High-purity pharmaceutical grade tasimeltheon

Abstract

We offer batches of high purity pharmaceutical grade tasimelteon. The present invention provides a batch of tasimelteon for pharmaceutical use that has been analyzed and shown to contain 0.15 wt% or less of one or more of seven identified impurities, preferably a batch of tasimelteon for pharmaceutical use that has been analyzed and shown to contain less than 0.15 wt% or none of any of the seven identified impurities.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 61 / 938,932, filed on February 12, 2014, and U.S. Provisional Patent Application No. 62 / 087,394, filed on December 4, 2014. Both applications are incorporated herein by reference.

Background Art

[0002] This disclosure generally relates to the synthesis of tasimelteon. In some embodiments, impurities are analyzed and managed to maintain them within the following preset specifications. The impurities may be by - products or degradation products.

[0003] Tasimelteon, that is, N - (((1R,2R)-2-(2,3 - dihydrobenzofuran - 4 - yl)cyclopropyl)methyl)-propionamide, is a melatonin agonist useful for the treatment of individuals suffering from certain sleep - related disorders.

[0004] The synthesis of tasimelteon is disclosed, for example, in Example 2 of U.S. Patent No. 5,856,529. The final - step synthesis in this example involves reacting ((1R,2R)-2-(2,3 - dihydrobenzofuran - 4 - yl)cyclopropyl)methanamine with propionyl chloride. The synthesis of the methanamine intermediate is described in Preparation 24 and involves reacting ((1R,2R)-2-(2,3 - dihydrobenzofuran - 4 - yl))cyclopropanecarboxaldehyde with hydroxylamine hydrochloride. The synthesis of the carboxaldehyde intermediate is described in Preparation 18 and involves cyclizing a propenoyl intermediate, specifically (1R,2R)-2-(2,3 - dihydrobenzofuran - 4 - yl)propenoyl)-2,10 - camphorsultam, with a palladium catalyst.

Summary of the Invention

Means for Solving the Problems

[0005] In one exemplary embodiment, the present invention is A process for synthesizing high-purity pharmaceutical grade tasimelteon, (a) Propionylation of ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof to obtain tasimelteon. (b) Crystallize the tasimeltheon produced in step (a), (c) Analyze the crystallized tasimelteon from step (b) for the presence of one or both of impurities 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide) and 6 (2-hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate), and (d)(i) If the crystallized tasimeltheon meets the pre-set specifications for impurity 5, impurity 6, or both, recover high-purity pharmaceutical grade tasimeltheon, or (d)(ii) A process comprising further purifying the tasimeltheon and repeating steps (c) and (d) or discarding the batch if the crystallized tasimeltheon does not meet predetermined specifications for impurity 5 or impurity 6 or both.

[0006] In another exemplary embodiment, the present invention relates to a process for preparing a batch of high-purity pharmaceutical-grade tasimelteon, (a) Batch of tasimeltheone synthesized under the manufacturing and quality control standards ("GMP conditions") N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7), To analyze the presence of one or more of these, and (b) If the batch satisfies a predetermined specification regarding the amount of one or more impurities 1, 2, 3, 4, 5, 6, and 7, the processing of tasimelteon is continued to prepare bulk tasimelteon active pharmaceutical ingredient for formulation, or (c) If the tasimeltheon does not meet the pre-set specifications, further purify the tasimeltheon (by recrystallization, grinding, extraction, or chromatography, etc.) and repeat steps (a) and (b), or discard the batch. Regarding the process, including the matter.

[0007] In another exemplary embodiment, further specifications for continuing the processing of tasimeltheon are predefined, for example, the tasimeltheon has a purity of 95.0% or more ("not less than:NLT") or 98.0%NLT (by area under the curve), and / or the amount of other impurities is 0.10 area% or less ("not more than:NMT"), each individually.

[0008] In another exemplary embodiment, the present invention relates to a process for preparing a batch of tasimelteon formulations (i.e., tasimelteon and excipients), wherein the release of a batch of tasimelteon bulk active pharmaceutical ingredient used in the manufacture of tasimelteon formulations depends on testing and application of acceptable standards for one or more of the following impurities: ·N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), ·N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), · 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), ·N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), ·N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), · 2-Hydroxy-6-(2-(propionamidomethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidomethyl)cyclopropyl)phenyl carbonate (impurity 6), N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7).

[0009] In further exemplary embodiments, the present invention relates to purified tasimeltheone that does not contain any of impurities 1 to 7 in concentrations greater than about 0.15%. In related exemplary embodiments, such compositions do not contain any related impurities (i.e., impurities structurally related to tasimeltheone, such as decomposition products or dimers) in concentrations greater than about 0.15% by weight. [Modes for carrying out the invention]

[0010] The synthesis of tasimelteon may result in multiple impurities after the final synthesis step. An exemplary synthesis of tasimelteon is a linear process that includes a methaneamine intermediate and four purification steps: one purification step for each of the three isolated intermediates and the unmicronized tasimelteon drug substance, as described below, via the process described in U.S. Patent No. 5,856,529. (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate (referred herein as Intermediate 3 or Step 9), (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide (referred herein as Intermediate 4 or Step 10), and the methaneamine intermediate (referred herein as Intermediate 5 or Step 11), and the tasimelteon (unmicronized) drug substance are each isolated by crystallization and, if necessary, recrystallized to improve purity.

[0011] The inventors have found that in the synthesis of tasimeltheone, certain impurities may form as both by-products and degradation products, and that such impurities can be suppressed or reduced to undetectable levels or acceptable detectable levels. While not wishing to be constrained by theory, the inventors identified some of these impurities based on mass spectrometry data, nuclear magnetic resonance data, and other data. The inventors have found that the above impurities may include one or more of the following: N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), and N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7).

[0012] Impurities 1-3 and 5-6 may be byproducts of a step in tasimeltheone synthesis, while impurities 4 and 7 may be degradation products.

[0013] Furthermore, the inventors have found that in the synthesis of tasimelteon, certain further impurities can arise as degradation products, reaction by-products, residual reagents, and residual intermediates. These further impurities can be suppressed or reduced to undetectable levels or acceptable detectable levels. Examples of these impurities include: (+)-dehydroabietylamine, propionyl chloride, propionic acid, ethyl propionate [presumably a further potential degradation product of propionyl chloride], ethyl diazoacetate, intermediates 2, 4, and 5, 4-vinyl-2,3-dihydrobenzofuran (VBF), 4-(2-chloroethyl)-2,3-dihydrobenzofuran (VBF-int-2), benzene, and heavy metals such as As, Al, Fe, Li, Ni, Ru, Pd, Mn, Rh, Cu, and Co.

[0014] Some such impurities, such as ethyl diazoacetate and propionyl chloride, are potentially genotoxic and thus must be suppressed to ppm levels in order to render bulk GMP tasimelteon suitable for formulation into bulk pharmaceutical compositions and subsequent dispensing into pharmaceutical dosage units.

[0015] Identifying such impurities facilitates product quality control and consistency. With knowledge of what these impurities are, manufacturers of tasimelteon can set specifications regarding the maximum allowable amounts of impurities in bulk GMP tasimelteon, and then formulate bulk GMP tasimelteon into bulk pharmaceutical compositions and subsequently dispense it into pharmaceutical dosage units.

[0016] Thus, in one aspect, the present invention includes batches of pharmaceutical-grade high purity tasimelteon that have been analyzed for the presence of any or each of these impurities and for which it has been determined that one or more of these impurities are less than a predetermined amount. The predetermined amount of these intermediates, i.e., the pre-set specifications, can be set to meet regulatory requirements. For example, the pre-set specifications for impurities 1-7 and further impurities may be 0.15 wt%. In a further embodiment, the pre-set specifications may be, for example, 0.10 area% in the case of unidentified impurities. In addition, the pre-set specifications may include ethyl diazoacetate (EDA) of 100 ppm or less (NMT) or 10 ppm or less (NMT).

[0017] Impurities are detectable, in particular, by analytical chemistry techniques such as chromatography techniques and mass spectrometry techniques. For example, HPLC, GC, or other chromatography methods can be used. In that case, the amount of one or each of the impurities can be determined based on wt% or the area under the curve.

[0018] As abbreviations for methods and techniques used herein, the following can be mentioned: high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC), supercritical fluid chromatography (SFC), gas chromatography (GC), Good Manufacturing Practice (GMP), current Good Manufacturing Practice (cGMP), not more than (NMT), and not less than (NLT).

[0019] As used herein, when referring to percent (%) purity, it is based on area. Such relative amounts are an approximation of wt%, but those skilled in the art know how to determine the amount in more accurate wt% if necessary.

[0020] The synthesis of tasimelteon is disclosed, for example, in Example 2 of U.S. Patent No. 5,856,529. The final step of the synthesis in that example involves reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine with propionyl chloride. The synthesis of the methaneamine intermediate is described in Preparation 24 and involves reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl))cyclopropanecarboxaldehyde with hydroxylamine hydrochloride. The synthesis of the carboxaldehyde intermediate is described in Preparation 18 and involves cyclizing the propenoyl intermediate, specifically ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)propenoyl)-2,10-camphorsultam with a palladium catalyst.

[0021] An alternative pathway for the methanamine intermediate or its salt (hereinafter referred to as intermediate 5) proceeds from (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate (intermediate 3) to (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxamide (intermediate 4), and then to intermediate 5 or its salt.

[0022] The synthesis of intermediate 2 by stereoselective cyclization of 4-vinyl-2,3-dihydrobenzofuran is described, for example, in U.S. Patent No. 7,754,902.

[0023] An exemplary final step synthesis of tasimeltheone from intermediate 5 is presented in Scheme 6 below. Generally speaking, this synthesis is (a) Propionylation of ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof to obtain tasimelteon. (b) Crystallize the tasimeltheon produced in step (a), (c) Analyze the crystallized tasimelteon from step (b) for the presence of one or both of impurities 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide) and 6 (2-hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate), and (d)(i) If the crystallized tasimeltheon meets the pre-set specifications for impurity 5, impurity 6, or both, recover high-purity pharmaceutical grade tasimeltheon, or (d)(ii) If the crystallized tasimeltheon does not meet the predetermined specifications for impurity 5, impurity 6, or both, further purify the tasimeltheon and repeat steps (c) and (d), or discard the batch.

[0024] In such a final step synthesis, the propionylation step may involve contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof with halogenated propionyl, propionyl anhydride, propionyl ester, propionylamide, propionylimidazolide, or propionic acid and a dehydrating agent or its product. Water is a byproduct of coupling ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine with propionic acid to form tasimelteon. The dehydrating agent, also known as a peptide coupling reagent, is an agent that activates propionic acid to promote the reaction with ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine and consumes the byproduct water. Commonly used dehydrating agents include, but are not limited to, dicyclohexylcarbodiimide (DCC), DCC and aminopyridine, N,N'-carbonyldiimidazole, chlorosilane, Amberlyst-15, MeSO2Cl-Et3N, BF3, TiC14, other Lewis acids, ArB(OH)2 type reagents, Sn[N(TMS)2], POCl3, molecular sieves, Lawson's reagent, and (MeO)2POCl.

[0025] Propionylation is carried out in the presence of an organic solvent (e.g., ter-butyl methyl ether) and a water-soluble base (e.g., NaOH). After the propionylation step but before the crystallization step, the tasimelteon mixture may be analyzed for the presence of intermediate 5 (or its free base or other salts). If the mixture does not meet the predetermined specifications for intermediate 5 (e.g., 0.15% or less or 0.10% or less), step (a) is repeated or the mixture is discarded. After the propionylation step but before the crystallization step, the tasimelteon mixture may be washed with a water-soluble base and the aqueous layer discarded. The washed mixture may then be distilled (e.g., in ethanol at about 58°C or less and at less than 100 mmHg). The crystallization step may include dissolving the tasimelteon by stirring and heating (e.g., about 35 to about 40°C) a mixture of tasimelteon and C1-C4 alkanols, and then cooling (e.g., to about 13 to about 17°C). The crystallization step may optionally include seeding.

[0026] In one embodiment, an exemplary tasimeltheone synthesis may involve first synthesizing several intermediates in the reaction scheme described below.

[0027] Synthesis of 4-(2-chloroethyl)-2,3-dihydrobenzofuran (VBF-int-2)

[0028] The synthesis of VBF-int-2 may involve contacting and reacting 2,3-bis(2-hydroxyethyl)phenol (triol) with N,N-dimethylchloromethyleneiminium chloride (Vilsmeyer's reagent) in an organic solvent, and then reacting the resulting N,N'-[(3-hydroxy-1,2-phenylene)-bis(ethane-2,1-diyloxymethylidene)]-bis(N-methylmethaneaminium)dichloride (VBF-int-1) with triethylamine in an organic solvent. Vilsmeyer's reagent can be prepared in situ from N,N-dimethylformamide (DMF) and oxalyl chloride. This reaction is shown in the following scheme.

[0029] [ka]

[0030] [Scheme 1] For example, the first reaction mixture can be prepared by slowly adding oxalyl chloride (approximately 2.45–2.55 equivalents) to a solution of DMF in CH3CN (approximately 2.45–2.55 equivalents) (acetonitrile (e.g., 16 wt% DMF)) while maintaining a batch temperature of -10±5°C. Stirring may be continued at this temperature for approximately 30–40 minutes to complete the in situ formation of Vilsmeyer's reagent (N,N dimethylchloromethyleneiminium chloride). While maintaining a batch temperature of -10±5°C, the triol (step 3) (1.00 equivalent; e.g., 30 kg) is added to the Vilsmeyer's reagent solution in several portions from an addition funnel. Stirring is continued at approximately -20–approximately -5°C for at least 90 minutes until testing by high-pressure liquid chromatography (HPLC) shows that less than 2.0% (NMT) of triol (step 3) remains in the solution. If necessary, the mixture may be sampled again at 150 minutes and the triol level may be tested again. Then, while maintaining the batch temperature at -10±5°C, a solution of Et3N (triethylamine) (approximately 3.8-4.1 equivalents) in CH3CN (e.g., 47 wt% Et3N) may be slowly added to the reaction mixture. This step is an exothermic step. The total volume of CH3CN may be approximately 5-17 L per kg of added triol (step 3), and in one embodiment, it may be 10 L / kg per kg of added triol (step 3). Once the addition is complete, the mixture may be heated to 55±5°C for 3-3.5 hours. Then the mixture is cooled to 25±5°C and analyzed by HPLC to obtain VBF-int-1 (step 4) Each may be stirred in up to 4 increments of up to approximately 1 hour until it is shown that the concentration is 2.0 area %NMT. Then, tap water (e.g., 2.3 L per 1 kg of triol (stage 3)) is added to the reaction mixture and stirring is continued for 30-40 minutes. The mixture is distilled at <100 torr at approximately 40°C until no more organic distillates are collected. Then, TBME (e.g., 5.6 kg per 1 kg of triol (stage 3)) and tap water (e.g., 3.2 L per 1 kg of triol (stage 3)) are added to the batch residue. The mixture is stirred for 30-40 minutes and allowed to settle for 30-40 minutes. The aqueous layer is removed.Slowly add the H3PO4 solution (8.5 wt%) in an aqueous brine solution (e.g., 5 kg of H3PO4 solution per 1 kg of triol (stage 3)) to the remaining organic layer. Stir the mixture for 30-40 minutes, and allow to settle for 30-40 minutes. Remove the aqueous layer again. The organic layer may be washed once or multiple times with tap water (e.g., 5 L per 1 kg of triol (stage 3)), stirring for approximately 30-40 minutes each time, allowing to settle for approximately 30-40 minutes, and removing the aqueous layer. After washing with tap water, the organic layer is distilled at <100 torr at approximately 40°C until no more distillate can be collected. The batch residue is subjected to short-pass distillation at 0.1-4 torr. Discard all distillates that boil below 105°C. Distillates that boil at 105-130°C are subjected to HPLC analysis. Materials that meet pre-defined specifications, such as having 95.0% or more (NLT) of VBF-int-2 (stage 5), are used directly in the next step.

[0031] Synthesis of 4-vinyl-2,3-dihydrobenzofuran (VBF) (Step 6)

[0032] The synthesis of VBF may involve contacting and reacting 4-(2-chloroethyl)-2,3-dihydrobenzofuran (VBF-int-2) with tetrabutylammonium hydroxide in the presence of an organic solvent. This reaction is shown in the following scheme.

[0033] [ka]

[0034] [Scheme 2] In one embodiment, tetrabutylammonium hydroxide (0.78 kg per kg of VBF-int-2 (step 5)) and potassium iodide (0.09 kg per kg of VBF-int-2 (step 5)) are added to a mixture of TBME (tert-butylmethyl ether) (5.60 kg per kg of VBF-int-2 (step 5)) and a 45% NaOH aqueous solution (4.80 kg per kg of VBF-int-2 (step 5)). In some embodiments, the amounts of NaOH, tetrabutylammonium hydroxide, and KI added are in the range of 7-10, 0.15-0.50, and 0.08-0.10 molar equivalents, respectively. The mixture may be heated to 50±5°C and stirred for approximately 3-3.5 hours. Subsequently, the mixture is cooled to 25±5°C and stirred at a maximum of 4 increments of NLT for 1 hour each until HPLC testing shows that VBF-int-2 (stage 5) is 1.0% NMT. ​​The mixture is allowed to settle for 20-30 minutes, and 40-60 L of aqueous layer is drained. A 16% HCl aqueous solution (e.g., no more than 6.2 kg per kg of VBF-int-2 (stage 5)) is slowly added to the remaining mixture until the pH of the mixture is 9.5-10.5. If necessary, a 4.5% NaOH aqueous solution is added to adjust the pH to this range. The mixture is then filtered using TBME (1 kg per kg of VBF-int-2 (stage 5)) to complete the transfer, and the filtrate may be allowed to settle for 20-30 minutes. The aqueous layer may then be removed. Add 8% Na2S2O3 (e.g., 4.3 kg of Na2S2O3 solution per 1 kg of VBF-int-2 (stage 5)) in a 9% brine aqueous solution to the organic layer, then stir the mixture for 10-15 minutes, allow to settle for 20-30 minutes, and remove the aqueous layer. Add 4% NaOH (e.g., 4.2 kg of NaOH solution per 1 kg of VBF-int-2 (stage 5)) in a 9% brine aqueous solution to the organic layer, then stir, allow to settle, and remove the aqueous layer. Then add quinol (e.g., 7 g or 1 mol) per 1 kg of VBF-int-2 (stage 5) to the organic layer, and stir the mixture for 20-30 minutes. Analyze the purity of the resulting solution by HPLC analysis. Materials that meet the pre-set purity specifications, e.g., VBF (stage 6) with 95.0 area %NLT, are used directly in the next step.HPLC analysis results are reported as wt / wt%.

[0035] Synthesis of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl (intermediate 3) (step 9))

[0036] The synthesis of intermediate 3 (step 9) may also involve asymmetric cyclopropanation of 4-vinyl-2,3-dihydrobenzofuran (VBF (step 6)) by contacting and reacting it with EDA in the presence of a chiral catalyst. Alternatively, the synthesis may involve hydrolysis of the ester group of 2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanecarboxylate ethyl ester (VEC-int-1 (step 7)), followed by improved resolution of 2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanecarboxylate (intermediate 2 (step 8)) with (+)-dehydroabiethylamine (DAA) in an organic solvent. This reaction is shown in the following scheme.

[0037] [ka]

[0038] [Scheme 3] In one embodiment, several processes can be used in the preparation to form intermediate 3.

[0039] A lithium diisopropylamide (LDA) solution may be prepared. For example, a solution of n-butyllithium (0.03 equivalents; 1 M in hexane) is slowly added to a solution of diisopropylamine (DISPA; 0.04 equivalents; e.g., 10 M) in THF at 5 ± 5 °C. After the addition is complete, stirring is continued at 5 ± 5 °C for 30 to 40 minutes. The resulting lithium diisopropylamide (LDA) solution is then used directly for the subsequent deprotonation of BTBSC(R,R)-(-)-N,N'bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine) as further described below.

[0040] The Ru catalyst may be prepared from BTBSC and LDA solutions. For example, the preparation may involve stirring a mixture of BTBSC (0.02 equivalents; e.g., 0.04 M) in THF (tetrahydrofuran) at 25±5°C for 30-40 minutes, and then cooling the mixture to 5±5°C. The LDA solution may then be slowly added to this mixture at 5±5°C, and the mixture may be stirred for approximately 60 minutes. To the resulting mixture, [Ru(p-cymene)Cl2)2 (0.02 equivalents, assuming 2 equivalents of Ru per 1 mole of [Ru(p-cymene)Cl2)2) is added in several portions. The reactor is purged three times with N2. The mixture is stirred at 25±5°C for 30-40 minutes. Finally, VBF (step 6) solution (approximately 0.01 equivalents) in TBME is added to this mixture. The resulting mixture is stirred at 20-25°C for at least approximately 8 hours. The resulting Ru catalyst mixture is used directly in the subsequent VBF cyclopropanation step.

[0041] VBF (Step 6) can undergo cyclopropanation. For example, in one embodiment, such preparation may involve adding toluene (e.g., 20 kg) to a VBF (Step 6) solution (1.00 equivalent) prepared in TBME as described in the previous steps (e.g., weight of solution (kg) = 8.9 / analyte%), and distilling the mixture at <100 torr and <50°C until the residue remaining in the reactor is about 20 L. Add toluene (e.g., 60 L) and distill the mixture again at <100 torr and <50°C until the residue remaining in the reactor is about 20 L. Cool the batch residue to 30±2°C and add the Ru catalyst prepared above. The amount of Ru catalyst added may be about 0.02 molar equivalents. Add the toluene solution of EDA to this mixture over 8-16 hours at 30±2°C. The amount of ethyl diazoethyl added may be about 2.5 molar equivalents. Once the addition is complete, stir the mixture at 30±2°C for at least approximately 3 hours. The material, which UPLC analysis has shown to have VBF (step 6) at approximately 2.0% NMT, is used directly in the next preparation step, which will be described in more detail below.

[0042] VEC-int-1 (step 7) can undergo saponification. A descriptive example may involve adding 45% aqueous NaOH (4 equivalents), 55% aqueous tetrabutylammonium hydroxide (TBAH; 0.45 equivalents), and tap water (e.g., 10 L) to the final reaction mixture derived from the cyclopropanation of VBF. The mixture is then stirred at 50-70°C for 16-18 hours until HPLC shows that VEC-int-1 (step 7) is <2.0%. If this limit is not met, stirring is continued at 50-70°C for 2-4 hours and the analysis is repeated. Once the limit is met, the mixture is cooled to 25-30°C. Tap water (e.g., 60.0 L) is added, the mixture is stirred for at least approximately 30 minutes, and allowed to settle for 30-40 minutes. The organic layer is discarded. TBME (e.g., 107.0 kg) is added to the resulting aqueous layer, and the mixture is cooled to 0-10°C. Add phosphoric acid (85% aqueous solution, e.g., 24.0 kg) slowly at 0-25°C until the pH of the aqueous layer reaches 4.0-4.5. If necessary, add 10% NaOH aqueous solution to adjust the pH within this range. Then, stir the mixture for at least approximately 30 minutes, allow to settle for another 30-40 minutes, and discard the aqueous layer. Add tap water (e.g., 70.0 L), stir the mixture for at least approximately 30 minutes, allow to settle again for approximately 30-40 minutes, and discard the aqueous layer. This tap water wash may be repeated, for example, up to three further washes may be used.

[0043] Finally, intermediate 3 (step 9) (DAA salt) may be formed. In a descriptive example, TBME (e.g., 22.9 kg per 1 kg of VBF (step 6)) and ethanol (EtOH; anhydrous, e.g., 4.49 kg per 1 kg of VBF (step 6)) may be added to the organic layer obtained in the above saponification preparation step. The ratio of intermediate 2 (step 8) to TBME may be within the range of 0.040 to 0.079 kg of intermediate 2 (step 8) per 1 L of TBME, and in further embodiments, TBME The intermediate 2 (step 8) setting point may be 0.040 kg per liter. In one embodiment, the ratio of TBME (kg):EtOH (kg) may be 7.78 to 9.08, and in a further embodiment, it may be 7.78. Next, (+)-dehydroabiethylamine (1.44 equivalents) as a 28% wt / wt solution in TBME may be added to the resulting mixture. In one embodiment, the amount of (+)-dehydroabiethylamine added may be 1.44 to 1.76 molar equivalents, and in a further embodiment, it may be 1.44 molar equivalents. The reaction mixture is heated to 45-55°C, stirred in NLT for 20 minutes, cooled to 25-30°C over a period of 2 hours in NLT, stirred in NLT at this temperature for 1 hour, heated to 45-55°C, stirred in NLT for 20 minutes, and cooled to 15-25°C over a period of 2 hours in NLT. The mixture may be stirred in NLT for 4 hours, cooled to 0-5°C for 1 hour in NLT, and stirred in NLT for 1 hour. The precipitated solid is collected by centrifugation, washed with TBME, and centrifuged for 20±5 minutes at maximum speed, for example. The collected wet cake is added to ethanol (anhydrous, e.g., 11.2 kg per 1 kg of VBF (step 6)) that has been cooled to 0-5°C. The mixture is stirred at this temperature for 30-40 minutes, and then centrifuged for 20±5 minutes at maximum speed, for example. This washed wet cake is subjected to purity analysis by HPLC. Materials that meet pre-defined specifications, e.g., (R,R)-trans-intermediate 3 (step 9) is 99.0 area % NLT and total impurities are 2.0% NMT, are NLT dried at 80 torr NMT and 60±5°C for 12 hours until the loss on drying (LOD) meets pre-defined specifications, e.g., the LOD is 2.0% NMT.Materials that do not meet these specifications are further dried using 80 torr NMT and NLT at 60±5℃ for 6 hours, and then resampled.

[0044] Release the material that meets the specifications. If it does not pass the purity test, process the wet cake again. The second process may include adding the wet cake to a cooled (e.g., 0-10°C) mixture of 45% NaOH aqueous solution (e.g., 3.60 kg per 1 kg of VBF (stage 6)), tap water (e.g., 11.9 kg per 1 kg of VBF (stage 6)), and toluene (e.g., 4.49 kg per 1 kg of VBF (stage 6)), stirring for about 30 minutes, allowing to settle for about 30 minutes, and separating the phases. Add TBME (e.g., 12.0 kg per 1 kg of VBF (stage 6)) to the aqueous layer and cool the mixture (e.g., to 0-10°C). Adjust the pH of the aqueous layer to a value of 4.0-4.5 with phosphoric acid (85% aqueous solution, e.g., 24.0 kg) and, if necessary, 10% NaOH aqueous solution. After thorough mixing and sedimentation, separate the layers and wash the organic phase several times with tap water. Repeat the formation, isolation, drying, and LOD and purity analysis of intermediate 3 (step 9) DAA salt as described above. Release the material that meets the specifications.

[0045] Synthesis of (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide (intermediate 4) (step 10)

[0046] The synthesis of intermediate 4 may also involve liberating the free carboxylic acid from (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate (+)-dehydroabiethylamine salt (intermediate 3), and then converting it to the amide (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxamide (intermediate 4 (step 10)) via the corresponding acid chloride. This reaction is shown in the following scheme.

[0047] [ka]

[0048] [Scheme 4] In a descriptive example, intermediate 4 may be synthesized by adding intermediate 3 (step 9) (1 equivalent, e.g., 20.0-21.0 kg) to a first reaction mixture of tap water (e.g., 5.2 L per 1 kg of intermediate 3 (step 9)), 45% NaOH aqueous solution (4 equivalents), and toluene (e.g., 1.8 kg per 1 kg of intermediate 3 (step 9)) at 20-30°C. The mixture is then stirred with NLT for 30 minutes at 25-30°C, allowed to settle for 30-40 minutes, and the organic layer is discarded. Toluene (e.g., 1.8 kg per 1 kg of intermediate 3 (step 9)) is added to the aqueous layer, then stirred with NLT for 60 minutes, allowed to settle for 30-40 minutes, and the organic layer is discarded. The toluene washing may be repeated. Next, sodium chloride (e.g., 0.3 kg per 1 kg of intermediate 3 (step 9)) is added to the remaining aqueous layer. The temperature is adjusted to 15-20°C. Add butyl acetate (e.g., 1.2 kg per 1 kg of intermediate 3 (step 9)). Slowly add hydrochloric acid (32% aqueous solution, 2.9 equivalents). Maintain the temperature at 15-20°C while stirring in NLT for 60 minutes and allowing to settle for 30-40 minutes. If the pH of the aqueous layer exceeds 3, add additional 32% HCl until the pH is less than 3. Separate the layers and set aside the organic layer for later use. Add the aqueous layer to butyl acetate (e.g., 1.1 kg per 1 kg of intermediate 3 (step 9)). Maintain the temperature at 15-20°C while stirring in NLT for 60 minutes and allowing to settle for 30-40 minutes. Discard the aqueous layer. Mix the organic layer and distill at a pot temperature of <100 torr and 82°C NMT until the batch residue is approximately 30 L. Discard the distillate. Add butyl acetate (e.g., 0.71 kg per kg of intermediate 3 (step 9)) to the batch residue. Distill the mixture at a pot temperature of <100 torr and 82°C NMT until the batch residue is approximately 30 L. Discard the distillate. Repeat this step one or two more times until Karl Fischer moisture analysis shows a value of less than approximately 0.1%. Cool the batch residue to 15-20°C. Add DMF (0.03 equivalents) and thionyl chloride (1.3 equivalents). Heat the mixture to 50-55°C, stir for 1.5-2.0 hours, cool to 21±4°C, and analyze by HPLC. Further process the material to meet the pre-defined specifications, e.g., intermediate 2 (step 8) being 1.0% NMT.If this specification is not met, add an additional thionyl chloride (0.12 equivalents), heat the mixture to 50-55°C, stir for 1.5-2.0 hours, cool to 21±4°C, and resample. Then, cool the mixture of ammonium hydroxide (9.0 equivalents) and tap water (e.g., 0.8 L per 1 kg of intermediate 3 (step 9)) to 0-5°C. While maintaining the batch temperature at 0-10°C, add the acid chloride solution from the previous step that meets the predetermined specification in several batches. After addition, continue stirring at 0-10°C for 30-40 minutes. Then, add n-heptane (e.g., 1.3 kg per 1 kg of intermediate 3 (step 9)) and continue stirring at 0-10°C for 2-3 hours. Collect the resulting precipitate by centrifugation. Wash the wet cake with tap water (e.g., 15 L / cart) in a centrifugation cart, and then centrifuge at maximum speed for 20±5 minutes. This wet cake is added to a mixture of butyl acetate (e.g., 0.71 kg per kg of intermediate 3 (step 9)) and n-heptane (e.g., 0.3 kg per kg of intermediate 3 (step 9)) at 0-10°C. The resulting mixture is stirred at 0-10°C for 30-40 minutes, and then centrifuged at maximum speed for 20 ± 5 minutes. The wet cake is analyzed by HPLC to determine whether it meets a predetermined specification, for example, that intermediate 4 (step 10) is 98.0% NLT. If it does not meet this specification, the wet cake is added to another mixture of butyl acetate and n-heptane, and the stirring and centrifugation are repeated until the wet cake meets the specification analyzed by HPLC, for example, that intermediate 4 (step 10) is 98.0% NLT. Wet cakes that meet pre-defined specifications are NLT dried at 80 torr NMT and 45±5°C for 12 hours until they meet pre-defined specifications, for example, an LOD of 1.0% NMT and a moisture content of 0.2% NMT as determined by Karl Fischer analysis. Materials that do not meet these pre-defined specifications are further NLT dried at 80 torr NMT and 45±5°C for 6 hours and resampled. Materials that meet the pre-defined specifications are released as intermediate 4 (step 10), which may be stored in one or more polyethylene (PE) bags, or they may be sealed in a paper drum.

[0049] Synthesis of ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneaminium chloride (intermediate 5)

[0050] The synthesis of intermediate 5 may involve contacting and reacting (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide (intermediate 4) with lithium aluminum hydride in an organic solvent, followed by aqueous analysis to isolate the resulting amine as its hydrochloride salt. This reaction is shown in the following scheme.

[0051] [ka]

[0052] [Scheme 5] In one example, intermediate 5 (step 11) may be synthesized by the scheme described above, and the synthesis may include the following steps: For example, wash a reactor (e.g., SS316) with refluxed acetone (e.g., 100 kg), drain it, dry it under reduced pressure for 1-2 hours, and fill it with N2 gas. Add intermediate 4 (step 10) (1.00 equivalent) and THF (e.g., 8 kg per 1 kg of intermediate 4 (step 10)) prepared above to the drying reactor and cool to -10°C. Add lithium aluminum hydride (LAH) solution (10% in THF, 3.5-3.8 equivalents, 1 equivalent = 1 mol per 1 mol of intermediate 4 (step 10)) in several batches while maintaining a batch temperature of 25°C NMT. ​​Rinse the LAH supply line with THF (e.g., 10 kg). Heat the mixture to 20-30°C and stir for 20-30 minutes. Subsequently, the mixture is slowly heated to 65-70°C while maintaining an internal pressure of 0.1 kg / cm²NMT. The mixture is stirred at 65-70°C for 3-4 hours, cooled to 15-25°C, and analyzed by HPLC to determine whether a predetermined specification, such as intermediate 4 (step 10) being 1.0% NMT, is met. If this condition is not met, the heating and cooling process from the previous step is repeated while stirring. Once HPLC indicates that only approximately 1.0% or less of intermediate 4 remains, the reaction mixture is cooled to -5-5°C. A 91% THF aqueous solution (e.g., 1.09 kg per 1 kg of 10% LAH) is added at 25°C NMT, and stirring is continued for 20-30 minutes. The amount of water added (as THF aqueous solution) may be 1.0-1.1 L of water per 1 kg of LAH, and in further embodiments, 1.1 L of water per 1 kg of LAH. Add an aqueous solution of NaOH (5.3%, e.g., 0.37 kg per 1 kg of 10% LAH) at 25°C NMT (to induce an exothermic reaction) and continue stirring for 20-30 minutes. The amount of NaOH added may be 0.17-0.19 mol per 1 mol of LAH, and in further embodiments, it may be 0.18-0.19 mol / mol per 1 mol of LAH. Slowly heat the mixture to 65-70°C, stir for 3-4 hours, and cool to 15-25°C. Filter the mixture using THF (e.g., 30 kg) to complete the transfer of the reaction mixture to the filter. Store the filtrate in a container.The filtrate cake is then returned to the reactor and resuspended in fresh THF (1.3 kg per 1 kg of 10% LAH). The mixture is stirred at 15-25°C for 1-1.5 hours, then filtered using THF (0.65 kg per 1 kg of 10% LAH) to complete the transfer. The wet cake is discarded. The filtrate is mixed and distilled at <100 torr and 40°C NMT until the batch residue is approximately 40 L. The distillate is discarded. TBME (e.g., 30 kg) is added to the remaining batch residue, and the mixture is distilled at <100 torr and 40°C NMT until the batch residue is approximately 40 L. The distillate is discarded. Then, TBME (e.g., 20 kg) and tap water (e.g., 20 kg) are added to the batch residue, and the mixture is stirred at 15-20°C for 60-70 minutes, followed by 30-40 minutes of settling. Discard the aqueous layer. Then, add tap water (e.g., 20 kg) to the organic layer and stir the mixture at 15-20°C for 60-70 minutes, followed by 30-40 minutes of settling. Discard the aqueous layer. The organic layer is analyzed by inductively coupled plasma atomic emission spectroscopy to determine whether the predetermined specifications, e.g., Li at 10 ppm NMT and Al at 10 ppm NMT, are met. If these specifications are not met, repeat washing with tap water until the specifications are met. Once the specifications are met, add anhydrous ethanol (e.g., 30 kg) to the organic layer that meets the specifications and distill the mixture at a pot temperature of <100 torr and 40°C NMT until the batch residue is approximately 40 L. Discard the distillate. Add anhydrous ethanol (e.g., 82.8 kg) to the residue and distill the mixture again at <100 torr and 40°C NMT until the batch residue is approximately 40 L. Discard the distillate. This azeotropic distillation step may be repeated one or two more times until the predetermined specifications are met, for example, until the Karl Fischer moisture analysis shows a value of 0.5% NMT. ​​The batch residue is then cooled to 15-25°C, and TBME ((tert-butyl methyl ether), e.g., 13.8 kg per kg of intermediate 4 (step 10)) is added to the residue. The mixture is then cooled to 0-5°C.Hydrogen chloride (HC1) gas (3.3 equivalents) is added in several portions at 25°C NMT, and after addition is complete, stirring is continued at 20-25°C for 60-70 minutes. If the pre-set specification, for example, pH of 1.0 NMT, is not met, additional HC1 gas is added until the specification is met. The resulting precipitate is collected by centrifugation. The wet cake is washed in a centrifugation cart with TBME:EtOH (anhydrous, 1.5:1.0, e.g., 5.0 kg), and the cake is centrifuged at maximum speed for 20 ± 5 minutes. The cake is analyzed by HPLC to determine whether the pre-set specification, for example, intermediate 5 (step 11) being 98.0% NLT, is met. If this specification is not met, the cake can be resuspended in TBME:EtOH (anhydrous, 1.5:1.0, 6.6 kg per 1 kg of intermediate 4 (step 10)), centrifuged, and washed until the specification is met. Cakes that meet the specifications are NLT dried at 80 torr NMT and 35±5°C for 12 hours until the LOD reaches 1.0% NMT. ​​Materials that do not meet the pre-set specifications are further NLT dried at 80 torr NMT and 35±5°C for 6 hours and resampled. Materials that meet the pre-set specifications are released as intermediate 5 (step 11). The resulting intermediate 5 (step 11) may be stored in one or more PE bags and then sealed in a paper drum.

[0053] Synthesis of N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (tasimelteon, before particle size reduction (i.e., not micronized))

[0054] After synthesizing the intermediates disclosed above, undeleted tasimeltheone may be synthesized. The final step in the synthesis of tasimeltheone may involve contacting and reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneaminium chloride (intermediate 5) with propionyl chloride in the presence of an organic solvent and a base. This reaction is shown in the following scheme.

[0055] [ka]

[0056] [Scheme 6] For example, in an exemplary final step synthesis, a 45% aqueous NaOH solution (8 equivalents) is added at 0 - 10°C to a mixture of intermediate 5 (step 11, 1.00 equivalent), TBME (e.g., 15.2 kg per 1 kg of intermediate 5 (step 11)), and tap water (e.g., 14.6 kg per 1 kg of intermediate 5 (step 11)) to prepare the first reaction mixture. Propionyl chloride (1.28 - 1.46 equivalents) is added at 5 - 10°C, and then the mixture is stirred at this temperature for 90 - 120 minutes. This mixture can be analyzed by HPLC to determine whether the resulting solution meets a preset specification, e.g., intermediate 5 (step 11) is 0.10% NMT. After stirring at 25 - 30°C and then allowing it to settle, the aqueous layer is discarded. The organic layer can be washed with a 5% aqueous NaOH solution and then washed twice with water. The organic layer is filtered and distilled at about <100 Torr (1 Torr ~ = 1 mmHg = 133.3 Pa) and about <= 58°C, and the distillate is discarded. 95% EtOH (e.g., 24.0 kg) is charged into the pot containing this residue from a clean filter. The resulting mixture is distilled at about <100 Torr and about <= 58°C, the distillate is discarded, and this solvent exchange step is repeated two more times with fresh 95% EtOH. 95% EtOH and process water are added to the pot containing the residue via a filter. The volume of EtOH may be 2.8 - 5.0 equivalent volumes, assuming a 90% yield of tasimelteon (non - micronized) based on the input amount of intermediate 5 (step 11), 1 equivalent volume = 1 L of EtOH / kg per 1 kg of tasimelteon (non - micronized). In another embodiment, the volume of EtOH may be 3.0 - 5.0 equivalent volumes. The EtOH:water ratio may be 0.7:1 - 1.4:1 (volume / volume). In another embodiment, the EtOH:water ratio may be 1.0:1.0. The mixture may be heated to 35 - 40°C, stirred for 30 - 40 minutes, cooled to 13 - 17°C over a period of 60 - 120 minutes, and stirred at 13 - 17°C for 60 - 90 minutes. If crystallization does not occur, tasimelteon (non - micronized) crystals may be seeded into the mixture.After adding process water (for example, 19.2 kg per 1 kg of intermediate 5 (step 11) is added over 2 to 2.5 hours at 10 to 15°C, followed by stirring at the same temperature for 60 to 90 minutes), the precipitate is collected by centrifugation, and the cake is analyzed by HPLC to determine whether the product meets the predefined specifications, e.g., tasimelteon is 99% NLT, impurities 5 and 6 are 0.15% NMT a / a, and other individual impurities, e.g., impurities 1, 2, 3, 4, and 7 are 0.10% NMT a / a. The material that meets the predefined specifications is washed with n-heptane, e.g., and then dried until the LOD is 0.7% NMT, e.g., 0.7% NMT. ​​The particle size of the dried material is also analyzed. For example, material that does not meet the pre-defined specifications for impurities 5 and 6 is returned to the reaction vessel and recrystallized as described above, i.e., redissolved in heated EtOH:water, filtered, the mixture is cooled and crystallized, and then precipitated by slowly adding water and collected by centrifugation. Such reprocessed material that meets the above impurity specifications is washed, dried and analyzed as described above, and then released for pulverization, disposal, or further reprocessing.

[0057] The final step synthesis described above is merely illustrative. For example, other organic solvents or mixtures thereof can be used instead of tert-butyl methyl ether (TBME). Also, a base can be used in addition to or in combination with NaOH. The solvent for crystallization may be an aqueous solution of C1-C4 alcohols, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, or tert-butanol, or a mixture of organic solvents such as MTBE-EtOH-cyclohexane.

[0058] The tasimelteon active pharmaceutical ingredient (API) is stored as an unmicronized API and micronized as needed immediately before use in capsule formulation manufacturing. The use of a jet mill and a dry nitrogen atmosphere has been found to be advantageous for achieving uniform particle size, good handling characteristics, and minimizing losses. APIs that meet particle size specifications (e.g., in the process, D 0.1<15μm (i.e., 10% of the particles have a diameter of 15μm or less); in the case of emission, D 0.5 <30μm;D 0.9 <75μm; and (i)D 90 The specification is set to <105 μm; (ii) D 50 The specification is set to <45 μm; and (iii) D 10 The material (specified to <15μm) is tightly sealed in, for example, a PE bag and / or aluminum bag along with a desiccant such as silica desiccant.

[0059] When manufacturing pharmaceutical-grade tasimerteon, i.e., tasimerteon intended for human use, manufacturing and quality control standards (GMP) are used, including those that may be required by the applicable regulatory authority. Subsequently, bulk pharmaceutical-grade tasimerteon is mixed with excipients to prepare bulk formulation tasimerteon, which is then formed into appropriate pharmaceutical dosage forms, such as capsules, each containing 10 mg to 100 mg, for example, 20 mg of tasimerteon.

[0060] The above description refers to pulverization. However, those skilled in the art will recognize that other particle size reduction techniques, such as sieving and high-shear fluid treatment, can also be used. Similarly, pulverization techniques other than jet milling, such as grinding, cryogenic grinding, cutting, or impact, can also be used.

[0061] Although the present invention is described in detail with respect to only a limited number of embodiments, it should be readily understood that the present invention is not limited to such disclosed embodiments. Rather, the present invention can be modified to incorporate any number of variations, changes, substitutions, or equivalent configurations that are not described herein but correspond to the spirit and scope of the invention. In addition, although various embodiments of the present invention are described, it should be understood that aspects of the present invention may include only some of the embodiments described. Accordingly, the present invention is not limited by the foregoing description but is limited only by the scope of the appended claims. Exemplary embodiments of the present invention are described below. <1> A process for synthesizing high-purity pharmaceutical grade tasimelteon, (a) Propionylation of ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof to obtain tasimelteon. (b) Crystallize the tasimeltheon produced in step (a), (c) Analyze the crystallized tasimelteon from step (b) for the presence of one or both of impurities 5 (N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide) and 6 (2-hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate), and (d)(i) If the crystallized tasimeltheon meets the pre-set specifications for impurity 5, impurity 6, or both, recover high-purity pharmaceutical grade tasimeltheon, or (d)(ii) A process comprising: if the crystallized tasimeltheon does not meet the predetermined specifications for impurity 5 or impurity 6 or both, further purifying the tasimeltheon and repeating steps (c) and (d), or discarding the batch. <2> The propionylation step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof with halogenated propionyl, propionyl anhydride, propionyl ester, propionylamide, propionyl imidazolide, or propionic acid and a dehydrating agent or a product thereof. <1> The process described above. <3> The propionylation step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof with a halogenated propionyl, propionyl anhydride, propionyl ester, propionylamide, propionyl imidazolide, or propionic acid and a dehydrating agent or product thereof in the presence of an organic solvent. <2> The process described above. <4> The propionylation step comprises contacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof with propionyl chloride in the presence of an organic solvent and a water-soluble base. <3> The process described above. <5> The organic solvent comprises tert-butyl methyl ether (TBME), and the water-soluble base comprises NaOH. <4> The process described above. <6> The ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof is intermediate 5 (((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneaminium chloride), and after the propionylation step and before the crystallization step, the mixture of tasimeltheone is analyzed for the presence of intermediate 5, and if the mixture does not meet the predetermined specifications for intermediate 5, step (a) is repeated or the mixture is discarded. <3> , <4> ,or <5> The process described above. <7> After the propionylation step and before the crystallization step, the mixture of tasimeltheone is washed with a water-soluble base and the aqueous layer is discarded. <3> , <4> , <5> ,or <6> The process described above. <8> The washed mixture is distilled, and the distillate is discarded. <7> The process described above. <9> The aforementioned distillation step is carried out in ethanol at a pot temperature of approximately 58°C or lower and a pressure of approximately 100 mmHg or lower. <8> The process described above. <10> The crystallization step includes dissolving tasimeltheone by stirring and heating a mixture of tasimeltheone and C1-C4 alkanols. <1> , <2> , <3> , <4> , <5> , <6> , <7> , <8> ,or <9> The process described above. <11> The mixture of C1-C4 alkanols and tasimelteon is heated to approximately 35-40°C while stirring, and then cooled to approximately 13-17°C while stirring. <10> The process described above. <12> The crystallization step may optionally include seeding. <1> ~ <11> The process described in any one of the following items. <13> The aforementioned analysis step is performed by HPLC. <1> ~ <12> The process described in any one of the following items. <14> The aforementioned pre-set specifications for one or both of impurities 5 and 6 are 0.15% or less (area / area), <1> ~ <13> The process described in any one of the following items. <15> The further purification includes recrystallizing tasimeltheone. <1> ~ <14> The process described in any one of the following items. <16> The particle size of the crystals recovered in step (d) is reduced to meet the particle size specifications for pharmaceutical grade tasimelteon. <1> The process described above. <17> A pharmaceutical composition containing pharmaceutical-grade tasimelteon is prepared by mixing crystals that meet the particle size specifications for pharmaceutical-grade tasimelteon with one or more excipients. <16> The process described above. <18> A process for preparing a batch of high-purity pharmaceutical grade tasimelteon, (a) Batch of tasimeltheone synthesized under GMP conditions, N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7), To analyze the presence of one or more of these, and (b) If the batch satisfies a predetermined specification regarding the amount of one or more impurities 1, 2, 3, 4, 5, 6, and 7, the processing of tasimelteon shall be continued to prepare a bulk active pharmaceutical ingredient for tasimelteon for formulation, or (c) If the tasimeltheon does not meet the pre-set specifications, further purify the tasimeltheon (by recrystallization, grinding, extraction, or chromatography, etc.) and repeat steps (a) and (b), or discard the batch. A process that includes this. <19> The pre-set specification for each of the one or more impurities is 0.15 wt% or less. <18> The process described above. <20> The analysis in step (a) above is performed by HPLC. <18> or <19> The process described above. <21> Step (a) includes analyzing the batch for the presence of impurities 3, 5, and 6, wherein the analysis in step (a) is performed by HPLC. <18> or <19> The process described above. <22> Step (a) includes analyzing the batch for the presence of all impurities 1, 2, 3, 4, 5, 6, and 7, wherein the analysis in step (a) is performed by HPLC. <21> The process described above. <23> Further pre-defined specifications for continuing the processing of tasimeltheone include the tasimeltheone having a purity of 95.0% or higher by area. <18> or <19> The process described above. <24> Further pre-defined specifications for continuing the treatment of tasimeltheon include the fact that the amount of any other impurities, individually, is 0.10 area percent or less. <23> The process described above. <25> The tasimeltheon treatment in step (b) includes reducing the tasimeltheon particle size to satisfy the particle size specification. <18> , <19> , <20> , <21> ,or <22> The process described above. <26> The particle size reduction is carried out using a jet mill under an inert gas (e.g., nitrogen, argon, or helium), and the particle size specification includes one or more of the following: (i) D90 specification set to less than approximately 105 μm; (ii) D50 specification set to less than approximately 45 μm; and (iii) D10 specification set to less than approximately 15 μm. <25> The process described above. <27> The tasimelteon treatment in step (b) further comprises mixing the pulverized tasimelteon with one or more pharmaceutically acceptable excipients to prepare a bulk tasimelteon active pharmaceutical ingredient. <26> The process described above. <28> The mixed tasimelteon is prepared for use in pharmaceutical compositions in drug dose units for human use. <27> The process described above. <29> The batch of tasimelteon analyzed in step (a) is synthesized by contacting and reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneaminium chloride (intermediate 5) with propionyl chloride in the presence of an organic solvent and a base. <18> , <19> , <20> , <21> , <22> , <23> , <24> ,or <25> The process described above. <30> Tasimelteon, synthesized by contacting and reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneaminium chloride (intermediate 5) with propionyl chloride in the presence of the base, is then prepared in crystalline form by filtering the reaction mixture to prepare a filtrate containing tasimelteon before the analysis in step (a), and then crystallizing the tasimelteon in a solvent. <29> The process described above. <31> The solvent for crystallizing tasimeltheone is an aqueous alcohol solution, such as EtOH and water. <30> The process described above. <32> The solvent for recrystallizing tasimeltheone is an aqueous alcohol solution, such as EtOH and water. <18> , <19> , <20> , <21> , <22> , <23> , <24> , <25> , <26> , <27> , <28> , <29> ,or <30> The process described above. <33> The organic solvent is TBME, and the base is NaOH. <29> , <30> , <31> ,or <32> The process described above. <34> (i) The filtrate is concentrated by distillation before crystallization, (ii) An alcohol, such as EtOH, is added. (iii) The mixture of residue / alcohol is concentrated by distillation, (iv) The residue is dissolved in an aqueous alcohol solution, such as EtOH and water. (v) Tasimeltheone is crystallized from the alcohol / water solution, and (vi) The tasimeltheon crystal is recovered for the analysis in step (a), <30> , <31> , <32> ,or <33> The process described above. <35> The recrystallization in step (c) is carried out by subjecting any tasimeltheon that did not meet the predetermined specifications to steps (iv), (v), and (vi), if necessary. <34> The process described above. <36> The crystallization step (v) is accelerated by seeding. <34> or <35> The process described above. <37> A method for analyzing a batch of high-purity pharmaceutical grade tasimelteon, (a) Prepare a batch of tasimeltheone synthesized under GMP conditions. (b) The batch of tasimeltheone is prepared using HPLC, N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), A method comprising analyzing for the presence of one or more of N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7). <38> A process for preparing a batch of high-purity tasimeltheon, (a) synthesizing batches of tasimertheon in crystalline form, and (b) The batch N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), Analyze one or more of the following: N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7); Furthermore (c) The aforementioned batch of Tasimertheon (i) Contains one or more of impurities 1 to 7 in an amount of 0.15 wt% or less, and (ii) If any of the unidentified impurities in the batch are individually 0.10 wt% or less, (d) Mincing the tasimeltheon to meet the particle size specifications, or (e) A process comprising recrystallizing and reanalyzing the batch of tasimeltheon if the batch does not meet the purity specifications described in (c)(i) and (ii). <39> A method for evaluating the purity of a bulktasimeltheone composition, (a) Prepare a standard batch for each of one or more of impurities 1 to 7, and (b) A method comprising determining the level of one or more of the impurities 1 to 7 in the tasimeltheone composition using the standard batch as a reference marker. <40> A batch of tasimelteon used in the preparation of pharmaceutical compositions for human use, A batch of tasimeltheone containing tasimeltheone, which has been analyzed and shown to have a purity of at least 98.0 area%, and contains one or more of the impurities 1-7 at a concentration of 0.15 wt% or less. <41> The following limitations: The batch of tasimeltheon is analyzed to determine whether it complies with a predetermined specification for each of the one or more impurities, and the predetermined specification is that none of the one or more impurities are present in an amount exceeding 0.15 wt%, The aforementioned analysis is performed by HPLC. The aforementioned analysis is performed to detect the presence of all impurities 3, 5, and 6. The aforementioned analysis is performed to detect the presence of all impurities 1, 2, 3, 4, 5, 6, and 7. The aforementioned analysis includes determining that Tasimertheon occupies at least 98.0% of the area. The aforementioned analysis includes determining that the amounts of other impurities are 0.10 area percent or less individually. One or more of the following apply: <37> , <38> ,or <39> Methods used. <42> The following impurities: N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), Purified tasimelteon that does not contain any of the following impurities (N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7) at concentrations exceeding approximately 0.15%. <43> It does not contain other impurities at concentrations exceeding approximately 0.15%. <42> The composition described above. <44> The following impurities: (+)-dehydroabiethylamine or a salt thereof, 2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanecarboxylic acid or its salt (intermediate 3), (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide (intermediate 4), ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or its salt (intermediate 5), None of the 4-vinyl-2,3-dihydrobenzofurans (VBF) are present in concentrations exceeding approximately 0.15% by weight. <42> Tasimeltheon as described. <45> It does not contain related impurities at a concentration exceeding approximately 0.1% by weight. <42> ~ <44> Tasimertheon as described in any one of the items. <46> It does not contain ethyl diazoethyl at a concentration exceeding approximately 10 ppm. <42> ~ <45> Tasimertheon as described in any one of the items. <47> The following impurities are not present, individually or in whole, in concentrations exceeding approximately 20 ppm: propionyl chloride, propionyl anhydride, propionic acid, or ethyl propionate. <42> ~ <46> Tasimertheon as described in any one of the items. <48> The total amount of impurities is less than approximately 2.0%. <42> ~ <47> Tasimertheon as described in any one of the items. <49> N-(((1S,2S)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide is not contained in a concentration exceeding approximately 0.4% of the total amount of both enantiomers of N-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide. <42> ~ <48> Tasimertheon as described in any one of the items. <50> <1> ~ <36> and <38> Prepared by the process disclosed in any one of the paragraphs, <42> ~ <49> Tasimertheon as described in any one of the items. <51> A method for determining the purity of a batch of Tasimertheon, a) Obtain a high-performance liquid chromatogram or ultrahigh-performance liquid chromatogram of the sample from the batch. b) Identifying the peaks in the chromatogram corresponding to the impurities, and c) Including measuring the area of ​​the peaks and determining their relative concentrations, The method described above is (i) The following substances: N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), Prepare a standard batch for each of the following: N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7), (ii) A method further comprising determining the elution characteristics of the substance under the chromatographic conditions used for the analysis of the tasimelteon composition, using the standard batch as a reference marker. <52> A method for synthesizing Tasimertheon, To prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide by contacting and reacting it with a reducing agent and an acid in an organic solvent to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof; and A method comprising contacting and reacting ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine with a propionylating agent to prepare tasimelteon. <53> The reducing agent includes LiAlH4, <52> Methods used. <54> The acid includes HCl, <52> or <53> Methods used. <55> The organic solvent includes TBME, <52> , <53> ,or <54> Methods used. <56> The propionylating agent includes propionyl chloride. <52> , <53> , <54> ,or <55> Methods used. <57> The propionylation step further comprises an organic solvent and a base. <52> , <53> , <54> , <55> ,or <56> Methods used. <58> The aforementioned base contains NaOH. <57> Methods used. <59> The aforementioned ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide is reduced to prepare ((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methaneamine or a salt thereof. <52> Methods used. <60> <52> ~ <58> A composition comprising tasimeltheone prepared by the process described in any one of the items.

Claims

[Claim 1] Purified tasimelteon for pharmaceutical use, in which the content of any of the following impurities 1-7 is reduced to less than 0.15 wt%: N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)-3-methylbutanamide (impurity 1), N-(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)pentanamide (impurity 2), 1,3-Bis(((1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)urea (impurity 3), N-(((1R,2R)-2-(benzofuran-4-yl)cyclopropyl)methyl ) Propionamide (impurity 4), N-((2-(2,3-dihydrobenzofuran-4-yl)-1-((2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl)(propionamide)methyl)cyclopropyl)methyl)propionamide (impurity 5), 2-Hydroxy-6-(2-(propionamidemethyl)cyclopropyl)phenethyl 2-(2-hydroxyethyl)-3-(2-(propionamidemethyl)cyclopropyl)phenyl carbonate (impurity 6), and N-(((1R,2R)-2-(3-oxo-2,3-dihydrobenzofuran-4-yl)cyclopropyl)methyl)propionamide (impurity 7).

Images