram 2] FIG. 1 shows the single crystal x-ray structure of (2R,6R)-hydroxynorketamine hydrochloride. [Diagram 3] FIG. 1 shows the XPRD spectrum of (2R,6R)-hydroxynorketamine hydrochloride. [Figure 4] 1 shows DSC and TGA of (2R,6R)-hydroxynorketamine hydrochloride. The DSC profile shows an endotherm with onset and minimum at 223.0° C. The TGA trace shows a weight loss of approximately 0.02% from 20° C. to 120° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] This disclosure provides the first reported synthetic methods for producing enantiomerically pure 2R,6R-HNK and enantiomerically pure 2S,6S-HNK. (2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone ((2R,6R)-hydroxynorketamine (HNK)), a ketamine metabolite, has the structure [ka] has.

[0017] (2S,6S)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone ((2S,6S)-hydroxynorketamine (HNK)), a ketamine metabolite, has the structure [ka] has.

[0018] The present disclosure provides pure crystalline forms of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) hydrochloride salts. The compounds (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine can be synthesized using a similar reaction sequence, but starting from the opposite enantiomer of norketamine. Details of the methods for producing the pure HCl crystalline forms and results supporting these findings can be found in the Examples section.

[0019] [Terminology] The compounds disclosed herein are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0020] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). The recitation of ranges of values ​​is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, unless otherwise stated herein, and each separate value is to be incorporated herein as if it were recited herein. All range endpoints are included within the range and can be independently combined. All methods described herein can be performed in any suitable order unless otherwise stated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") is intended merely to provide a more detailed description of the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention as used herein. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0021] The term "alkyl" as used herein typically, but not necessarily, refers to branched or unbranched saturated hydrocarbon groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups, such as cyclopentyl, cyclohexyl, and the like, which may contain from 1 to about 24 carbon atoms. Generally, but not necessarily, alkyl groups herein may contain from 1 to about 18 carbon atoms, and such groups may contain from 1 to about 12 carbon atoms. The term "lower alkyl" contemplates alkyl groups of 1 to 6 carbon atoms. As described in more detail below, "substituted alkyl" refers to an alkyl group substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl substituent in which at least one carbon atom has been replaced with a heteroatom. "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0022] "Alkoxy" refers to an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge (-O-). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and the like. "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens.

[0023] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image counterpart.

[0024] The term "carbamate bond" refers to the linking group "-O-(CO)-NR-", which when "cleaved" results in a compound having "RNH-" in place of the carbamate bond.

[0025] "Stereoisomers" are compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0026] "Diastereomers" are stereoisomers with two or more centers of chirality whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures, such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column.

[0027] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0028] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.

[0029] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds preceded by (+) or d are dextrorotatory.

[0030] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity. A racemic mixture may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0031] Where a compound exists in various tautomeric forms, the invention is not limited to any one particular tautomer, but rather includes all tautomers.

[0032] The present disclosure includes compounds with all possible isotopes of atoms present in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 123, 134, 140, 141, 152, 163, 170, 171, 18 11 C. 13 C, and 14 There is C.

[0033] "Patient" means any human or non-human animal in need of medical treatment. Medical treatment can be treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment of a patient known to be at risk for suffering from anxiety or depression symptoms, or diagnostic treatment. In some embodiments, the patient is a human patient.

[0034] As used herein, "halide" is chloride, bromide, or iodide.

[0035] As used herein, HPLC is high performance liquid chromatography utilizing a refractive index detector, the method of which is described in the Examples section.

[0036] Percentage purity (% purity) refers to the area percentage obtained by dividing the area of ​​the desired HPLC peak by the sum of the areas of the desired HPLC peak and the HPLC peaks of each reactive impurity, and multiplying this dividend by 100.

[0037] "Percentage yield or isolated yield (% yield)" is the weight of isolated product divided by the molecular weight of the isolated product divided by the number of moles of starting material used in the reaction.

[0038] "Reaction impurities" are process related impurities (by-products) including all residual starting materials, residual intermediates, and other products detected by HPLC other than the desired product. The FDA uses the term "process related impurities" to describe impurities that originate from the manufacturing process.

[0039] "Stereoselective" is any reaction that results in less than 10% of the undesired epimeric by-product.

[0040] The term "enantioenriched" is used to indicate that when a compound may exist as two or more enantiomers, one of the enantiomers is present in excess of the other. For example, when two enantiomers of a compound are possible, an enantioenriched sample may contain more than 50%, more than 60%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, or more than 99% of one of the enantiomers. If the method favors the production of one enantiomer over the production of the other, the method is "enantioenriched" or "enantioselective". Similarly, the term "diastereomerically enriched" is used to indicate that when a compound may exist as two or more diastereomers, one of the diastereomers is present in excess of the other. For example, if two diastereomers of a compound are possible, a diastereomerically enriched sample may contain greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, or greater than 99% of one of the diastereomers. A method is "diastereomerically enriched" or "diastereoselective" if it favors the production of one diastereomer over the other.

[0041] Unless otherwise specified, a reference to an atom is meant to include all isotopes of that atom. For example, a reference to H is 1 H, 2 H (i.e., D) and 3 is meant to include H (i.e., T) and the reference to C is 12 C and all isotopes of carbon ( 13 C, etc.) is included.

[0042] The transitional phrases "comprising," "consisting essentially of," and "consisting of" have the meanings ascribed to those terms under current patent law. Any embodiment claimed with one of the transitional phrases may also be claimed using the other transitional phrase. For example, an embodiment claimed with "comprising" as the transitional phrase also includes embodiments that may be claimed with the transitional words "consisting essentially of" or "consisting of," and vice versa.

[0043] [Chemical Description] The structure of (2R,6R)-hydroxynorketamine, IUPAC name (2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone, is: [ka] It is.

[0044] The structure of (2S,6S)-hydroxynorketamine, IUPAC name (2S,6S)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone, is: [ka] It is.

[0045] The method herein is stereospecific. This means that if the synthesis begins with (R)-norketamine, the synthesis passes through intermediates Formula Ia and Formula IIa and is completed with the final product (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). Similarly, if the synthesis begins with (S)-norketamine, the synthesis passes through intermediates Formula Ib and Formula IIb and is completed with the final product (2S,6S)-hydroxynorketamine ((2S,6S)-HNK). The stereospecific nature of the synthetic method is shown below. [ka]

[0046] The present disclosure provides a method for producing (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a salt thereof, comprising producing a compound of formula Ia or Ib from norketamine. [ka] Formula Ia [ka] Formula Ib (In the formula, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, benzyl, 4-methoxybenzyl, or trimethylsilylethyl. 1 is a tert-butyl group. (R)-Norketamine can be obtained by chiral resolution from racemic norketamine via chiral resolution with L-pyroglutamic acid (or tartaric acid).

[0047] (R)-norketamine can be reacted with a carbamate forming reagent to produce the carbamate compound formula Ia, and (S)-norketamine can be reacted with a carbamate forming reagent to produce the carbamate compound formula Ib. The goal is to produce a carbamate that can protect the amine during some subsequent steps and then deprotect when protection is no longer required. The carbamate reagent can be a dialkyl dicarbonate such as di-tert-butyl dicarbonate, or an alkyl haloformate such as methyl chloroformate, ethyl chloroformate, or tert-butyl chloroformate. The carbamate reagent can be other chloroformates such as bromoethyl chloroformate, benzyl chloroformate, 4-methoxybenzyl chloroformate, or trimethylsilylethyl chloroformate. The reaction can be carried out with a variety of bases, including carbonate bases such as potassium carbonate, lithium carbonate, sodium carbonate, or sodium bicarbonate, hydroxide bases such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, amine bases such as trimethylamine, trimethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or combinations of the above, or without any base at all. A variety of solvents can be used, including toluene, ethyl acetate, methylene chloride, water, or combinations of the above.

[0048] In some embodiments, producing a compound of formula Ia or formula Ib comprises reacting (R)-norketamine with (R 1 O2C)2O or R 1 or reacting (S)-norketamine with (R 1 O2C)2O or R 1 with O2C-X to produce a compound of formula Ib, where X is a halogen.

[0049] In one embodiment, R1 is tert-butyl, producing a compound of formula Ia comprises reacting (R)-norketamine with (tert-butyl-O2C)2O, and producing a compound of formula Ib comprises reacting (S)-norketamine with (tert-butyl-O2C)2O.

[0050] The present disclosure provides a method for producing (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a salt thereof, comprising treating a compound of formula Ia or formula Ib with a strong base, then with a trialkylsilyl chloride, then with a peroxy compound, and optionally with an acid or a fluoride source, to obtain a compound of formula IIa when formula Ia is treated, or a compound of formula IIb when formula Ib is treated. [ka] Formula IIa [ka] Formula IIb (In the formula, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, benzyl, 4-methoxybenzyl, or trimethylsilylethyl).

[0051] The compound of formula IIa or IIb is treated with a base to produce an intermediate, believed to be a silyl enol ether, which is used in the next reaction without characterization. Without wishing to be bound by any theory, it is believed that the base transfers an alpha proton to the carbonyl of the compound of formula IIa or IIb to produce an enolate, whose oxygen atom then reacts with a trialkylsilyl chloride to produce the silyl enol ether.

[0052] The present disclosure provides methods for producing crystalline forms of 2R,6R-HNK and 2S,6S-HNK, as well as the corresponding crystalline forms of the hydrochloride salts.

[0053] The present disclosure also provides a method for obtaining 2R,6R-hydroxynorketamine HCl by recrystallization from crude or semi-crude 2R,6R-hydroxynorketamine HCl, by dissolving the crude 2R,6R-hydroxynorketamine HCl in water and then adding acetone at a constant flow rate, thereby allowing precipitation of purified 2R,6R-hydroxynorketamine HCl. 2R,6R-hydroxynorketamine has already been described in the literature and is well known for its antidepressant activity. At present, no recrystallization method has been described in the literature for any formulation of the compound or its salts.

[0054] The present disclosure provides 2R,6R-hydroxynorketamine hydrochloride recrystallized from crude, semi-crude, or purified 2R,6R-hydroxynorketamine hydrochloride. Two notable problems can arise in the later stages of the formation of 2R,6R-HNK. The first is the presence of trace amounts of by-product impurities that cannot be easily removed by standard methods. The second is the "trapping" of organic solvents in the formation of the final salt. These "trapped" solvents cannot be removed by standard methods (vacuum, heating under vacuum, etc.), resulting in a small percentage of organic solvent in the final product. The present recrystallization method reduces the impurity levels and precisely removes the solvent levels in the final 2R,6R-hydroxynorketamine hydrochloride product. Thus, the present disclosure provides a method for purifying 2R,6R-HNK, characterized by dissolving 2R,6R-hydroxynorketamine hydrochloride in an equal mass of water (1 g / 1 g). Under magnetic stirring, 20 volume equivalents (20 ml per gram) of acetone are added at a constant flow rate of 0.75 equivalents per minute while stirring the solution. The resulting suspension is stirred for an additional 1.5 hours, then filtered and dried in vacuum at room temperature for 16 hours to obtain the final product.

[0055] Thus, an embodiment of the present disclosure includes dissolving solid, preferably crystalline, 2R,6R-HNK hydrochloride in about an equal mass of water (1 g compound / 1-1.2 grams water), adding about 20 volumes of solvent, or 15-25 volumes of solvent, preferably acetone, at a constant flow rate with stirring to form a suspension, followed by filtration to form a filtrate and drying under vacuum. In certain embodiments, the suspension is stirred for 1-4 hours, or 1-2 hours after the addition of the solvent is complete. In certain embodiments, the filtrate is dried for more than 8 hours, more than 12 hours, 12-20 hours, or about 16 hours.

[0056] The present disclosure further provides additional synthetic methods that are variations of the methods described above for the production of 2,6-HNK or intermediates useful for producing various enantiomers of 2,6-HNK.

[0057] In one such method, 2-chlorophenyl cyclopentyl ketone can be used to produce (R)- or (S)-norketamine. The present disclosure provides a cost-effective method for producing the 2-chlorophenyl cyclopentyl ketone starting material by first forming the tosyl hydrazide, followed by reaction with 2-chlorobenzaldehyde. This reaction is shown in Scheme 1. [ka]

[0058] The present disclosure also provides a method (Scheme 2) using diphenyl ether that allows for thermal rearrangement at slightly lower temperatures, in contrast to the published route using DowTherm A. [ka]

[0059] The present disclosure provides an improved deprotection of the Rubotom oxidation product using formic acid (Scheme 3). Previous methods used tetrabutylammonium fluoride to achieve the deprotection. [ka]

[0060] The present disclosure also provides a method for final deprotection using hydrochloric acid in ethyl acetate (Scheme 4), which directly forms the desired HCl salt. [ka]

[0061] The present disclosure also provides the synthesis of 2R,6S-hydroxynorketamine and 2S,6R-hydroxynorketamine. Although the 2R,6S-hydroxynorketamine compound is known in the literature, the present disclosure provides a synthetic route that is greatly improved in terms of time, yield, and reproducibility. Although 2R,6S-hydroxynorketamine has been found to have antidepressant effects in the forced swim test that are equal to or greater than those of 2R,6R hydroxynorketamine, the stability of 2R,6S-hydroxynorketamine is questionable. The route (Scheme 5) involves triflating the enantiopure compound 8, followed by inversion of the alcohol with the anion of nitrobenzoic acid. The nitrobenzoate group is then cleaved and the BOC group is carefully deprotected to obtain the desired 2R,6S-hydroxynorketamine. This route has also been applied to its enantiomers. [ka]

[0062] Accordingly, the present disclosure provides a method for preparing 2R,6S-hydroxynorketamine comprising triflation of tert-butyl ((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8), followed by inversion of the alcohol with the anion of nitrobenzoic acid to cleave the nitrobenzoate group and remove the BOC protecting group to generate 2R,6S-HNK.

[0063] The present disclosure provides a method for preparing 2R,6S-HNK, comprising (i) triflating enantiopure isopropyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 8 to form (1S,3S)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl trifluoromethanesulfonate. In some embodiments, the triflating is carried out in the presence of pyridine in a non-polar solvent such as dichloromethane or other solvent. The reaction may be quenched, for example, by adding sodium bicarbonate. The solvent may be removed by evaporation or other means to form crude triflate 9.

[0064] The method for preparing 2R,6S-hydroxynorketamine further comprises (ii) dissolving the crude triflate in DMF or other aprotic solvent such as NMP, followed by addition of 4-nitrobenzoic acid and a weak base such as potassium carbonate or sodium carbonate. In certain embodiments, the product is extracted with an aqueous solution and the organic phase is evaporated to give (1S,3R)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate 10.

[0065] The method further comprises (iii) cleaving the nitrobenzoate group by dissolving nitrobenzoate 10 in methanol or other suitable solvent, such as ethanol, followed by addition of potassium carbonate or other carbonate salt to generate the protected 2R,6S-HNK, 11. In some embodiments, the protected 2R,6S-HNK is washed with water and a saturated aqueous salt solution, such as saturated sodium chloride.

[0066] The method for preparing 2R,6S-HNK further comprises (iv) slowly deprotecting the protected 2R,6S-HNK, 11, by adding an acid, such as trifluoroacetic acid, in a non-polar solvent, such as DCM. The solvent and acid may be removed by evaporation, such as rotary evaporation. In some embodiments, the product, 2R,6S-HNK, 12, is washed by extraction into a neutral aqueous solution, such as ethyl acetate and pH 7 potassium phosphate buffer, to give a crude material. Purified material may be obtained from the organic phase by evaporation.

[0067] Steps (i) through (iv) may also be used to generate 2S,6R-HNK by starting with the enantiomer of ((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 8A.

[0068] A variety of bases can be used to transfer the alpha proton to the carbonyl of formula I during the reaction to provide the compound of formula II. These bases include strong bases such as lithium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or various alkyllithium reagents such as sec-butyllithium. Under some conditions, weaker bases may be used including carbonate bases such as potassium carbonate, lithium carbonate, sodium carbonate, or sodium bicarbonate, hydroxide bases such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, amine bases such as trimethylamine, trimethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When using strong bases, the transfer of the proton should be performed at a temperature below 25°C, preferably below 0°C, more preferably below -50°C, and can range from -50°C to -85°C. When a weak base is used, the temperature may vary widely from -25°C to 100°C. The compound of formula IIa or IIb should be stirred with the base for a time sufficient to transfer the alpha proton to the carbonyl, which may vary from 5 minutes to 24 hours depending on the conditions and base used. The solvent for this step should be one that does not appreciably react with the base under the conditions used. When a strong base is used, suitable solvents include tetrahydrofuran, diethyl ether, methyl-tert-butyl ether, and the like. When a weak base is used, a variety of solvents can be used, including tetrahydrofuran, diethyl ether, methyl-tert-butyl ether, methylene chloride, toluene, N,N-dimethylformamide, and the like.

[0069] In certain embodiments, treating the compound of Formula Ia or Formula Ib with a strong base comprises treating the compound of Formula Ia or Formula Ib with lithium diisopropylamide at a temperature less than -50°C.

[0070] It is believed that after (or possibly during) the alpha proton transfer to the carbonyl of the compound of formula Ia or formula Ib, a trialkylsilyl chloride is added to react with the intermediate enolate to form a silyl enol ether. This reaction may be carried out for a time period of 5 minutes to 24 hours, depending on the conditions, and at a temperature of -78°C to 100°C. In some embodiments, the trialkylsilyl chloride is added simultaneously with the base to transfer the alpha proton to the carbonyl and react the resulting enolate with the trialkylsilyl chloride reaction in a sequential manner. The trialkylsilyl chloride can be trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropylsilyl chloride, and the like.

[0071] In certain embodiments, the trialkylsilyl chloride is trimethylsilyl chloride.

[0072] Once the silyl enol ether is formed, it is treated with a peroxy compound and then, optionally, with an acid or fluoride source to give a compound of formula IIa or IIb. The peroxy compound can be a peroxy acid, such as peroxybenzoic acid or peracetic acid, or a peroxide, such as dimethyldioxirane, tert-butyl hydroperoxide, or hydrogen peroxide. Treatment with the peroxy compound can be carried out in a variety of solvents and at a variety of temperatures and reaction times. For example, treatment with the peroxy compound can be carried out in dichloromethane or chloroform for 5 minutes to 24 hours, and at a temperature of -30°C to 50°C.

[0073] In certain embodiments, the peroxy compound is meta-chloroperoxybenzoic acid.

[0074] In some embodiments, after treatment with peroxy compound, an acid or fluoride source is added to produce a compound of formula IIa or formula IIb. Without wishing to be bound by any theory, it is believed that treatment with peroxy compound produces an alpha-siloxy epoxide, and the acid or fluoride source cleaves the silicon-oxygen bond in the alpha-siloxy epoxide to produce an alpha-hydroxy epoxide, which then ring-opens to produce an alpha-hydroxy ketone product formula IIa or formula IIb. The fluoride source can be any fluoride-containing reagent that can cleave the silicon-oxygen bond, and can include sodium fluoride, potassium fluoride, cesium fluoride, tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine, etc. The addition of the fluoride source can be carried out in various solvents and at various temperatures and reaction times. For example, treatment with a fluoride source can be carried out in tetrahydrofuran, diethyl ether, or methyl-tert-butyl ether for 5 minutes to 24 hours, and at a temperature of -30° C. to 50° C. In some embodiments, the silicon-oxygen bond can be cleaved without a fluoride source, such as by treatment with an acid, which can include treatment with hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid, and the like. In some embodiments, the alpha siloxy epoxide is not treated with an acid or a fluoride source, yet the desired product is still produced.

[0075] In some embodiments, after treatment with a peroxy compound, the compound of Formula Ia or Formula Ib is treated with tetra-n-butylammonium fluoride.

[0076] The disclosure provides a method for producing (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a salt thereof, comprising cleaving a carbamate bond of formula IIa or formula IIb to obtain (2R,6R)-hydroxynorketamine when the carbamate bond of formula IIa is cleaved, or (2S,6S)-hydroxynorketamine when the carbamate bond of formula IIb is cleaved. [ka] (2R,6R)-Hydroxynorketamine [ka] (2S,6S)-Hydroxynorketamine; (In the formula, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, benzyl, 4-methoxybenzyl, or trimethylsilylethyl).

[0077] The method for cleaving the carbamate bond is R 1 Due to the nature of the enumerated R 1 Any carbamate having one of the groups can be cleaved by a mild base. 1 If R is tert-butyl, then an acid can be used to cleave the tert-butyl carbamate bond. Acids that can be used for this step include hydrochloric acid, sulfuric acid, and acetic acid, such as trifluoroacetic acid. 1 When R is a 2-haloalkyl, such as 2-bromoethyl or 2,2,2-trichloroethyl, the carbamate bond can be cleaved by treatment with zinc. 1 If R is benzyl, the carbamate bond can be cleaved by hydrogenation, and R 1 If R is 4-methoxybenzyl, then the carbamate bond can be cleaved by hydrogenation or oxidation, and R 1If is 2-trimethylsilylethyl, the carbamate bond can then be cleaved by treatment with fluoride. If any of these treatments produce an acid salt of the product, the resulting salt can then be converted to the free base using a base such as potassium carbonate, lithium carbonate, sodium carbonate, or sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, trimethylamine, trimethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferably, a carbonate base such as sodium bicarbonate is used. The resulting free base can then be treated with hydrochloric acid to produce (2R,6R)-hydroxynorketamine hydrochloride or (2S,6S)-hydroxynorketamine hydrochloride. Other acids can be used to make other salts of (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine.

[0078] In one embodiment, R 1 is tert-butyl, and cleaving the carbamate bond involves treatment with acid.

[0079] In one embodiment, R 1 is tert-butyl, and cleaving the carbamate bond involves treatment with trifluoroacetic acid.

[0080] In certain embodiments, a hydrochloride salt is produced and the method further comprises treating (2R,6R)-hydroxynorketamine with hydrochloric acid to produce (2R,6R)-hydroxynorketamine hydrochloride or treating (2S,6S)-hydroxynorketamine with hydrochloric acid to produce (2S,6S)-hydroxynorketamine hydrochloride.

[0081] In one embodiment, a method for producing (2R,6R)-hydroxynorketamine, or a salt thereof, includes producing a compound of formula Ia; [ka] Formula Ia treating the compound of formula Ia with lithium diisopropylamide at less than -50°C, then with trimethylsilyl chloride, then with meta-chloroperoxybenzoic acid, then with tetra-n-butylammonium fluoride to obtain the compound of formula IIa; [ka] Formula IIa and The carbamate bond of formula IIa is cleaved by treatment with acid to give (2R,6R)-hydroxynorketamine. [ka] (2R,6R)-Hydroxynorketamine (In the formula, R 1 is tert-butyl).

[0082] In certain embodiments, the hydrochloride salt is prepared.

[0083] In one embodiment, a method for producing (2S,6S)-hydroxynorketamine, or a salt thereof, includes producing a compound of formula Ib; [ka] Formula Ib treating the compound of formula Ib with lithium diisopropylamide below -50°C, then with trimethylsilyl chloride, then with meta-chloroperoxybenzoic acid, then with tetra-n-butylammonium fluoride to obtain the compound of formula IIb; [ka] Formula IIb and The carbamate bond of formula IIb is cleaved by treatment with acid to give (2S,6S)-hydroxynorketamine. [ka] (2S,6S)-Hydroxynorketamine (In the formula, R 1 is tert-butyl).

[0084] (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine are prepared according to the synthesis of Scheme 6 below, which shows the synthesis of (2S,6S)-hydroxynorketamine. Details of the synthesis of (2S,6S)-HNK and (2R,6R)-HNK are provided in Examples 1-8. Compound numbers shown in the (2S,6S)-HNK synthetic pathway are used in the examples. Scheme 6 [ka]

[0085] Scheme 7 shows the synthetic route for 6,6-dideuteroketamine hydrochloride. Details of deuteration are given in Example 9. Scheme 7 [ka]

[0086] In one embodiment, the synthesis for (2S,6S)-hydroxynorketamine shown in Scheme 7 above begins with chiral resolution of racemic norketamine 13, which resolves racemic norketamine into (S)-norketamine 14 and its enantiomer (R)-norketamine. This can be accomplished by using a chiral resolving agent such as D-tartaric acid, or by other methods that may include chromatography on a chiral medium such as a chiral HPLC column. Alternatively, homochiral or enantioenriched norketamine can be obtained by enantioselective synthetic methods. The subsequent steps of Scheme 1 can be applied to (S)-norketamine 13 to ultimately produce (2S,6S)-hydroxynorketamine 17, or the steps can be applied to (R)-norketamine to ultimately produce (2R,6R)-hydroxynorketamine.

[0087] In Scheme 6, (S)-norketamine 14 is reacted with di-tert-butyl-dicarbonate in the presence of potassium carbonate in toluene at 80° C. to produce the Boc-protected compound 15.

[0088] Further in Scheme 6, compound 15 in THF at -78°C is treated with lithium diisopropylamide and trimethylsilyl chloride to produce an intermediate, believed to be the enol ether 16, which is used in the next reaction without characterization. Without wishing to be bound by any theory, it is believed that lithium diisopropylamide transfers an alpha proton to the carbonyl of compound 15 to produce an enolate, whose oxygen atom then reacts with trimethylsilyl chloride to produce the silyl enol ether 16.

[0089] After the alpha proton is transferred to the carbonyl of 15, trimethylsilyl chloride is added and reacted with the enolate generated from 15.

[0090] In Scheme 6, once intermediate 16 is formed, it is treated with m-peroxybenzoic acid (mCPBA) followed by a fluoride source to give compound 8, the Boc-protected (2S,6S)-hydroxynorketamine.

[0091] Without wishing to be bound by any theory, it is believed that treatment with mCPBA produces an alpha-siloxy epoxide, and treatment with fluoride cleaves the silicon oxygen bond to produce an alpha-hydroxy epoxide, which then undergoes ring opening to give the alpha-hydroxy ketone 8.

[0092] In Scheme 6, compound 8 is treated with trifluoroacetic acid to remove the Boc group, thus deprotecting the 2-amino group of (2S,6S)-hydroxynorketamine. The resulting salt is then converted to the free base using sodium bicarbonate. The resulting free base is then treated with hydrochloric acid to produce (2S,6S)-hydroxynorketamine hydrochloride 17. Other acids can be used to make other salts of (2S,6S)-hydroxynorketamine. EXAMPLES

[0093] [General method] (chemical method) All commercially available reagents and solvents were purchased and used without further purification. All microwave reactions were performed in sealed microwave vials equipped with a magnetic stir bar and heated with a Biotage Initiator Microwave Synthesizer. 1 HNMR and 13 C NMR spectra were recorded on a Varian 400 MHz or Varian 600 MHz spectrometer in CD3OD or CDCl3 as indicated. For spectra recorded in CD3OD, chemical shifts are 1 CD3OD (3.31 MHz) and 13C NMR spectra are reported in ppm using CD3OD (49.0 MHz) as the reference. Alternatively, for spectra recorded in CDCl3, chemical shifts are reported in ppm relative to deuterochloroform ( 1 HNMR: 7.26 ppm. 13 77.23 ppm for C NMR. Coupling constants (J values) are reported in Hertz (Hz). Peak splitting patterns were described as singlet (s); doublet (d); triplet (t); quartet (q); multiplet (m) and septet (septet). Samples were analyzed for purity on an Agilent 1200 system LC / MS equipped with a Luna C18 (3 mm x 75 mm, 3 μm) reversed-phase column with UV detection at λ = 220 nm and λ = 254 nm. The mobile phase consisted of water with 0.05% trifluoroacetic acid as component A and acetonitrile with 0.025% trifluoroacetic acid as component B. A linear gradient was run at a flow rate of 0.8 mL / min as follows: 0 min 4% B; 7 min 100% B; 8 min 100% B. High resolution mass spectra (HRMS) were recorded on an Agilent 6210 Time-of-Flight (TOF) LC / MS system. Optical rotations were measured on a PerkinElmer Model 341 polarimeter using a 10 cm cell at 589 nM and room temperature.

[0094] Chiral analysis was performed using an Agilent 1200 system HPLC with an analytical ChiralPak AD or OJ column (4.6 mm × 250 mm; 5 μm). The mobile phase consisted of ethanol with 0.1% diethylamine as component A and hexane with 0.1% diethylamine as component B. An isocratic gradient was run with 60% A at 0.4 mL / min.

[0095] (2R,6R)-hydroxynorketamine hydrochloride and (2S,6S)-hydroxynorketamine have been previously described in US 2014 / 0296241. The synthesis and crystalline forms disclosed herein have not yet been described.

[0096] Example 1: Chiral resolution of (S)-(+)-norketamine (14) [ka] (14) Racemic norketamine (22.7 grams, 101 mmol) (Cayman Chemicals, Ann Arbor, MI, USA, prepared as described in Hong, SC & Davisson, JN, J. Pharm. Sci. (1982) 71:912-914) was dissolved in 1.1 L of ethanol. (D)-(R)-(+)-pyroglutamic acid (15.8 g, 0.5 eq., 121 mmol) was then added as a solid. The reaction was stirred and heated to reflux for 5 minutes. Upon heating, a white suspension formed. Once the suspension reached reflux, it was cooled to room temperature with stirring for 16 hours. The reaction was filtered and the white solid collected. The resulting white solid was then resuspended in 0.9 L of ethanol and the suspension was heated to reflux for 5 minutes. The suspension was allowed to cool to room temperature with stirring over 2 hours. The solid was collected by filtration, then suspended a third time in ethanol (0.8 L), heated to reflux for 5 min, and then cooled to room temperature with stirring. The solid was filtered, collected, and dried under vacuum to give (S)-(+)-norketamine D-pyroglutamate. The enantiomeric excess was determined by chiral HPLC to give an enantiomeric excess of 98.3%. The (S)-(+)-norketamine D-pyroglutamate salt was converted to the free base by treatment with 1N aqueous sodium hydroxide, extracted into ethyl acetate, and removed the organic solvent by rotary evaporation to give (S)-(+)-norketamine as the free base (from the pyroglutamate salt) (Chiralpak AD column, 60% ethanol in hexane with 0.01% diethylamine, 1.0 mL, room temperature: 5.2 min) [α] D 20 :(+)-81°(c1.0, H2O, D-pyroglutamate salt).

[0097] Example 2: Chiral resolution of (R)-(-)-norketamine (14A) [ka] (14A) (R)-(-)-Norketamine (14a) was prepared in a similar manner to (S)-(+)-Norketamine (2), except that (L)-(S)-(-)-pyroglutamic acid was used as the chiral resolving agent instead of (D)-(R)-(+)-pyroglutamic acid. Chiral HPLC: 98% ee. (Chiralpak AD, 60% ethanol in hexane, 1 mL / min, room temperature: 6.8 min) [α] D 20 :(-)-75°(c1.0, H2O, L-pyroglutamate salt).

[0098] Example 3: Synthesis of (S)-TERT-butyl(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate (15) [ka] (15) To a solution of (S)-(+)-norketamine (14) (1.85 g, 8.27 mmol) in toluene (100 mL) was added potassium carbonate (3.43 g, 24.8 mmol) and BOC-anhydride (2.71 g, 12.4 mmol). The reaction was heated to 80 °C and stirred for 16 h. The reaction was then cooled and extracted with ethyl acetate and washed with water. The organic layer was taken out and the solvent was removed in vacuo to give the crude product. Purification by silica gel chromatography (0% to 60% ethyl acetate in hexanes) gave the final product (15) as a white solid.

[0099] 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.28 - 7.13 (m, 1H), 6.59 (s, 1H), 3.83 (d, J = 14.3 Hz, 1H), 2.45 - 2.36 (m, 1H), 2.36 - 2.25 (m, 1H), 2.04 (ddq, J = 11.5, 5.5, 3.0 Hz, 1H), 1.89 - 1.56 (m, 4H), 1.29 (s, 9H).

[0100] 13 C NMR (101 MHz, CDCl3) δ 209.0, 153.4, 135.1, 133.7, 131.5, 130.9, 129.2, 126.2, 79.0, 67.1, 39.4, 38.4, 30.8, 28.2, 22.3.

[0101] HRMS (ESI+): expected 346.1186 [M+Na] + (C 17 H 22 ClNO3Na). Found value: 346.1180. [α] D 20 : (+)-39.5°(C=1.0, CH2Cl2).

[0102] <Example 4: Synthesis of (R)-TERT-butyl(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate (15A)> [ka] (15A) The title compound was prepared in a similar manner to (S)-tert-butyl (1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate (15) utilizing (R)-(−)-norketamine (14A) instead of (S)-(+)-norketamine (14).

[0103] 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.0, 1.4 Hz, 2H), 7.30 - 7.21 (m, 1H), 6.61 (s, 1H), 3.84 (d, J = 14.4 Hz, 1H), 2.47 - 2.37 (m, 1H), 2.38 - 2.29 (m, 1H), 2.09 - 2.02 (m, 1H), 1.86 - 1.62 (m, 4H), 1.31 (s, 9H).

[0104] 13 13C NMR (101 MHz, CDCl3) δ 209.0, 153.4, 135.0, 133.7, 131.5, 130.8, 129.2, 126.2, 79.0, 67.1, 39.4, 38.4, 30.8, 28.2, 22.3.

[0105] HRMS (ESI+): Calcd for 346.1186 [M+Na]+ (C17H18ClNO3Na). Found 346.1188. + (C 17 H 22 ClNO3Na). Found 346.1188. [α] D 20 : (-)-60.7° (c 1.0, CH2Cl2).

[0106] <Example 5: Synthesis of tert-Butyl ((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8)>

Chem.

[0107] 11H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.34 (ddd, J = 8.8, 7.1, 1.4 Hz, 2H), 7.29 - 7.18 (m, 1H), 6.60 (s, 1H), 4.12 (dd, J = 11.8, 6.7 Hz, 1H), 3.87 (d, J = 14.3 Hz, 1H), 3.38 (s, 1H), 2.36 (ddq, J = 13.1, 6.5, 3.2 Hz, 1H), 1.74 (ddt, J = 7.8, 5.7, 2.8 Hz, 2H), 1.69 - 1.59 (m, 1H), 1.59 - 1.40 (m, 1H), 1.30 (s, 9H).

[0108] 13 13C NMR (100 MHz, CDCl3) δ 209.9, 153.3, 134.1, 133.8, 131.4, 131.0, 129.7, 126.3, 79.4, 72.4, 66.7, 40.4, 38.8, 28.2, 19.6.

[0109] HRMS (ESI+): Calculated value 362.1135 [M+Na] + (C 17 H 22 ClNO4Na). Measured value 362.1134. [α] D 20 : (+)-60.7°(c 1.0, CHCl3).

[0110] <Example 6: Synthesis of tert-Butyl ((1R,3R)-1-(2-Chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8A)>

Chemical Structure

[0111] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 8.5, 6.9 Hz, 2H), 7.32 - 7.21 (m, 1H), 6.60 (s, 1H), 4.12 (ddd, J = 11.5, 8.9, 6.3 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.37 (d, J = 6.5 Hz, 1H), 2.36 (ddq, J = 13.0, 6.5, 3.2 Hz, 1H), 1.74 (dq, J = 6.4, 3.2, 2.5 Hz, 2H), 1.63 (dq, J = 16.8, 9.2, 8.2 Hz, 1H), 1.59 - 1.40 (m, 1H), 1.30 (s, 9H).

[0112] 13 C NMR (100 MHz, CDCl3) δ 209.9, 153.3, 134.1, 133.8, 131.4, 131.0, 129.7, 126.3, 79.4, 72.4, 66.7, 40.4, 38.8, 28.2, 19.5.

[0113] HRMS (ESI+): expected 362.1135 [M+Na] + (C 17 H 22 ClNO4Na). Found value: 362.1134. [α] D 20 : (-)-63.7°(c1.0, CHCl3).

[0114] Example 7: Synthesis of (2S,6S)-(+)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone hydrochloride ((2S,6S)-(+)-hydroxynorketamine hydrochloride) (17) [ka] (17) To a solution of tert-butyl ((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 8 (4.85 grams) in dichloromethane (10 mL) was added trifluoroacetic acid (11.0 mL, 10 eq.). The reaction was stirred at room temperature for 1 hour. The solvent and trifluoroacetic acid (TFA) were then removed by rotary evaporation. The resulting TFA salt was dissolved in water, washed with a mixture of 50 / 50 saturated aqueous sodium bicarbonate and saturated aqueous potassium carbonate, and extracted with ethyl acetate (2x) to give the free base. The ethyl acetate was removed by rotary evaporation. Ethyl acetate (4 mL) was added, followed by HCl in dioxane (4.0 M, 6.0 mL). A white solid precipitated out. The suspension was agitated for 30 seconds, then the solid was filtered off and dried under vacuum to give the desired final product (17).

[0115] 1 H NMR (400 MHz, MeOD) δ 7.92 - 7.81 (m, 1H), 7.66 - 7.50 (m, 3H), 4.28 (dd, J = 11.7, 6.6 Hz, 1H), 3.19 (dd, J = 14.0, 3.0 Hz, 1H), 2.30 (dddd, J = 12.2, 6.6, 4.1, 2.3 Hz, 1H), 1.80 - 1.70 (m, 2H), 1.68 - 1.52 (m, 2H).

[0116] 13 C NMR (100 MHz, MeOD): δ 206.8, 134.0, 132.1, 131.6, 130.5, 130.0, 128.3, 73.0, 67.0, 38.4, 37.1, 18.7.

[0117] Chiral HPLC: 98.3% ee (Chiralpak AD column, 60% ethanol in hexane, 1.0 mL / min, rt = 6.0 min.)

[0118] HRMS (ESI+): Expected value 240.0786 [M+H] + (C 12 H 15 ClNO2). Found value: 240.0782. [α] D 20 : (+)-95°(c 1.0, H2O).

[0119] <Example 8: Synthesis of (2R,6R)-(-)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone hydrochloride (17A) ((2R,6R)-(-)-hydroxynorketamine hydrochloride)> [ka] (17A) The title compound was prepared in a manner similar to that of (2S,6S)-(+)-hydroxynorketamine hydrochloride utilizing tert-butyl ((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (17A) instead of the S,S-enantiomer.

[0120] 1 H NMR (400 MHz, MeOD): δ 7.94 - 7.83 (m, 1H), 7.62 - 7.53 (m, 3H), 4.29 (dd, J = 11.6, 6.7 Hz, 1H), 3.19 (dd, J = 14.0, 3.0 Hz, 1H), 2.30 (dddd, J = 12.2, 6.6, 4.1, 2.3 Hz, 1H), 1.99 - 1.82 (m, 2H), 1.82 - 1.56 (m, 2H) ppm.

[0121] 13C NMR (100 MHz, MeOD): δ 206.8, 134.0, 132.1, 131.6, 130.5, 130.1, 128.3, 73.3, 67.0, 38.4, 37.2, 18.7 ppm.

[0122] Chiral HPLC: 98.3% ee (Chiralpak AD column, 60% ethanol in hexane, 1.0 mL / min, rt = 7.9 min)

[0123] HRMS (ESI+): expected 262.0605 [M+Na] + (C 12 H 14 ClNO2Na). Measured value: 262.0605 [α] D 20 : (-)-92°(C=1.0, H2O).

[0124] Example 9: Synthesis of 6,6-dideuteroketamine hydrochloride (19) [ka] (19) Sodium deuterium oxide (30% in deuterium oxide, 3.0 mL) was added to a solution of ketamine hydrochloride racemate (0.80 grams, 2.9 mmol) in a mixture of tetrahydrofuran (8.0 mL) and deuterium oxide (3.0 mL). The reaction was heated by microwave irradiation at 120° C. for 2 hours in a sealed vial. The reaction was cooled, extracted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic phase was removed and the solvent was removed by rotary evaporation to give the crude product. Purification by reverse phase liquid chromatography (5% to 95% acetonitrile in water with 0.1% trifluoroacetic acid) gave the purified TFA salt. The free base was formed and the TFA salt was isolated by washing with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The HCl salt was formed by adding HCl (4.0 M in dioxane) and the resulting white solid was filtered to give the title compound as a white solid.

[0125] 1 H NMR (400 MHz, MeOD): δ7.94-7.88 (m, 1H), 7.66-7.57 (m, 3H), 3.41-3.34 (m, 1H), 2.38 (s, 3H), 2.27-2.20 (m, 1H), 1.93-1.83 (m, 2H), 1.83-1.69 (m, 2H).

[0126] 13 C NMR (100 MHz, MeOD): δ 208.6, 136.1, 134.1, 133.6, 133.5, 129.9, 129.4, 73.8, 40.3 (septet, J C-D = 21 Hz, 1C), 37.6, 31.2, 28.1, 23.0.

[0127] HRMS (ESI+): Expected value 240.1119 [M+H] + , (C 13 H 15 D2ClNO). Found value 240.1120

[0128] Example 10: X-ray crystallography of (2S,6S)-(+)-hydroxynorketamine hydrochloride Single crystal X-ray diffraction studies were performed on MoK α Diffraction measurements were performed on a Bruker Kappa APEX-IICCD diffractometer equipped with a 1000 nm radiation (λ=0.71073 Å). Crystals of the target compounds were grown by slow evaporation of a 50 / 50 dichloroethane / methanol solution. A 0.227×0.215×0.106 mm colorless block piece was mounted in a Cryoloop containing Paratone oil. Data were collected using φ and ω scans at 100(2) K in a nitrogen gas stream. The crystal-to-detector distance was 40 mm and the exposure time was 5 seconds per frame using a scan width of 2.0°. Data collection was 100% complete for 25.00°θ. A total of 9466 reflections were collected covering the indices -9≦h≦9, -9≦k≦9, -14≦l≦14. 2949 reflections gave an R of 0.0376. intand was found to be symmetry independent. Indexing and unit cell refinement indicated a basic monoclinic lattice. The space group was found to be P21. Data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) gave a complete phase model consistent with the proposed structure.

[0129] All non-hydrogen atoms were anisotropically refined by full-matrix least-squares (SHELXL-2014). All carbons bonded to hydrogen atoms were placed using the riding model. Their positions were constrained relative to their parent atoms in SHELXL-2014 using the appropriate HFIX command. All other hydrogen atoms (H-bonds) were shown in a separate map. Their relative positions were restrained using the DFIX command and refined without restraining these heats. The absolute stereochemistry of the molecule was established by anomalous dispersion using Parsons' method with a Flack parameter of -0.001. A diagram of the crystal structure is shown in Figure 1. The crystallographic data are summarized in Tables 1-6.

[0130] [Table 1]

[0131] [Table 2]

[0132] [Table 3]

[0133] [Table 4]

[0134] [Table 5]

[0135] [Table 6]

[0136] [Table 7]

[0137] Example 11: X-ray crystallography of (2R,6R)-hydroxynorketamine hydrochloride Single crystal X-ray diffraction studies were performed on MoK α The diffractometer was equipped with a Bruker Kappa APEX-IICCD diffractometer equipped with a 1000 nm NMR spectroscopy (NMR spectroscopy) radiation (λ = 0.71073 Å). Crystals of the target compounds were grown by slow evaporation of an isopropanol solution. A 0.157 × 0.131 × 0.098 mm colorless block piece was mounted in a Cryoloop containing Paratone oil. Data were collected using φ and ω scans at 100(2) K in a nitrogen gas stream. The crystal-to-detector distance was 40 mm and the exposure time was 3 seconds per frame using a scan width of 2.0°. Data collection was 100% complete for 25.00°θ. A total of 7618 reflections were collected covering the indices, -9 ≤ h ≤ 9, -9 ≤ k ≤ 9, -14 ≤ l ≤ 14. The 2927 reflections gave an R of 0.035. int and was found to be symmetry independent. Indexing and unit cell refinement indicated a basic monoclinic lattice. The space group was found to be P21. Data were integrated using the Bruker SAINT software program and scale corrected using the SADABS software program. A direct solution (SHELXT) gave a complete phase model consistent with the proposed structure.

[0138] All non-hydrogen atoms were anisotropically refined by full-matrix least-squares (SHELXL-2014). All carbons bonded to hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atoms in SHELXL-2014 using the appropriate HFIX command.

[0139] All other hydrogen atoms (H-bonds) are shown on a separate map. Their relative positions were restrained using the DFIX command and refined without restraining these heats. The absolute stereochemistry of the molecule was established by anomalous dispersion using the Parsons method with a Flack parameter of 0.023(32). A diagram of the crystal structure is shown in Figure 2. The crystallographic data are summarized in Tables 7-12.

[0140] [Table 8]

[0141] [Table 9]

[0142] [Table 10]

[0143] [Table 11]

[0144] [Table 12]

[0145] [Table 13]

[0146] [Table 14]

[0147] Example 12: (2R,6R)-hydroxynorketamine hydrochloride XRPD > The powder X-ray diffraction spectrum of (2R,6R)-hydroxynorketamine hydrochloride is shown in Figure 3. XRPD It was added to the sample holder.

[0148] A Rigaku Smart-Lab X-ray diffraction system was set up for reflection Bragg-Brentano geometry with an X-ray beam at the source. The x-ray source was a Cu LongFineFocus tube operated at 40 kV and 44 ma. The source provides an incident beam profile at the sample that varies from a narrow line at high angles to a wide rectangle at low angles. Beam-tuning slits are used at the X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and perpendicular to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits, with the sample itself acting as the focusing component for the optics. The intrinsic resolution of the Bragg-Brentano geometry is controlled in part by the diffractometer radius and width of the receiving slits used. Typically, the Rigaku Smart-Lab is operated to obtain peak widths of less than 0.1° 2θ. The longitudinal divergence of the X-ray beam is controlled by 5.0 degree Soller slits in both the incident and diffracted beam paths. Powder samples were prepared in a low background Si holder using light finger pressure to keep the sample surface flat and at the same height as the reference plane of the sample holder.

[0149] The powder was gradually pressed using a sample flattening tool and the sample holder was placed into the automatic sample changer. Each sample was analyzed from 2 to 40° 2θ using a continuous scan of 6° 2θ per minute with an effective step size of 0.02° 2θ.

[0150] Run parameters: Solar (inc.) 5.0 deg, IHS 10.0 mm, SS 1.250 deg, DS 1.250 deg, Solar (rec) 5.0 deg, RS 0.3 mm, scan axis theta / 2-theta, continuous mode, start (deg) 3.0, stop (deg) 45.0, step (deg) 0.020, speed (deg / min) 2.5, spin-yes, voltage (kV) 40, current (mA) 15. The spectrum demonstrates the following characteristic peaks (2θ):

[0151] [Table 15]

[0152] Example 13: TGA and DSC of (2R,6R)-hydroxynorketamine hydrochloride Thermogravimetric and differential scanning calorimetry plots for (2R,6R)-hydroxynorketamine hydrochloride are shown in Figure 4. For DSC, 1-3 mg of (2R,6R)-HNK was weighed into a TZero pan. A TZero lid was placed on the pan and pressure was applied slowly. The pan was then transferred to the DSC and analyzed at 10°C / min up to 300°C. A DSC standard without HNK was prepared using the same procedure. For TGA, the standard aluminum pan was placed into a platinum TGA pan and the weight of the blank was subtracted from the instrument. 1-5 mg of (2R,6R)-HNK was added to the standard aluminum pan and analyzed at 10°C / min up to 300°C. The sample showed a 0.02% weight loss by approximately 125°C. This weight loss is likely due to residual solvent and suggests that the material is anhydrous. The onset of melting was observed at 223.017°C.

[0153] <Example 14: Synthesis of 2-chlorophenyl cyclopentyl ketone> [ka] Compound 1 (4.00 kg, 21.5 mol) was dissolved in MeOH (40.0 L). Compound 1-2 (1.90 kg, 22.6 mol, 2.00 L) was then added dropwise into the mixture. After addition, the reaction mixture was stirred at 20° C. under N2 atmosphere for 12 h. TLC (PE:EA=5:1) showed that the starting material was consumed and the desired compound was detected. A precipitate was formed. The reaction mixture was filtered, the cake was collected, and then dried to give compound 2 (5.00 kg, 19.8 mol, 92.2% yield) as a white solid. [ka]

[0154] A solution of compound 1-4 (1.51 kg, 10.8 mol, 1.34 L), compound 2 (3 kg, 11.9 mol) and Cs2CO3 (5.28 kg, 16.2 mol) in 1,4-dioxane (40.0 L) was stirred at 100-110 °C for 48 h. TLC (PE:EA=5:1) showed that the starting material was consumed and the desired compound was detected. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was triturated with PE (20 L) to give compound 3 (2.00 kg, crude) as a red oil.

[0155] Example 15: Preparation of norketamine [ka] Compound 4 (300 g, 1.15 mmol, HCl) was dissolved in diphenyl ether (3.00 L), and the mixture was stirred at 170-185 °C for 15 min. TLC (PE:EA = 1:1, starting material: R f =0.6, product: R f=0.5) indicated that the starting material was consumed and one new spot was detected. The reaction mixture was cooled to 25-30°C, water (6 L) was added, and then filtered. The filtrate was extracted with EtOAc (2 L x 3). The aqueous layer was adjusted to pH = 8-9 with saturated Na2CO3 solution, then extracted with EtOAc (2 L x 2), the combined organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 13 (1.10 kg, 61.0% yield) as a yellow solid.

[0156] Example 16: Preparation of TERT-butyl ((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate [ka] Compound 6 (200 g, 485 mmol) was dissolved in THF (4.00 L) and H2O (200 mL) and then added to formic acid (200 mL, 98% purity) and the mixture was stirred at 15 °C for 1 h. HPLC showed that the starting material was consumed and the desired compound was detected. The reaction mixture was quenched by adding saturated Na2CO3 (2 L) and saturated NaHCO3 (2 L) and then extracted with EtOAc (2 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1 to 8:1) to give a yellow gum. The gum was then triturated with PE (500 mL) to give compound 7 (60 g, 169 mmol, 34.8% yield) as a white solid.

[0157] Example 17: Deprotection in ethyl acetate to obtain 2R,6R-hydroxynorketamine hydrochloride [ka] Compound 7 (150 g, 441 mmol) was dissolved in EtOAc (2.00 L). Then HCl / EtOAc (4 M, 331 mL) was added to the mixture under N2 at 15° C. After the addition, the reaction mixture was stirred at 15° C. for 12 h. A precipitate formed. TLC (PE:EA=2:1) ​​showed that the starting material was consumed and the desired compound was detected. The mixture was filtered, washed with EtOAc (1 L), then PE (1 L), and dried under vacuum to give a white solid. The white solid was combined with another batch and then triturated with EtOAc (3.5 L) and MeOH (100 mL) to give compound 5, 2R,6R-hydroxynorketamine hydrochloride, as a white solid.

[0158] Example 18: Preparation of (1S,3R)-3-((TERT-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate (10A) [ka] (10A) tert-Butyl ((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8A) (2.82 grams, 8.30 mmol) was placed in a round bottom flask equipped with a stir bar. Dichloromethane (20 ml) was added followed by pyridine (1.31 grams, 16.6 mmol). The reaction was stirred until all reagents were dissolved and then placed under a nitrogen atmosphere and cooled to 0° C. Trifluoromethanesulfone anhydride (1.0 M in dichloromethane, 9.43 mL, 9.43 mmol) was then added via syringe. The reaction was stirred at 0° C. for 45 minutes and then quenched by pouring into saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane and the solvent removed by rotary evaporation to give the crude triflate (9A), which was used without further purification. The triflate was unstable and had to be used immediately or stored at -80°C.

[0159] The crude triflate (3.92 grams, 8.3 mmol for 100% yield) was then dissolved in dimethylformamide (50 ml). 4-Nitrobenzoic acid (5.55 grams, 33.2 mmol) was then added followed by potassium carbonate (1.15 grams, 8.30 mmol). The suspension was stirred vigorously at room temperature for 16 hours. The reaction was then poured into a separatory funnel containing diethyl ether (200 ml) and water (100 ml). The organic phase was washed twice with water (100 ml) and once with saturated aqueous sodium chloride solution (100 ml). The organic phase was removed and the solvent removed by rotary evaporation. Purification by silica gel chromatography (0% to 100% ethyl acetate in diethyl ether) gave the title compound.

[0160] 1 H NMR (400 MHz, chloroform-d) δ 8.23 ​​- 8.11 (m, 2H), 7.95 - 7.85 (m, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.20 - 7.14 (m, 1H), 5.99 (s, 1H), 5.93 (dd, J = 8.7, 4.9 Hz, 1H), 3.19 --3.09 (m, 1H), 2.43 - 2.31 (m, 2H), 2.27 - 2.00 (m, 3H), 1.32 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 199.5, 163.3, 153.9, 150.5, 136.2, 134.8, 133.6, 131.3, 130.9, 129.7, 128.6, 126.4, 123.3, 80.5, 76.2, 68.5, 37.9, 33.8, 28.0, 18.9. HRMS (ESI+): expected 511.1242 [M+Na + ] (C 24 H 25 ClN2NaO7 + ). Actual value: 511.1248. [α] D 20 : + 9.5°(c 1.0, chloroform).

[0161] Example 19: Preparation of TERT-butyl ((1R,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (11A) [ka] (11A) (1S,3R)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate (10A) (2.00 grams, 4.09 mmol) was dissolved in methanol (50 ml). The reaction was cooled to 0° C. and potassium carbonate (0.565 mg, 4.09 mmol) was added. The reaction was stirred at 0° C. for 30 minutes. The reaction was then quenched by pouring into a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, the organic layer was removed, and the solvent was removed by rotary evaporation. Purification by silica gel chromatography (0% to 100% ethyl acetate in hexanes) afforded the desired product (11A) in 65% yield.

[0162] 1 H NMR (400 MHz, chloroform-d) δ 7.45 - 7.40 (m, 1H), 7.40 - 7.33 (m, 1H), 7.33 - 7.23 (m, 2H), 5.28 (s, 1H), 4.65 (dd, J = 12.1, 6.5 Hz, 1H), 3.02 - 2.88 (m, 1H), 2.50 - 2.40 (m, 1H), 2.19 - 2.00 (m, 2H), 1.85 - 1.75 (m, 1H), 1.75 - 1.64 (m, 1H), 1.38 (s, 1H) 13 C NMR (101 MHz, cdcl3) δ 203.4, 154.3, 136.6, 133.4, 131.8, 129.1, 127.7, 126.7, 81.2, 72.7, 67.8, 38.3, 36.7, 28.1, 19.1 HRMS (ESI+): expected 362.1130 [M+Na + ] (C17 H 22 ClNaNO4 + ). Actual value: 362.1139. [α] D 20 : -2.3°(c 1.0, chloroform).

[0163] Example 20: Preparation of (2R,6S)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one (12A) [ka] (12A) tert-Butyl ((1R,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (11A) (860 mg, 2.5 mmol) was dissolved in dichloromethane (8.0 ml) and cooled to 0° C. Trifluoroacetic acid (4.0 ml, 52 mmol) was then added. The reaction was stirred at 0° C. for 45 minutes. The solvent and trifluoroacetic acid were then removed by rotary evaporation. Ethyl acetate and a saturated potassium phosphate buffer at pH 7 were added to the crude material, and the material was transferred to a separatory funnel where it was extracted twice with ethyl acetate while maintaining the pH between 6 and 7. The organic phase was removed and the solvent was removed by rotary evaporation to give a crude white solid. This solid was purified by reverse phase high pressure liquid chromatography (MeCN-HO mobile phase with 0.1% TFA). The desired fraction was neutralized with pH 7 buffer and extracted twice with ethyl acetate, the organic phase was removed and the solvent was removed by rotary evaporation to give a white solid. The solid was dissolved in ethanol and the ethanol was removed by rotary evaporation to give the desired product. The absolute configuration was verified by single crystal x-ray crystallography.

[0164] 1H NMR (400 MHz, chloroform-d) δ 7.64 - 7.58 (m, 1H), 7.43 - 7.36 (m, 1H), 7.36 - 7.23 (m, 2H), 4.89 (dd, J = 11.8, 6.5 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.46 - 2.42 (m, 1H), 2.22 - 2.08 (m, 1H), 1.98 (ddt, J = 14.1, 3.9, 2.5 Hz, 1H), 1.93 - 1.80 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 210.3, 141.0, 133.0, 131.1, 129.1, 127.1 (2C), 72.3, 64.9, 39.4, 35.3, 19.4. HRMS (ESI+): Expected value 240.0786 [M+H + ] (C 12 H 15 ClNO2 + ). Actual value: 240.0794. [α] D 20 : +75.4°(c 1.0, chloroform)

[0165] Example 21: Preparation of (1R,3S)-3-((TERT-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate (10) [ka] Compound 10 was synthesized using tert-butyl ((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate, compound 8, as the starting material.

[0166] 1H NMR (400 MHz, chloroform-d) δ 8.27 - 8.10 (m, 2H), 7.92 (s, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.32 (td, J = 7.6, 1.6 Hz, 1H), 7.27 - 7.12 (m, 2H), 6.03 (s, 1H), 5.94 (dd, J = 8.8, 4.9 Hz, 1H), 3.23 - 2.99 (m, 1H), 2.37 (dq, J = 12.5, 6.2 Hz, 2H), 2.28 - 1.92 (m, 3H), 1.33 (s, 9H). 13 C NMR (101 MHz, cdcl3) δ 200.2, 163.4, 154.0, 150.7, 136.2, 134.8, 133.8, 131.4, 131.0, 129.2, 128.9, 126.5, 123.4, 80.8, 76.5, 68.6, 38.1, 34.2, 28.2, 18.9. [α] D 20 : -11°(c 1.0, chloroform).

[0167] Example 22: Preparation of TERT-butyl ((1S,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (11) [ka] (11) The compound was synthesized in a similar manner to its enantiomer (11A) using (1R,3S)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate as the starting material.

[0168] 1H NMR (400 MHz, chloroform-d) δ 7.59 - 7.21 (m, 4H), 5.15 (s, 1H), 4.71 - 4.55 (m, 1H), 3.63 (d, J = 4.6 Hz, 1H), 3.04 - 2.90 (m, 1H), 2.47 (ddq, J = 12.9, 6.4, 3.2 Hz, 1H), 2.23 - 2.00 (m, 2H), 1.95 - 1.68 (m, 2H), 1.39 (s, 9H). 13 C NMR (101 MHz, cdcl3) δ 203.5, 154.4, 136.7, 133.6, 132.0, 129.3, 127.9, 126.9, 72.9, 68.0, 38.5, 36.9, 28.3, 19.3, HRMS (ESI+): expected 362.1130 [M+Na + ] (C 17 H 22 ClNaNO4 + ). Actual value: 362.1135. [α] D 20 : +1.2°(c 1.0, chloroform).

[0169] Example 23: Preparation of (2S,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one (12) [ka] (12) Compound 12 was synthesized in a manner similar to its enantiomer (12A) using tert-butyl ((1S,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate as the starting material.

[0170] 1H NMR (400 MHz, chloroform-d): 7.61 (dd, J = 1.9, 7.8 Hz, 1H), 7.38 (dd, J = 1.5, 7.7 Hz, 1H), 7.30 (dt, J = 1.5, 7.7 Hz, 1H), 7.24 (dt, J = 1.9, 7.7 Hz, 1H), 4.89 (dd, J = 7.0, 12 Hz, 1H), 3.52 (bs, 1H), 2.51 (dt, J = 4.4 Hz, 13.6 Hz, 1H), 2.48-2.40 (m, 1H), 2.22-2.07 (m, 1H), 1.99-1.82 (m, 1H), 1.91-1.78 (m, 4H). 13 C NMR (101 MHz, cdcl3) δ 210.3, 141.3, 132.9, 130.9, 128.8, 126.9 (2C), 72.0, 64.6, 39.4, 35.2, 19.4.HRMS (ESI+): Expected value 240.0786 [M+H + ] (C 12 H 14 ClNNaO2 + ). Found value 240.0786. Optical rotation: -73.6°(c 1.0, chloroform).

[0171] Example 24: Recrystallization of 2R,6R-hydroxynorketamine 100.25 grams of 2R,6R-hydroxynorketamine hydrochloride was dissolved in 100 mL of water.

[0172] Acetone (2000 ml) was added at a rate of 0.75 equivalents (75 ml) per minute. Nucleation was observed at 5 minutes and 20 seconds. The reaction was stirred for 2 hours, then filtered and dried in vacuum overnight to give the final product in good yield.

[0173] [Specific embodiment] Embodiment 1. A crystalline form of (2R,6R)-hydroxynorketamine hydrochloride characterized by single crystal parameters approximately equal to the following: a=7.35Å alpha=90° b=7.49Å beta=96.87° c= 11.34 Å Gamma=90° V=621.02Å 3 The lattice dimensions, including Space group = P1211, crystal system = monoclinic, molecules per unit cell = 2 , density (calculated value) = 1.477 mg / m 3 .

[0174] Embodiment 2. The crystalline form of embodiment 1, characterized in that it does not contain detectable amounts of other crystalline forms of hydroxynorketamine or hydroxynorketamine salts as determined by x-ray powder diffraction.

[0175] Embodiment 3. A crystalline form of (2S,6S)-hydroxynorketamine hydrochloride characterized by single crystal parameters approximately equal to the following: a=7.35Å alpha=90° b=7.48Å beta=96.87° c=11.34Å gamma=90° V=619.32Å 3 The lattice dimensions, including Space group = P1211, crystal system = monoclinic, molecules per unit cell = 1, density (calculated) = 1.481 Mg / m 3 .

[0176] Embodiment 4. The crystalline form of embodiment 3, characterized in that it does not contain detectable amounts of other crystalline forms of hydroxynorketamine or hydroxynorketamine salts as determined by x-ray powder diffraction.

[0177] Embodiment 5. A method for chiral resolution of norketamine comprising adding (D)-(R)-pyroglutamic acid to racemic norketamine in a solvent to form solid (S)-norketamine D-pyroglutamate.

[0178] Embodiment 6. The method of embodiment 5, further comprising converting (S)-norketamine D-pyroglutamate to (S)-norketamine.

[0179] Embodiment 7. A method for chiral resolution of norketamine, comprising adding (L)-(S)-pyroglutamic acid to racemic norketamine in a solvent to form solid (R)-norketamine L-pyroglutamate, and converting (R)-norketamine L-pyroglutamate to (R)-norketamine.

[0180] Embodiment 8. A method for producing (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a salt thereof, comprising: [ka] Formula Ia [ka] Formula Ib treating a compound of formula Ia or formula Ib with a base, then with a trialkylsilyl chloride, then with a peroxy compound, and then optionally with an acid or a fluoride source to obtain a compound of formula IIa if treated with formula Ia, or a compound of formula IIb if treated with formula Ib, wherein the compound of formula IIa or formula IIb contains a carbamate bond; [ka] Formula IIa [ka] Formula IIb and Cleavage of the carbamate bond of the compound of formula IIa or formula IIb to obtain (2R,6R)-hydroxynorketamine when the carbamate bond of the compound of formula IIa is cleaved, or (2S,6S)-hydroxynorketamine when the carbamate bond of the compound of formula IIb is cleaved. [ka] (2R,6R)-Hydroxynorketamine [ka] (2S,6S)-Hydroxynorketamine; (In the formula, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, benzyl, 4-methoxybenzyl, or 2-trimethylsilylethyl. The method according to claim 1, further comprising:

[0181] Embodiment 9. The method of embodiment 8, comprising: 1 is tert-butyl, and cleaving the carbamate bond comprises treating the compound of Formula IIa or Formula IIb with an acid.

[0182] Embodiment 10. The method of embodiment 9, wherein the acid is trifluoroacetic acid.

[0183] Embodiment 11. The method of embodiment 8, further comprising treating (2R,6R)-hydroxynorketamine with hydrochloric acid to produce (2R,6R)-hydroxynorketamine hydrochloride, or treating (2S,6S)-hydroxynorketamine with hydrochloric acid to produce (2S,6S)-hydroxynorketamine hydrochloride.

[0184] Embodiment 12. The method according to embodiment 8, wherein the base used to treat the compound of formula Ia or formula Ib is a strong base.

[0185] Embodiment 13. The method of embodiment 12, wherein the strong base is lithium diisopropylamide, sodium hexamethyldisilazane, potassium hexamethyldisilazane, or sec-butyllithium, and the compound of formula Ia or formula Ib is treated with the strong base at a temperature below 0°C.

[0186] Embodiment 14. The method of embodiment 8, wherein treating the compound of formula Ia or formula Ib with a base comprises treating the compound of formula Ia or formula Ib with lithium diisopropylamide at a temperature less than -50°C.

[0187] Embodiment 15. The method according to any one of embodiments 8 to 14, wherein the trialkylsilyl chloride is trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, or triisopropylsilyl chloride.

[0188] Embodiment 16. The method of embodiment 15, wherein the trialkylsilyl chloride is trimethylsilyl chloride.

[0189] Embodiment 17. The method according to any one of embodiments 8 to 16, wherein the peroxy compound is a peroxyacid or a peroxide.

[0190] Embodiment 18. The method of embodiment 17, wherein the peroxy compound is meta-chloroperoxybenzoic acid, peroxybenzoic acid, peracetic acid, dimethyldioxirane, tert-butyl hydroperoxide, or hydrogen peroxide.

[0191] Embodiment 19. The method according to any one of embodiments 8 to 18, wherein after treatment with a peroxy compound, the compound of formula Ia or formula Ib is treated with tetra-n-butylammonium fluoride.

[0192] Embodiment 20. The method according to any one of embodiments 8 to 19, wherein the peroxy compound is meta-chloroperoxybenzoic acid.

[0193] Embodiment 21. The method of any one of embodiments 8 to 20, wherein (R)-norketamine is administered as (R 1O2C)2O or R 1 or reacting (S)-norketamine with (R 1 O2C)2O or R 1 2. The method of claim 1, further comprising reacting O2C-X to produce a compound of formula Ib, wherein X is a halogen.

[0194] Embodiment 22. The method of embodiment 21, comprising: 1 is tert-butyl, producing a compound of formula Ia comprises reacting (R)-norketamine with (tert-butyl-O2C)2O, and producing a compound of formula Ib comprises reacting (S)-norketamine with (tert-butyl-O2C)2O.

[0195] Embodiment 23. The method of embodiment 8, comprising: [ka] Formula Ia and treating the compound of formula Ia with lithium diisopropylamide, then with trimethylsilyl chloride, then with meta-chloroperoxybenzoic acid, then with tetra-n-butylammonium fluoride at a temperature below −50° C. to obtain a compound of formula IIa, 1 is tert-butyl), [ka] Formula IIa and the carbamate bond of formula IIa is cleaved by treatment with acid to give (2R,6R)-hydroxynorketamine; [ka] ((2R,6R)-Hydroxynorketamine) The method according to claim 1, further comprising:

[0196] Embodiment 24. The method according to any one of the embodiments, [ka] Formula Ib and treating the compound of formula Ib with lithium diisopropylamide, then with trimethylsilyl chloride, then with meta-chloroperoxybenzoic acid, then with tetra-n-butylammonium fluoride at a temperature below −50° C. to obtain a compound of formula IIb, 1 is tert-butyl), [ka] Formula IIB and The carbamate bond of formula IIb is cleaved by treatment with acid to give (2S,6S)-hydroxynorketamine. [ka] ((2S,6S)-Hydroxynorketamine) The method according to claim 1, further comprising:

[0197] Embodiment 25. A crystalline form of (2R,6R)-hydroxynorketamine, characterized in that it exhibits an XRPD spectrum of peaks characteristic of any combination of at least 4, at least 5, at least 8, at least 10, or at least 12, or at least 15 of the following (2θ) values: 12.1, 13.6, 14.1, 15.1, 15.6, 16.9, 18.0, 19.2, 19.5, 20.8, 22.1, 23.5, 24.0, 24.3, 24.6, 24.8, 25.2, 26.4, 27.0, 27.4, 27.7, 28.1, 29.9, 30.2, 31.5, 31.9, 32.4, 32.7, 33.5, 34.7, 36.5, 37.1, 37.7, 38.3, 38.7, 39.1, and 39.6.

[0198] Embodiment 26. A crystalline form of (2R,6R)-hydroxynorketamine, characterized in that it has an XRPD spectrum substantially as shown in FIG.

Claims

[Claim 1] A crystal of (2R,6R)-hydroxynorketamine hydrochloride, The crystal is characterized by single crystal parameters equal to the following: a = 7.35 Å alpha = 90° b = 7.49 Å beta = 96.87° c=11.34 Å gamma=90° Unit cell volume V = 621.02 Å ３ The unit cell dimensions, including Space group = P1211, crystal system = monoclinic, molecules per unit cell = 2, density (calculated) = 1.477 mg / m ３

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