Intermediate salts for preparation of bis (fluoroalkyl) benzodiazepine compounds

Abstract

The invention provides a salt represented by the structure of Formula (I): wherein Q is an ammonium cation; and a process comprising the use of said salts for the preparation of benzodiazepine compounds, in particular bis (fluoroalkyl) derivatives thereof.

Description

Invention Field

[0001] This invention provides a salt represented by the structure of formula (I):

[0002]

[0003] Where Q is an ammonium cation; and

[0004] The process includes using the salt to prepare benzodiazepines. Ketone (benzodiazepinone) compounds, especially their bis(fluoroalkyl) derivatives. Background of the Invention

[0006] bis(fluoroalkyl)benzodiazepine Ketone compounds can be used as active pharmaceutical ingredients in the pharmaceutical and fine chemical industries. For example, gamma-secretase inhibitors (GSIs):

[0007] (2R,3S)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) -3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide:

[0008] and

[0009] (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine] -3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide:

[0010]

[0011] Promising results have been shown in current clinical trials for the treatment of a variety of cancers, particularly those with defects in Notch regulation (see U.S. Patents 9,273,014 and 8,629,136, which are incorporated herein by reference).

[0012] In (2R,3S)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) -3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide and (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine] In the preparation of [-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide, the free acid (2R)-2-(2-tert-butoxy-2-oxoethyl)-5,5,5-trifluorovaleric acid is formed and used (as above):

[0013]

[0014] The free acid compound was found to be oily and unstable.

[0015] Stability is a critical consideration when selecting synthetic intermediates in drug manufacturing processes, especially when the process involves several synthetic stages. Each intermediate should be pure and stable to limit impurities / degradation products in subsequent synthetic stages, which could interfere with the chemical reactions of the synthesis, the final drug substance, and the purity of the final drug product.

[0016] Furthermore, the stability of the intermediate synthesis product is also beneficial, allowing different synthetic stages to proceed at different locations and / or at different times. Therefore, prolonged stability, especially at room temperature or higher, will alleviate the logistical requirements for the synthesis, handling, and transportation of the intermediate.

[0017] Therefore, for providing a stable form of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5,5,5-trifluorovaleric acid in the preparation of (2R,3S)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) -3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide and (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine] There is an unmet need for reliable and efficient synthetic processes for succinimide [-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide. Invention Overview

[0019] In one embodiment, the present invention provides a salt represented by the structure of formula (I):

[0020]

[0021] Formula (I)

[0022] Q is an ammonium cation.

[0023] In another embodiment, the present invention provides a method for preparing compound (3a) or compound (3b), the method comprising steps A-B:

[0024] - Step A:

[0025] From equation (I):

[0026]

[0027] Where Q is an ammonium cation

[0028] Preparation of compound (2):

[0029] as well as

[0030] - Step B:

[0031] From compound (3-1):

[0032] Or (3-2): Compound (3a) was prepared from compound (2) and compound (2) respectively:

[0033]

[0034] Or (3b):

[0035]

[0036] In some implementations, Q in formula (I) is a cyclohexylammonium cation.

[0037] Detailed Description of the Invention

[0038] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, those skilled in the art will understand that the invention can be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the invention.

[0039] Formula (I)

[0040] In one embodiment, the present invention provides a salt represented by the structure of formula (I):

[0041]

[0042] in

[0043] Q is an ammonium cation. In another embodiment, the ammonium cation is a primary ammonium cation, a secondary ammonium cation, or a tertiary ammonium cation. In another embodiment, the primary ammonium cation comprises a cycloalkyl moiety (as a substituent for nitrogen). In another embodiment, non-limiting examples of the primary ammonium cation are selected from the group consisting of: cyclohexylammonium cation, cyclopentylammonium cation, cycloheptylammonium cation, and cyclooctylammonium cation. In another embodiment, non-limiting examples of the secondary ammonium cation are selected from the group consisting of: dicyclohexylammonium cation, dicyclopentylammonium cation, dicycloheptylammonium cation, and dicyclooctylammonium cation. In another embodiment, non-limiting examples of the tertiary ammonium cation are selected from the group consisting of: diisopropylethylammonium cation, diethylisopropylammonium cation, and N-methylmorpholinium cation. In another embodiment, Q is a cyclohexylammonium cation, and the compound is (1):

[0044]

[0045] Each possibility represents a separate embodiment of the invention.

[0046] In one embodiment, the salt of formula (I) is stable for 2-52 weeks at room temperature, 2°C-8°C, or 40°C / 75% RH (relative humidity). In another embodiment, the salt of formula (I) is stable for 2-30 weeks at room temperature, 2°C-8°C, or 40°C / 75% RH (relative humidity). In another embodiment, the salt is stable for 2-24 weeks. In another embodiment, the salt is stable for 2-20 weeks. In another embodiment, the salt is stable for 2-16 weeks. In another embodiment, the salt is stable for 2-8 weeks. In another embodiment, the salt is stable for 2-6 weeks. In another embodiment, the salt is stable for 2-4 weeks. In another embodiment, the salt is stable for 4-30 weeks. In another embodiment, the salt is stable for 4-24 weeks. In another embodiment, the salt is stable for 4-20 weeks. In another embodiment, the salt is stable for 4-16 weeks. In another embodiment, the salt is stable for 4-8 weeks. In another embodiment, the salt is stable for 4-6 weeks. In another embodiment, the salt is stable for 6-30 weeks. In another embodiment, the salt remains stable for 6-24 weeks. In another embodiment, the salt remains stable for 6-20 weeks. In another embodiment, the salt remains stable for 6-16 weeks. In another embodiment, the salt remains stable for 6-8 weeks. In another embodiment, the salt remains stable for 8-30 weeks. In another embodiment, the salt remains stable for 8-24 weeks. In another embodiment, the salt remains stable for 8-20 weeks. In another embodiment, the salt remains stable for 8-16 weeks. In another embodiment, the salt remains stable for 16-30 weeks. In another embodiment, the salt remains stable for 16-24 weeks. In another embodiment, the salt remains stable for 16-20 weeks. In another embodiment, the salt remains stable for 20-30 weeks. In another embodiment, the salt remains stable for 20-24 weeks. In another embodiment, the salt remains stable for 24-30 weeks. In another embodiment, the salt remains stable for 24 weeks. Each possibility represents a separate embodiment of the invention.

[0047] In one embodiment, the salt of formula (I) has an initial purity between 95% and 99.99% (i.e., the purity measured when prepared and separated). In another embodiment, the purity is between 95% and 97%. In another embodiment, the purity is between 95% and 98%. In another embodiment, the purity is between 95% and 99%. In another embodiment, the purity is between 95% and 99.5%. In another embodiment, the purity is between 95% and 99.9%. In another embodiment, the purity is between 97% and 98%. In another embodiment, the purity is between 97% and 99%. In another embodiment, the purity is between 97% and 99.5%. In another embodiment, the purity is between 97% and 99.9%. In another embodiment, the purity is between 98% and 99%. In another embodiment, the purity is between 98% and 99.5%. In another embodiment, the purity is between 98% and 99.9%. In another embodiment, the purity is between 99% and 99.5%. In another embodiment, the purity is between 99% and 99.9%. In yet another embodiment, the purity is between 99.5% and 99.9%. In some embodiments, purity is measured via HPLC, GC, GC-MS, or NMR. Each possibility represents a separate embodiment of the invention.

[0048] In one embodiment, the salt of formula (I) has an initial assay value between 94% and 99.99%. In another embodiment, the assay value is between 94% and 97%. In another embodiment, the assay value is between 94% and 99.99%. In another embodiment, the assay value is between 94% and 98%. In another embodiment, the assay value is between 94% and 99%. In another embodiment, the assay value is between 94% and 99.5%. In another embodiment, the assay value is between 95% and 99.9%. In another embodiment, the assay value is between 97% and 98%. In another embodiment, the assay value is between 97% and 99%. In another embodiment, the assay value is between 97% and 99.5%. In another embodiment, the assay value is between 97% and 99.9%. In another embodiment, the assay value is between 98% and 99%. In another embodiment, the assay value is between 98% and 99.9%. In another embodiment, the purity is determined to be between 99% and 99.5%. In another embodiment, the purity is determined to be between 99% and 99.9%. In yet another embodiment, the purity is determined to be between 99.5% and 99.9%. In some embodiments, the purity is determined by HPLC, GC, GC-MS, or NMR. Each possibility represents a separate embodiment of the invention.

[0049] In some embodiments, the salt of formula (I) is in powder form. In one embodiment, the cyclohexylamine salt (CHA) (i.e., where Q is a cyclohexylammonium cation), i.e., compound (1), is in powder form. In other embodiments, the salt of formula (I) is in crystalline form. In one embodiment, compound (1) is in crystalline form. In other embodiments, the salt of formula (I) is in a crystalline form having multiple polymorphs. In one embodiment, compound (1) is in a crystalline form having multiple polymorphs.

[0050] In some embodiments, formula (I) as described herein is stable for 1-12 months. In one embodiment, a salt of formula (I) is stable for 3-12 months. In another embodiment, a salt of formula (I) is stable for 3-6 months. In another embodiment, a salt of formula (I) is stable for 6-12 months. In another embodiment, a salt of formula (I) is stable for 6-9 months. In another embodiment, a salt of formula (I) is stable for 3-9 months. In another embodiment, a salt of formula (I) is stable for 6 months. In another embodiment, compound (1) is stable for 3-12 months. In another embodiment, compound (1) is stable for 3-6 months. In another embodiment, compound (1) is stable for 6-12 months. In another embodiment, compound (1) is stable for 6-12 months. In another embodiment, compound (1) is stable for 6-9 months. In another embodiment, compound (1) is stable for 3-9 months. In another embodiment, compound (1) is stable for 6 months. In some other embodiments, when compound (1) is found to be in powder form, compound (1) remains stable for each described time period. Each possibility represents a separate embodiment of the invention.

[0051] In one embodiment, without being bound by any mechanism or theory, it is contemplated herein that the high stability of the salts of the present invention is due to the low and / or minimal hygroscopicity and / or high hydrophobicity of the ammonium cation (Q, e.g., CHA). In another embodiment, the salt of formula (I) is not hygroscopic. In another embodiment, Q in formula (I) is hydrophobic. In yet another embodiment, the salt of formula (I) is not hygroscopic, and Q in formula (I) is hydrophobic. Each possibility represents a separate embodiment of the invention.

[0052] Synthetic application of formula (I)

[0053] In one embodiment, the present invention provides a method for preparing compound (3a) or compound (3b):

[0054] - Step A:

[0055] From equation (I):

[0056]

[0057] Where Q is an ammonium cation

[0058] Preparation of compound (2):

[0059] as well as

[0060] - Step B:

[0061] From compound (3-1):

[0062] and

[0063] Compound (2) is used to prepare compound (3a):

[0064]

[0065] Or from (3-2):

[0066] and

[0067] Compound (2) is used to prepare compound (3b):

[0068]

[0069] In another implementation scheme, the entire process is described in Scheme 1: Option 1: Preparation of compound (3a) or compound Method (3b)

[0070] Step A

[0071]

[0072] Step B

[0073]

[0074] In another embodiment, formula (I) is prepared by a method comprising: - from (1a):

[0075]

[0076] and (1a-1):

[0077]

[0078] Preparation of compound (1b):

[0079]

[0080] -Preparation of compound (1c) from (1b):

[0081]

[0082] -Preparation of compound (1d) from (1c):

[0083]

[0084] -Preparation of compound (1e) from (1d):

[0085] -By (1e); and (1e-1):

[0086] Preparation of compound (1f):

[0087] - Prepare compound (1g) from (1f):

[0088] And - prepared from compound (1g) of formula (I).

[0089] In another implementation scheme, the entire process is described in Scheme 2: Option 2: Method of Preparation (I)

[0090]

[0091] In another embodiment, (1b) is prepared by (1a) and (1a-1) under alkaline conditions. In another embodiment, NaOH is the base used. In another embodiment, (1a) is used in excess (when 1a-1 is the limiting reactant).

[0092] In another embodiment, (1c) is prepared from (1b) under alkaline conditions. In another embodiment, NaOH is the base used.

[0093] In another embodiment, (1d) is prepared from (1c) under acidic conditions. In another embodiment, the acid used is p-toluenesulfonic acid.

[0094] In another embodiment, (1e) is prepared from (1d) under catalytic conditions. In another embodiment, the catalyst is DMAP (N,N-dimethylaminopyridine). In another embodiment, (1d) is reacted with an imidazole coupling agent (e.g., 1,1'-carbonyldiimidazole) in excess of (1d). In another embodiment, (1e) is prepared from (1d) under catalytic conditions (e.g., DMAP as a catalyst) and (1d) is reacted with an imidazole coupling agent (e.g., 1,1'-carbonyldiimidazole) in excess of (1d).

[0095] In another embodiment, (1f) is prepared from (1e) under alkaline conditions. In another embodiment, the base is n-BuLi. In another embodiment, the reaction is carried out at -78°C.

[0096] In another embodiment, (1g) is prepared from (1f) under alkaline conditions. In another embodiment, the base is NaHMDS (sodium-hexamethyldisilazane). In another embodiment, the reaction is carried out at -78°C.

[0097] In another embodiment, the steps for preparing formula (I) from compound (1g) include:

[0098] -Preparation of compound (I-1) from compound (1g):

[0099]

[0100] as well as

[0101] - Prepare formula (I) from compound (I-1).

[0102] In another implementation scheme, the entire process is described in scheme 2a:

[0103] Scheme 2a: Method for preparing formula (I) from compound (1g)

[0104]

[0105] In another embodiment, (1g) is reacted with an alkali metal peroxide (e.g., LiOOH, NaOOH, KOOH, or CsOOH) or any other deprotecting group known in the art to remove the benzyloxazolidin-2-one moiety to form (I-1).

[0106] In another embodiment, (I-1) reacts with an amine (e.g., CHA, to provide (1); or other amines - see examples detailed in Q above) to form (I).

[0107] In another embodiment, compound (2) is prepared from formula (I) via a method comprising:

[0108] -From formula (I); and compound (1g-1):

[0109]

[0110] Preparation of compound (2a) (mixture of isomers):

[0111]

[0112] (2a: R,R isomer)(2a: R,S isomer)(2a: S,R isomer);

[0113] - Prepare compound (2b) from (2a):

[0114] as well as

[0115] - Compound (2) was prepared from (2b).

[0116] In one embodiment, the present invention provides a method for preparing compound (2) from formula (I), the method comprising: - from formula (I); and compound (1g-1):

[0117]

[0118] Preparation of compound (2a) (mixture of isomers):

[0119]

[0120] (2a: R,R isomer)(2a: R,S isomer)(2a: S,R isomer);

[0121] - Prepare compound (2b) from (2a):

[0122] as well as

[0123] - Compound (2) was prepared from (2b).

[0124] In some other embodiments, compound (1g-1) is prepared from compound (1g-11):

[0125]

[0126] In another embodiment, (2a) further includes an additional (S,S) isomer:

[0127]

[0128] (2a: S,S isomer).

[0129] In another implementation scheme, the entire process is described in Scheme 3:

[0130] Option 3: Method for preparing compound 2

[0131]

[0132] In another embodiment, (I) is first acidified to provide (I-1), and then reacted with (1g-1). In another embodiment, the reaction of (I-1) with (1g-1) is carried out under alkaline conditions. In another embodiment, the base is LDA (lithium diisopropylaminodimethylamine). In another embodiment, the reaction is carried out at -78°C and then heated to RT.

[0133] In another embodiment, the mixture of (R,R) and (R,S) isomers of (2a) is not separated. In another embodiment, tBuNH2 reacts with (2a) to purify the (R,S) isomer from the (R,R) isomer, thus the (R,R) isomer remains in the reaction mixture and is discarded; and (2b) (i.e., the (R,S) isomer of the tBuNH2 salt) is separated (and ultimately provided (2) after acidification). In another embodiment, tBuNH2 is used in the reaction in combination with LDA and CF3CONH2.

[0134] In another embodiment, compound (3-1) is prepared as detailed in Reider, PJ et al., J. Org. Chem., 52:955-957 (1987), which is incorporated herein by reference.

[0135] In another embodiment, compounds (3-2) are prepared as detailed in PCT Publication No. WO 2021 / 163676, which is incorporated herein by reference.

[0136] In another embodiment, compound (3a) is prepared from compound (3-1) and compound (2) as detailed in PCT Publication No. WO 2012 / 129353, which is incorporated herein by reference.

[0137] In another embodiment, compound (3b) is prepared via a method comprising:

[0138] - Compound (3b-11) was prepared from compounds (3-2) and (2):

[0139]

[0140] Compound (3b-1) was prepared from compound (3b-11):

[0141] as well as

[0142] Compound (3b) was prepared from compound (3b-1).

[0143] In another implementation scheme, the entire process is described in Scheme 4:

[0144] Option 4: A method for preparing compound (3b) from compounds (3-2) and (2).

[0145]

[0146] In another embodiment, (3b-11) is separated. In another embodiment, (3b-11) is not separated.

[0147] In another embodiment, (3b-11) is prepared by (2) and (3-2) under basic conditions. In another embodiment, the base is triethylamine. In another embodiment, the reaction is carried out in the presence of a coupling agent. In another embodiment, the coupling agent is TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium). In another embodiment, the reaction is carried out in the presence of a base (e.g., triethylamine) and in the presence of a coupling agent (e.g., TBTU).

[0148] In another embodiment, (3b-1) is prepared by acidification (e.g., with trifluoroacetic acid (TFA)) and subsequent basification with DABCO (1,4-diazabicyclo[2.2.2]octane).

[0149] In another embodiment, (3b) is prepared by amination (e.g., with ammonia) and coupling agent (e.g., EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)). In another embodiment, the reaction also uses coupling additives / enhancers such as HOBt (hydroxybenzotriazole).

[0150] In some embodiments, any intermediate presented in the preparation method of the present invention may be isolated or not isolated (used without further purification).

[0151] In some embodiments, a solvent is used in the method of the present invention. In one embodiment, the solvent includes alcohol solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, chlorinated solvents, nitrile solvents, polar solvents, or any combination thereof. In another embodiment, non-limiting examples of alcohol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or combinations thereof. In another embodiment, non-limiting examples of ester solvents include ethyl acetate, methyl acetate, isopropyl acetate, or combinations thereof. In another embodiment, non-limiting examples of ether solvents include tetrahydrofuran, diethyl ether, methyl tert-butyl ether (MTBE), or combinations thereof. In another embodiment, non-limiting examples of hydrocarbon solvents include toluene, hexane, heptane, cyclohexane, or combinations thereof. In another embodiment, non-limiting examples of polar aprotic solvents include dimethylacetamide, dimethylformamide, dimethyl sulfoxide, or combinations thereof. In another embodiment, non-limiting examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, or combinations thereof. In another embodiment, non-limiting examples of chlorinated solvents include dichloromethane, chloroform, dichloroethylene, or combinations thereof. In another embodiment, non-limiting examples of nitrile solvents include acetonitrile, propionitrile, or combinations thereof. In another embodiment, non-limiting examples of polar solvents include water. In another embodiment, the solvent is ethanol. In another embodiment, the solvent is isopropyl acetate. Each possibility represents a separate embodiment of the invention.

[0152] In another embodiment, the reaction in the method of the present invention is carried out at a temperature between -5°C and 100°C. In another embodiment, the temperature range is between 60°C and 65°C. In another embodiment, the temperature range is between 0°C and 45°C. In another embodiment, the temperature range is between -5°C and 45°C. In another embodiment, the temperature range is between 5°C and 10°C. In another embodiment, the temperature range is between -5°C and 35°C. In another embodiment, the temperature range is between 0°C and 35°C. In another embodiment, the temperature is 60°C. In another embodiment, the temperature range is between 0°C and 100°C. Each possibility represents a separate embodiment of the present invention.

[0153] definition

[0154] In one embodiment, the term "stable for X weeks / months" (e.g., as in "the salt of formula (I) is stable for 6-12 months") means that the product (salt) maintains its initial purity and / or is measured to be ±5% for at least the specified time. In one embodiment, "maintaining X initial purity for at least the specified time" means that the purity should remain substantially constant, or even beyond the specified time (e.g., for several additional months or years, depending on the specific circumstances and storage conditions in one embodiment). In another embodiment, the stability is found under the following conditions: at room temperature, 2°C-8°C or 40°C and 50%-80%, 50%, 60%, 70%, 75%, or 80% RH (relative humidity); or particularly at 2°C-8°C, 25°C / 60% RH or 40°C / 75% RH. Each possibility and / or condition represents a separate embodiment of the invention.

[0155] In some embodiments, the term "room temperature" means a temperature of 10°C to 40°C. In another embodiment, the term "room temperature" means a temperature of 15°C to 35°C. In another embodiment, the term "room temperature" means a temperature of 25°C to 35°C. In another embodiment, the term "room temperature" means a temperature of 20°C to 30°C. In another embodiment, the term "room temperature" means a temperature of 10°C to 20°C. In another embodiment, the term "room temperature" means a temperature of 10°C to 30°C. Each possibility represents a separate embodiment of the invention.

[0156] In one embodiment, the term "reacting" in the context of this invention is defined as providing one or more conditions (e.g., heating, reflux, mixing) sufficient to cause a chemical reaction in the reactants.

[0157] The following embodiments are presented to illustrate preferred embodiments of the invention more fully. However, they should not in any way be construed as limiting the broad scope of the invention. Example

[0158] Example 1

[0159] Synthesis of compound (I-1)

[0160] LiOH . H₂O + H₂O₂ → LiOOH . H2O + H2O

[0161]

[0162] program

[0163] 1. Load water (7.5L, 2 volumes) into a 600L (HLR-111) reactor at 20℃-25℃.

[0164] 2. LiOH·H2O (0.557Kg) was loaded into a 600L reactor at 20℃-25℃ and U / N2.

[0165] 3. Stir the reactants at 20℃-25℃ for 5-10 minutes.

[0166] 4. Cool the reactants to -5°C to 0°C.

[0167] 5. Slowly add hydrogen peroxide (30% w / v water content) (1.7 L, 1.7 equivalents) to 1 In reactants at temperatures below 5°C.

[0168] 6. Stir the reactants at -5°C to 0°C for 30 minutes.

[0169] 7. Dissolve in THF (20L, 5.3 g / L volume) 2 (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-6,6,6-trifluorohexanoate ((1 g); 3.8 kg, limiting reagent) was slowly added to the reactants below 5 °C.

[0170] 8. Stir the reactants at -5°C to 0°C for 1-2 hours.

[0171] 9. The reaction was monitored by HPLC (limit: determination: <8% w / w (1g)).

[0172] (Sampling: Take 2 ml of sample from the reactants and submit it for process HPLC analysis).

[0173] 10. If the limit is exceeded, continue stirring for 1 hour.

[0174] 11. Quench the reactants at below 10°C with a 24.5% sodium bisulfite aqueous solution (15.2 L, 4 volumes). The pH of the aqueous solution is approximately 6–5.5.

[0175] 12. Raise the temperature of the reactants to 20℃-25℃.

[0176] 13. Stir the reactants at 20℃-25℃ for 30 minutes.

[0177] 14. Stop stirring and allow the layers to separate.

[0178] 15. Layer separation: the bottom aqueous layer in HDPE-1 and the top organic layer in HDPE-2.

[0179] 16. Load the aquifer from HDPE-1 into the reactor.

[0180] 17. Load fresh MTBE (40L, 10 volumes) into the reactor.

[0181] 18. Stir the mixture at RT for 10 minutes.

[0182] 19. Layer separation: the bottom aqueous layer in HDPE-1 and the top organic layer in HDPE-2.

[0183] 20. Load the combined organic layer from HDPE-2 into the reactor.

[0184] 21. Load a saturated sodium chloride solution (19 L, 5 volumes) into the reactor.

[0185] 22. Stir the mixture at RT for 10 minutes.

[0186] 23. Separate the layers: the bottom water-bearing layer in HDPE-3 and the organic layer in HDPE-4.

[0187] 24. Load the organic layer from HDPE-4 into a clean reactor.

[0188] 25. Concentrate the reactants under vacuum at 45℃-50℃ until the volume reaches 2.0.

[0189] 26. Load fresh n-heptane (11 L, 3 volumes) into the reactor and continue concentration until the 2-volume stage.

[0190] 27. Repeat the solvent swap once more with n-heptane (11 L, 3 volumes) until the 2-volume stage.

[0191] 28. Load MTBE (3L, 0.8 volume) into the reactor.

[0192] 29. Load n-heptane (19 L, 5 volumes) into the reactor.

[0193] 30. Cool the reactants to 0℃-5℃ (to form a solid).

[0194] 31. Stir the slurry at a temperature below 0°C for 1 hour.

[0195] 32. Filter the solids using a clean Nutsche filter and wash the wet filter cake with n-heptane (11 L, 3 volumes).

[0196] 33. Prepare the materials 3Unload into a double polythene bag.

[0197] 34. Unload the filtrate into clean HDPE-5 and label its contents.

[0198] 35. Load the filtrate from HDPE-5 into a clean reactor.

[0199] 36. Concentrate the reactants under vacuum at 45℃-50℃ until the volume reaches 2.0.

[0200] 37. Load MTBE (38L, 10 volumes) into the reactor.

[0201] 38. Load petroleum ether (38L, 10 volumes) into the reactor.

[0202] 39. Cool the reactants to 15℃-20℃.

[0203] 40. Add tert-butylamine (0.78 kg, 1.2 equivalents) slowly to the reactants at a temperature below 5°C (to form a solid).

[0204] 41. Stir the slurry at 20℃-25℃ for 1-2 hours.

[0205] 42. Filter the solids using a clean Nutsche filter and wash the wet filter cake with an MTBE / petroleum ether (1:1) mixture (12L, 3 volumes).

[0206] 43. Transfer the filtrate to clean HDPE-6 and label its contents.

[0207] 44. Blot the material dry at 20℃-25℃ for 1 hour.

[0208] 45. Unload the material into a double-layer polyethylene bag.

[0209] 46. ​​At RT, DCM (40L, 10 volumes) is loaded into a 600L (HLR-111) reactor.

[0210] 47. Load the material from step 44 into the reactor.

[0211] 48. Stir the reactants at 20℃-25℃ for 5-10 minutes.

[0212] 49. Load 30L (8 volumes) of 1.5N HCl solution into the reactor.

[0213] 50. Stir the reactants at 20℃-25℃ for 10 minutes.

[0214] 51. Separate the bottom organic layer in HDPE-7.

[0215] 52. Load fresh DCM (15L, 4 volumes) into the reactor.

[0216] 53. Stir the mixture at RT for 10 minutes.

[0217] 54. Layer separation: the bottom organic layer in HDPE-7 and the top water-impregnating layer in HDPE-8.

[0218] 55. Load the combined organic layer from HDPE-7 into the reactor.

[0219] 56. Load water (25L, 6.5 volume) into the reactor.

[0220] 57. Stir the mixture at RT for 10 minutes.

[0221] 58. Layer separation: the bottom organic layer in HDPE-7 and the top water-impregnated layer in HDPE-9.

[0222] 59. Load the organic layer from HDPE-7 into the reactor.

[0223] 60. Load a saturated sodium chloride solution (25 L, 6.5 volume) into the reactor.

[0224] 61. Stir the mixture at RT for 10 minutes.

[0225] 62. Layer separation: the bottom organic layer in HDPE-10 and the top water-impregnated layer in HDPE-7.

[0226] 63. Add anhydrous sodium sulfate (1.0 w / w) to HDPE-10 and treat the organic layer for about 1 hour.

[0227] 64. Use a clean Nutsche filter to filter the contents of the HDPE-10.

[0228] 65. Collect the filtrate into HDPE-11.

[0229] 66. Load the filtrate from HDPE-11 into a clean reactor.

[0230] 67. Concentrate the filtrate under vacuum at 45℃-50℃ until it reaches a volume of ~1.0-1.5.

[0231] 68. Unload the material from the reactor into a clean HDPE container and label its contents.

[0232] 69. Take a small sample of the product and submit it for complete analysis.

[0233] Notes

[0234] 1. The addition of hydrogen peroxide (30%) is exothermic. Typically, this addition takes 40 minutes.

[0235] 2. The addition of (1g) solution is exothermic. Typically, this addition takes 1.5 hours.

[0236] 3. The solid material is (S)-4-benzyloxazolidin-2-one.

[0237] Batch summary

[0238] Batch input: 3.8Kg

[0239] Batch output: 1.3Kg

[0240] Yield: 54.36%

[0241] AR ID: 95099-067-06

[0242] Appearance: Pale yellow liquid

[0243] Purity as a percentage of GC: 98.38 AP

[0244] Measurement: 97.60WP

[0245] Example 2

[0246] Synthesis of CHA salt (1)

[0247]

[0248] program:

[0249] 1. Load MTBE (10 w / w) into (I-1) and stir at 25℃±5℃ for 10 minutes.

[0250] 2. Add cyclohexylamine (0.252 w / w) slowly to the above-mentioned reactants at 25℃±5℃ and stir continuously at 25℃±5℃ for at least (NLT) 30 min.

[0251] 3. Raise the temperature of the reactants to 45℃±5℃ and stir at 45℃±5℃ for NLT 60 min.

[0252] 4. Cool the reactants to 25℃±5℃ and stir at 25℃±5℃ for NLT 60 min.

[0253] 5. Filter solids at 25℃±5℃ and wash with MTBE-commercially available (5w / w) washing bed.

[0254] 6. Blot the material dry for 30 minutes (NLT) and then unload the wet material.

[0255] 7. Send the wet material sample to QC to check (1) HPLC purity and chiral purity (by LCMS chiral purity method).

[0256] Acceptance criteria: HPLC purity: NLT 90.0%

[0257] Chiral purity: NLT 90.0 w / w%.

[0258] HPLC purity w / w: NLT 90.0 w / w%

[0259] Note: If the results meet the acceptance criteria, the material will then be purified.

[0260] 8. Load MTBE (commercially available, 8w / w) at 25℃±5℃, followed by loading wet material.

[0261] 9. Stir the mixture at 25℃±5℃ for NLT 60 min.

[0262] 10. Filter solids and wash the bed with MTBE (commercially available 5w / w).

[0263] 11. Blot the material dry for 30 minutes (NLT) and then unload the wet material.

[0264] 12. Send the wet material sample to QC to check (1) HPLC purity and chiral purity (by LCMS chiral purity method).

[0265] Acceptance criteria: HPLC purity: NLT 90.0%

[0266] Chiral purity: NLT 90.0 w / w%.

[0267] HPLC purity: NLT 90.0 w / w%

[0268] Note: If the results meet the acceptance criteria, the material will then be purified.

[0269] 13. Load the wet material into a VTD (vacuum tray dryer) and dry it under vacuum (NLT 300 mm Hg) at 25℃±5℃ for 2 hours.

[0270] Note: After drying for 2 hours, de-lumping and shuffling are performed.

[0271] 14. Raise the dryer temperature to 45℃±5℃ and dry the material in a vacuum (NLT-300mmHg) VTD at 45℃±5℃ until the water content of the sample meets the acceptance criteria.

[0272] 15. Starting from the 8th hour, send the samples to QC for water content determination every 4 hours until the water content of the samples meets the acceptance criteria.

[0273] ■Note: Mix the dried material before sampling.

[0274] ■ Acceptance criteria:

[0275] ■Water content: NMT 2.0% w / w

[0276] 16. Cool the VTD to 25°C ± 5°C and unload the dried product into a double-layer polyethylene bag placed in an HDPE container.

[0277] Example 3

[0278] Stability studies (I-1) and (1)

[0279] The determination of oily free acid (I-1) and water content was carried out after a 6-month period at 25°C / 60% RH and 40°C / 75% RH (Table 2a).

[0280] Table 2a: HPLC results at 25℃ / 60%RH and 40℃ / 75%RH at the initial stage and after a 6-month time period (I-1). Measurement and water content

[0281] test Initial results 25℃ / 60%RH 40℃ / 75%RH Determined, % w / w (according to HPLC) 93.5 92.8 84.5 Water content, % (according to KF) 0.8 2.0 2.3

[0282] Similarly, regarding the corresponding CHA salt (1) as a powder, its purity / determination was tested:

[0283] Table 2b: HPLC measurements at 25℃ / 60%RH and 40℃ / 75%RH at the initial stage and after a 6-month period (1) Moisture and water content:

[0284] test Initial results 25℃ / 60%RH 40℃ / 75%RH Determined, % w / w (according to HPLC) 95.0 95.1 94.4 Water content, % (according to KF) 0.2 0.3 0.3

[0285] Table 2c: At 25℃ / 60% RH, 40℃ / 75% RH and 2℃-8℃, initially and after 1 month, 3 months and 6 months. HPLC determination after a period of one month (1):

[0286]

[0287] As can be observed, the salt (1) is much more stable than the free acid compound (I-1). Under all test conditions, the high purity determination of the salt hardly changes over time, while the free acid starts with an HPLC purity of ~93%, which further decreases over time. It can be stated that the increased water content in the free acid over time leads to the observed degradation of the determination as the test proceeds.

[0288] Example 4

[0289] Stability of (I-1) Na salt and tBuNH2 salt

[0290] Na salt and tBuNH2 salt of (I-1) were prepared. The stability of the salts was tested and compared with that of CHA salt ((1)).

[0291] Table 3: GC / MS determination of salts under various conditions (I-1)

[0292]

[0293] As shown in Table 3, the CHA salt (compound (1)) is the most stable salt. This corresponds well with the results shown in Example 3, where the high purity of (1) hardly changes over time. It should also be noted that the CHA salt (compound (1)) shows an increase in purity after heating, which may be related to the evaporation of residual solvent during heating. Table 3 also highlights that specific salts of (I-1) provide high purity over time. However, it cannot be said that any possible salt (any possible cation) of (I-1) will result in such high stability over time.

[0294] Example 5

[0295] Synthesis of compound (2)

[0296] a. Preparation of (1b), (1c) and (1d)

[0297]

[0298] 1. Load DMF (4.72 kg, 4.72 w / w) into the reactor at 20°C to 30°C.

[0299] 2. Load sodium hydroxide pellets (0.2 kg, 0.2 w / w) into the reactor at 20°C to 30°C.

[0300] 3. Stir the reaction mixture under a nitrogen atmosphere for NLT 10 min.

[0301] 4. Raise the temperature of the reactants to 40℃±5℃.

[0302] 5. Stir the reaction mixture under a nitrogen atmosphere at 40℃±5℃ for NLT 10 min.

[0303] 6. Load (1a) (1.07 kg, 1.07 w / w) into the reactants at 40 °C ± 5 °C for 30 min NLT.

[0304] 7. Raise the temperature of the reactants to 45℃±5℃.

[0305] 8. Stir the reaction mixture at 45℃±5℃ under a nitrogen atmosphere for NLT 60 min.

[0306] 9. Slowly add (1a-1) (1.00 kg, 1.00 w / w) to the reactants at 45℃±5℃ under a nitrogen atmosphere.

[0307] 10. Stir the reaction mixture at 45℃±5℃ under a nitrogen atmosphere for NLT 60 min.

[0308] 11. Starting from the first hour, send samples to QC every 2 hours for GC testing of (1a-1) content until it meets the requirements. Acceptance criteria: (1a-1) content - NMT (not greater than) 3.0A (integral area)% according to GC. Note: Sample preparation: Take approximately 5 mL of the reaction mixture and submit it to QC.

[0309] 12. At 45℃±5℃, a methanol:water mixture (with methanol (0.79 kg, 0.79 w / w) added slowly and mixed in purified water (1.0 kg, 1.0 w / w)) is added to the reactor through a loading vessel.

[0310] 13. At 45℃±5℃, add 10N NaOH solution (NaOH (0.8 kg, 0.8 w / w) slowly and dissolved in purified water (2.0 kg, 2.0 w / w)) to the reactor through a loading vessel.

[0311] 14. Raise the material temperature to 50℃±5℃ under a nitrogen atmosphere.

[0312] 15. Stir the reaction mixture under a nitrogen atmosphere for NLT 60 min.

[0313] 16. Starting from the first hour, send samples to QC every 2 hours for GC inspection of (1b) content until compliance is achieved. Acceptance criteria: (1b) content - according to GC NMT 2.0A%.

[0314] Note: Sample preparation: Take about 5 mL of the reaction material into a vial, quench the reaction material with 2.5 mL of water, and extract with 5 mL of methyl tert-butyl ether (MTBE). Submit the MTBE layer for GC analysis.

[0315] 17. Cool the reactants to 25℃±5℃.

[0316] 18. Slowly add purified water (3.0 kg, 3.0 w / w) to the reactor at 25℃±5℃.

[0317] 19. Methyl tert-butyl ether (3.70 kg, 3.70 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0318] 20. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0319] 21. Allow reactants to settle for NLT 15 minutes.

[0320] 22. Collect the bottom aquifer in a separate HDPE container.

[0321] 23. Collect the top organic layer in a separate HDPE container.

[0322] 24. Load the aquifer from step 22 back into the reactor at 25℃±5℃.

[0323] 25. Methyl tert-butyl ether (3.70 kg, 3.70 w / w) was loaded into the reactor described above at 25 °C ± 5 °C.

[0324] 26. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0325] 27. Allow the reactants to settle for NLT 15 minutes.

[0326] 28. Collect the bottom aquifer in a separate HDPE container.

[0327] 29. Collect the top organic layer in a separate HDPE container.

[0328] 30. The aquifer from step 28 is returned to the reactor via vacuum loading.

[0329] 31. Cool the reactants to 15℃±5℃.

[0330] 32. At 15℃±5℃, add a 6N HCl solution (by slowly adding concentrated HCl (3.22 kg to 4.50 kg, 3.22 w / w to 4.50 w / w) and mixing it with purified water (2.28 kg to 3.20 kg, 2.28 w / w to 3.20 w / w)) to the reactants.

[0331] Note: Adjust the pH of the reactants to acidic (1.0-1.5).

[0332] 33. Methyl tert-butyl ether (7.40 kg, 7.40 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0333] 34. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0334] 35. Allow reactants to settle for NLT 15 minutes.

[0335] 36. Collect the bottom aquifer in a separate HDPE container.

[0336] 37. Collect the top organic layer in a separate HDPE container.

[0337] 38. Load the aquifer from step 36 back into the reactor.

[0338] 39. Methyl tert-butyl ether (3.70 kg, 3.70 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0339] 40. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0340] 41. Allow the reactants to settle for NLT 15 minutes.

[0341] 42. Collect the bottom aquifer in a separate HDPE container.

[0342] 43. Collect the top organic layer in a separate HDPE container.

[0343] 44. The aquifer from step 42 is returned to the reactor via vacuum loading.

[0344] 45. Load MTBE (3.70 kg, 3.70 w / w) into the reactor at 25℃±5℃.

[0345] 46. ​​Stir the reactants at 25℃±5℃ for NLT 30 min.

[0346] 47. Allow reactants to settle for NLT 15 minutes.

[0347] 48. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0348] 49. Load the organic layers from steps 37 and 43 back into the reactor at 25℃±5℃.

[0349] 50. Load water (5.0 kg, 5.0 w / w) into the reactor at 25℃±5℃.

[0350] 51. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0351] 52. Allow reactants to settle for NLT 15 minutes.

[0352] 53. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0353] 54. Load water (5.0 kg, 5.0 w / w) into the reactor at 25℃±5℃.

[0354] 55. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0355] 56. Allow reactants to settle for NLT 15 minutes.

[0356] 57. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0357] 58. Load water (5.0 kg, 5.0 w / w) into the reactor at 25℃±5℃.

[0358] 59. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0359] 60. Allow reactants to settle for NLT 15 minutes.

[0360] 61. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0361] 62. Load water (5.0 kg, 5.0 w / w) into the reactor at 25℃±5℃.

[0362] 63. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0363] 64. Allow reactants to settle for NLT 15 minutes.

[0364] 65. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0365] 66. Load sodium sulfate (0.5 kg - 1.0 kg, 0.5 w / w - 1.0 w / w) into the reactor.

[0366] 67. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0367] 68. The material is filtered under vacuum using a Nutsche filter.

[0368] 69. Wash the bed with methyl tert-butyl ether (2.25 kg, 2.25 w / w) at 25℃±5℃.

[0369] 70. Collect the filtrate in an HDPE container.

[0370] 71. Load the filtrate from step 70 into a clean and dry reactor at 25℃±5℃.

[0371] 72. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed, and apply high vacuum continuously for 60 minutes (NLT).

[0372] 73. The sample was sent to QC for HPLC testing of the (1c) content. Acceptance criteria: The (1c) content results were reported.

[0373] 74. Load dimethylformamide (4.20 kg, 4.20 w / w) into the reactor at below 50 °C and concentrate the material under vacuum at below 50 °C for 45 min.

[0374] 75. Cool the reactants to 25℃±5℃.

[0375] 76. At 25℃±5℃, p-toluenesulfonic acid monohydrate (1.20 kg, 1.20 w / w) was loaded into the reactor.

[0376] 77. Stir the reaction mixture under a nitrogen atmosphere at 25°C ± 5°C for NLT 10 min.

[0377] 78. Raise the material temperature to 105℃±5℃.

[0378] 79. Stir the reaction mixture at 105℃±5℃ for 4 hours. Then, starting from the 4th hour, send samples to QC every 2 hours for (1c) content determination by HPLC until the reaction meets the requirements. Acceptance criteria: (1c) content - according to HPLC NMT 1.0 w / w%.

[0379] Note: Sample preparation: Take about 5 mL of the reaction material and submit it to QC.

[0380] 80. Cool the temperature of the reactants to 20℃±5℃.

[0381] 81. Slowly add purified water (8.90 kg, 8.90 w / w) to the reactor at 20℃±5℃.

[0382] 82. Raise the temperature of the reactants to 25℃±5℃.

[0383] 83. Methyl tert-butyl ether (6.6 kg, 6.6 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0384] 84. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0385] 85. Allow reactants to settle for NLT 15 minutes.

[0386] 86. Collect the bottom aquifer in a separate HDPE container.

[0387] 87. Collect the top organic layer in a separate HDPE container.

[0388] 88. Load the aquifer from step 86 back into the reactor at 25℃±5℃.

[0389] 89. Methyl tert-butyl ether (6.6 kg, 6.6 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0390] 90. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0391] 91. Allow reactants to settle for NLT 15 minutes.

[0392] 92. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0393] 93. Load the organic layer back into the reactor from step 87.

[0394] 94. Load water (8.90 kg, 8.90 w / w) into the reactor at 25℃±5℃.

[0395] 95. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0396] 96. Allow reactants to settle for NLT 15 minutes.

[0397] 97. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0398] 98. Load water (8.90 kg, 8.90 w / w) into the reactor at 25℃±5℃.

[0399] 99. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0400] 100. Allow reactants to settle for NLT 15 minutes.

[0401] 101. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0402] 102. At 25℃±5℃, 8.90 kg of purified water (8.90 w / w) was loaded into the reactor.

[0403] 103. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0404] 104. Allow reactants to settle for NLT 15 minutes.

[0405] 105. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0406] 106. Load water (8.90 kg, 8.90 w / w) into the reactor at 25℃±5℃.

[0407] 107. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0408] 108. Allow reactants to settle for NLT 15 minutes.

[0409] 109. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0410] 110. Load sodium sulfate (0.5 kg to 1.0 kg, 0.5 w / w to 1.0 w / w) into the reactor.

[0411] 111. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0412] 112. The material is filtered under vacuum using a Nutsche filter.

[0413] 113. Wash the bed with methyl tert-butyl ether (2.25 kg, 2.25 w / w) at 25℃±5℃.

[0414] 114. Collect the filtrate in an HDPE container.

[0415] 115. Load the filtrate from step 114 into the reactor at 25℃±5℃.

[0416] 116. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed, and apply high vacuum continuously for NLT 180 minutes.

[0417] 117. Cool the reactants to 30℃±5℃. Unload the reactants into HDPE containers.

[0418] 118. Send the sample to QC for purity according to GC (1d). Acceptance criteria: (1d) content - NLT 80.0% area according to GC.

[0419] Yield: 0.49 kg

[0420] Theoretical yield: 0.696 kg

[0421] Yield %: 70.40%

[0422] b. Preparation of (1e) and (1f)

[0423]

[0424] 1. Load dried THF (4.44 kg, 4.44 w / w) into the reactor at 25℃±5℃.

[0425] A 10 ml sample of tetrahydrofuran was sent to QC for water content testing via Karl Fischer titration (KF). Acceptance criteria: Water content NMT 0.2 w / v%.

[0426] 2. (1d) (1.23kg, 1.23w / w) was loaded into the reactor at 25℃±5℃ under a nitrogen atmosphere.

[0427] 3. Stir the reaction mixture under a nitrogen atmosphere for NLT 5 min.

[0428] 4. Load 4-(dimethylamino)pyridine (0.103 kg, 0.103 w / w) into the reactants at 25 °C ± 5 °C.

[0429] 5. Stir the reaction mixture under a nitrogen atmosphere for NLT 5 min.

[0430] 6. Load N,N'-carbonyldiimidazole into the reactants in batches (1.47 kg, 1.47 w / w) at 25 °C ± 5 °C.

[0431] 7. Stir the reaction mixture at 25℃±5℃ under a nitrogen atmosphere for NLT 60 min.

[0432] 8. Starting from the first hour, send samples to QC every 2 hours for GC inspection of (1d) content until it meets requirements. Acceptance criteria: (1d) content - based on GC NMT 2.0% area.

[0433] 9. Unload the reactants into a clean HDPE drum under a nitrogen atmosphere.

[0434] 10. Under a nitrogen atmosphere at 25℃±5℃, dry THF (8.88 kg, 8.88 w / w) was loaded into another reactor.

[0435] A 10 ml tetrahydrofuran sample was sent to QC for water content testing via KF. Acceptance criteria: Water content NMT 0.2 w / v%.

[0436] 11. Add (1e-1) (1.0 kg, 1.0 w / w) to the reaction at 25 °C ± 5 °C under a nitrogen atmosphere.

[0437] 12. Stir the reaction mixture under a nitrogen atmosphere at 25℃±5℃ for NLT 5 minutes.

[0438] 13. Cool the reaction materials under a nitrogen atmosphere at -74℃±5℃.

[0439] 14. Under a nitrogen atmosphere at (-74℃) ± 5℃, slowly add n-butyllithium (2.5M in hexane) (1.72kg, 1.72w / w) from the cylinder to the reactants.

[0440] 15. Stir the reactants under a nitrogen atmosphere at -74℃±5℃ for NLT 120 min.

[0441] 16. By maintaining the temperature at -74℃±5℃ under a nitrogen atmosphere, the solution prepared above (step 9) is slowly added to the reactants through a loading container.

[0442] 17. Stir the reactants for 120 minutes at -74℃±5℃ under a nitrogen atmosphere.

[0443] 18. Starting from the 2nd hour, send samples to QC every 2 hours for (1e-1) content to be checked by HPLC until it meets the requirements. Acceptance criteria: (1e-1) - NMT 5.0% area according to HPLC.

[0444] Note: Sample preparation: Take about 5 mL of the reaction material in a vial and quench the reaction material with 5 mL of ammonium chloride aqueous solution (20%), and send the top organic layer to HPLC.

[0445] 19. Raise the temperature of the reactants to (-40℃) ±10℃ under a nitrogen atmosphere.

[0446] 20. Add a 30% ammonium chloride solution at -40℃±10℃ under a nitrogen atmosphere (add ammonium chloride (1.5 kg, 1.5 w / w) and dissolve it in purified water (5.0 kg, 5.0 w / w)).

[0447] 21. Raise the reaction temperature of the materials to 25℃±5℃.

[0448] 22. Methyl tert-butyl ether (7.40 kg, 7.40 w / w) was loaded into the reactants at 25 °C ± 5 °C.

[0449] 23. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0450] 24. Allow reactants to settle for NLT 15 minutes.

[0451] 25. Collect the bottom aquifer in a separate HDPE container.

[0452] 26. Collect the top organic layer in a separate HDPE container.

[0453] 27. Load the aquifer (step 25) back into the reactor at 25℃±5℃.

[0454] 28. Methyl tert-butyl ether (7.40 kg, 7.40 w / w) was loaded into the reactants at 25 °C ± 5 °C.

[0455] 29. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0456] 30. Allow reactants to settle for NLT 15 minutes.

[0457] 31. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0458] 32. Load the organic layer (step 26) back into the reactor.

[0459] 33. Add a 10% sodium bicarbonate solution (sodium bicarbonate (1.0 kg, 1.0 w / w) loaded and dissolved in purified water (10.0 kg, 10.0 w / w)) to the organic layer above at 25 °C ± 5 °C.

[0460] 34. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0461] 35. Allow reactants to settle for NLT 15 minutes.

[0462] 36. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0463] 37. Load purified water (10.0 kg, 10.0 w / w) into the reactor at 25℃±5℃.

[0464] 38. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0465] 39. Allow reactants to settle for NLT 15 minutes.

[0466] 40. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0467] 41. At 25℃±5℃, add a 1.5N HCl solution (concentrated HCl (1.61kg, 1.61w / w) slowly added and dissolved in purified water (8.64w / w)) to the reactor through a loading vessel.

[0468] 42. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0469] 43. Allow reactants to settle for NLT 15 minutes.

[0470] 44. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0471] 45. Load purified water (10.0 kg, 10.0 w / w) into the reactor at 25℃±5℃.

[0472] 46. ​​Stir the reactants at 25℃±5℃ for NLT 15 min.

[0473] 47. Allow reactants to settle for NLT 15 minutes.

[0474] 48. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0475] 49. Add a sodium chloride solution (sodium chloride (2.8 kg, 2.8 w / w) loaded and dissolved in purified water (10.0 kg, 10.0 w / w)) to the organic layer above at 25 °C ± 5 °C.

[0476] 50. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0477] 51. Allow reactants to settle for NLT 15 minutes.

[0478] 52. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0479] 53. Sodium sulfate (1.0 kg, 1.0 w / w) was loaded into the organic layer above at 25 °C ± 5 °C.

[0480] 54. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0481] 55. Use a Nutsche filter to filter the material under vacuum.

[0482] 56. Wash the bed with methyl tert-butyl ether (2.22 kg, 2.22 w / w) at 25℃±5℃.

[0483] 57. Collect the filtrate in an HDPE container.

[0484] 58. Load the filtrate (step 57) into a clean and dry reactor at 25℃±5℃.

[0485] 59. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed.

[0486] 60. Load n-heptane (2.05 kg, 2.05 w / w) into the reactor at a temperature below 50°C.

[0487] 61. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed.

[0488] 62. Load n-heptane (2.05 kg, 2.05 w / w) into the reactor at a temperature below 50 °C.

[0489] 63. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed, and apply high vacuum continuously for 60 minutes (NLT).

[0490] 64. Cool the reactants to 25℃±5℃.

[0491] 65. The sample is sent to QC for purity determination based on HPLC (1f).

[0492] 66. Rinse the reactor with ethyl acetate (0.902 kg, 0.902 w / w) at 25℃±5℃.

[0493] 67. Slowly add n-heptane (6.16 kg, 6.16 w / w) to the reactants at 25 °C ± 5 °C.

[0494] 68. Cool the reactants at a temperature below 20°C.

[0495] 69. At temperatures below 20°C, (1f) was loaded into the reactants as a seed material (0.010 kg, 0.010 w / w).

[0496] 70. Cool the reactants to 0℃±5℃.

[0497] 71. Stir the reaction mixture at 0℃±5℃ for NLT 1h.

[0498] 72. Rinse the reactor with n-heptane (3.42 kg, 3.42 w / w) at 0℃±5℃.

[0499] 73. Wash the bed with the n-heptane solvent described above at 0℃±5℃.

[0500] 74. Blot the material dry for 60 minutes (NLT), and unload the wet material into a double-layer polyethylene bag and place it in an HDPE container.

[0501] 75. Send the wet sample to QC for purity and water content based on HPLC (1f).

[0502] Acceptance criteria: (1f) Content - based on NLT 90.0% area and water content by HPLC.

[0503] Yield: ~1.16kg

[0504] Theoretical yield: 2.02 kg

[0505] Yield %: ~57.42%

[0506] c. Preparation of (1g), (I-1) and (1)

[0507] ((1g)→(1) Performed using the alternative procedure to the procedure in Examples 1-2)

[0508]

[0509]

[0510] 1. Under a nitrogen atmosphere at 25℃±5℃, dry THF (8.89 kg, 8.89 w / w) was loaded into the reactor.

[0511] Send a 10ml sample of tetrahydrofuran to QC for water content testing via KF. Acceptance criteria: Water content NMT (not greater than) 0.15 w / v%.

[0512] 2. Load (1f) (1.0 kg, 1.0 w / w) into the reactor and stir the reaction mixture under a nitrogen atmosphere for NLT 5 min.

[0513] A 5ml sample of the reactants was sent to QC for water content testing via KF. Acceptance criteria: Water content NMT 0.15 w / v%.

[0514] 3. Powdered molecular sieve 4a (0.5 kg, 0.5 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0515] 4. Stir the reaction mixture at 25℃±5℃ under a nitrogen atmosphere for NLT 30 min.

[0516] Samples are sent to QC every hour, starting 30 minutes later, for KF to check water content until it meets requirements. Acceptance criteria: Water content NMT 0.15 w / v%.

[0517] 5. Preparation of the diatomaceous earth bed: Diatomaceous earth (0.7 kg-1.5 kg, 0.7 w / w-1.5 w / w) and dried THF (0.89 kg-1.78 kg, 0.89 w / w-1.78 w / w) are loaded into an HDPE container. The diatomaceous earth solution is filtered through a sparkler filter. The solvent is unloaded and sent for disposal.

[0518] 6. Under a nitrogen atmosphere, filter the reactants (step 4) through the sparkler filter described above.

[0519] 7. Wash the wet filter cake with dry THF (0.89 kg - 1.78 kg, 0.89 w / w - 1.78 w / w), and transfer the filtrate to another reactor under closed conditions by nitrogen pressure.

[0520] Send a 5ml sample from the reactor (step 7) to QC for water content testing via KF. Acceptance criteria: Water content NMT 0.15 w / v%.

[0521] 8. Cool the reactants to -70℃±5℃ under a nitrogen atmosphere.

[0522] 9. Under a nitrogen atmosphere, add NaHMDS (1M THF solution) (3.15 w / w) to the loading container under vacuum.

[0523] 10. Under a nitrogen atmosphere at a temperature of -70℃±5℃, slowly add NaHMDS (1M THF solution) (3.15kg, 3.15w / w) to the reactants over a period of 45 minutes using NLT.

[0524] 11. Stir the reaction mixture under a nitrogen atmosphere at -70℃±5℃ for NLT 2 h.

[0525] 12. Under a nitrogen atmosphere at -70℃±5℃, tert-butyl bromoacetate (0.805 kg, 0.805 w / w) was slowly added to the reactants over a period of 30 min using NLT.

[0526] 13. Stir the reactants under a nitrogen atmosphere for NLT 60 min.

[0527] 14. Starting from the first hour, send samples to QC every 2 hours for (1f) content check by HPLC until the requirements are met. Acceptance criteria: (1f) content - NMT 5.0A% according to HPLC. Note: Sampling: Quench 2 ml of reactant with 2 ml of 20% NH4Cl solution and extract with 2 ml of EtOAc; submit the ethyl acetate layer for analysis.

[0528] 15. Raise the temperature of the reactants to 0℃±10℃ under a nitrogen atmosphere.

[0529] 16. Under a nitrogen atmosphere at 0℃±10℃, add a 20% ammonium chloride solution (ammonium chloride (2.0 kg, 2.0 w / w) slowly added and dissolved in purified water (10.0 kg, 10.0 w / w)) to the reactants.

[0530] 17. Raise the temperature of the reactants to 25℃±5℃.

[0531] 18. Load ethyl acetate (9.02 kg, 9.02 w / w) into the reactor at 25 °C ± 5 °C.

[0532] 19. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0533] 20. Allow reactants to settle for NLT 15 minutes.

[0534] 21. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0535] 22. Load a 10% sodium bicarbonate solution (sodium bicarbonate (1.0 kg, 1.0 w / w) dissolved in purified water (10.0 kg, 10.0 w / w)) into the organic layer above at 25 °C ± 5 °C.

[0536] 23. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0537] 24. Allow reactants to settle for NLT 15 minutes.

[0538] 25. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0539] 26. Add a sodium chloride solution (sodium chloride (2.8 kg, 2.8 w / w) loaded and dissolved in purified water (10.0 kg, 10.0 w / w)) to the organic layer above at 25 °C ± 5 °C.

[0540] 27. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0541] 28. Allow reactants to settle for NLT 15 minutes.

[0542] 29. Collect the bottom aquifer in a separate HDPE container.

[0543] 30. Collect the organic layer in a separate HDPE container.

[0544] 31. Load the organic layer (step 30) back into the clean and dry reactor at 25℃±5℃.

[0545] 32. Concentrate the organic layer under vacuum at a temperature below 50°C until no distillate is observed, and apply high vacuum continuously for 60 minutes (NLT).

[0546] 33. Cool the reactants to 25℃±5℃.

[0547] 34. Send the sample to QC for purity determination based on HPLC (1g).

[0548] 35. Load THF (5.0 kg, 5.0 w / w) into the reactor under vacuum and stir the material at 25 °C ± 5 °C for NLT 10 min.

[0549] 36. Unload the reactants into an HDPE container.

[0550] 37. Rinse the reactor with THF (1.50 kg, 1.50 w / w) at 25℃±5℃.

[0551] 38. Unload the rinsed THF into the HDPE container described above (step 36).

[0552] 39. Send 5 ml of sample to QC for determination according to HPLC (1 g).

[0553] 40. Load purified water (2.73 kg, 2.73 w / w) into a clean and dry reactor at 25 °C ± 5 °C.

[0554] 41. Lithium hydroxide monohydrate (0.20 kg, 0.20 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0555] 42. Stir the reactants at 25℃±5℃ for NLT 10 min.

[0556] 43. Cool the reactants to 0℃±5℃.

[0557] 44. Add hydrogen peroxide (30%) (0.61 kg, 0.61 w / w) slowly to the reactants at 0℃±5℃.

[0558] 45. Stir the reactants at 0℃±5℃ for NLT 30 min.

[0559] 46. ​​At 0℃±5℃, slowly add (1g) of the above-prepared THF solution (step 38) to the reactants.

[0560] 47. Stir the reactants at 0℃±5℃ for NLT 60 min.

[0561] 48. Starting from the 2nd hour, send samples to QC every 3 hours for the content (1g) determined by HPLC until it meets the requirements. Acceptance criteria: (1g) content: NMT 1.0 w / w%. Note: Sampling: Quench 2ml of the reaction material with 2ml of 25% sodium bisulfite and submit the top THF layer for analysis.

[0562] 49. At temperatures below 10°C, slowly add a 25% sodium bisulfite solution (sodium bisulfite (1.0 kg, 1.0 w / w) dissolved in purified water (4.0 kg, 4.0 w / w)) to the reactants.

[0563] 50. Raise the temperature of the reactants to 25℃±5℃.

[0564] 51. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0565] 52. Allow reactants to settle for NLT 15 minutes.

[0566] 53. Collect the bottom aquifer in a separate HDPE container. Use a pH meter to check the pH of the aquifer (5-7).

[0567] 54. Collect the top organic layer in a separate HDPE container.

[0568] 55. Load the aquifer (step 53) back into the reactor at 25℃±5℃.

[0569] 56. Methyl tert-butyl ether (10.0 kg, 10.0 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0570] 57. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0571] 58. Allow reactants to settle for NLT 15 minutes.

[0572] 59. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0573] 60. Load the organic layer (step 54) back into the reactor at 25℃±5℃.

[0574] 61. At a temperature below 25°C ± 5°C, add a 25% sodium bisulfite solution (sodium bisulfite (1.0 kg, 1.0 w / w) dissolved in purified water (4.0 kg, 4.0 w / w)) to the reactants.

[0575] 62. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0576] 63. Allow reactants to settle for NLT 15 minutes.

[0577] 64. Collect the bottom aquifer in a separate HDPE container and keep the organic layer in the reactor.

[0578] 65. Send 5 ml of the organic layer to QC to check the peroxide content. Acceptance criteria: Peroxide content: NMT 25 ppm

[0579] 66. Add a sodium chloride solution (sodium chloride (1.4 kg, 1.4 w / w) dissolved in purified water (5.0 kg, 5.0 w / w)) to the organic layer at 25 °C ± 5 °C.

[0580] 67. Stir the reactants at 25℃±5℃ for NLT 15 min.

[0581] 68. Allow reactants to settle for NLT 15 minutes.

[0582] 69. Collect the bottom aquifer in a separate HDPE container and the top organic layer in a separate HDPE container.

[0583] 70. Load the organic layer (step 69) into a clean and dry reactor.

[0584] 71. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed.

[0585] 72. Load n-heptane (3.72 kg, 3.72 w / w) into the reactor at a temperature below 50°C.

[0586] 73. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed.

[0587] 74. Load n-heptane (3.72 kg, 3.72 w / w) into the reactor at a temperature below 50°C.

[0588] 75. Concentrate the material under vacuum at a temperature below 50°C until no distillate is observed, and apply high vacuum continuously for 60 minutes (NLT).

[0589] 76. Cool the reactants to 25℃±5℃.

[0590] 77. Methyl tert-butyl ether (0.81 kg, 0.81 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0591] 78. Load n-heptane (2.80 kg - 4.65 kg, 2.80 w / w - 4.65 w / w) into the reactor.

[0592] 79. Cool the reactants to 0℃±5℃.

[0593] 80. Stir the reactants at 0℃±5℃ for NLT 60 minutes.

[0594] 81. Filter the solids through a Nutsche filter and collect the filtrate into an HDPE container.

[0595] 82. Load n-heptane (2.79 kg - 3.50 kg, 2.79 w / w - 3.50 w / w) into the reactor.

[0596] 83. Cool the solvent to 0℃±5℃.

[0597] 84. Wash the bed with the solvent mentioned above (step 83).

[0598] 85. Collect the filtrate into the same HDPE container (step 81).

[0599] 86. Blot the material dry for 30 minutes (NLT), and unload the wet material into a double-layered polyethylene bag and send it for disposal (byproduct: (S)-(-)-4-benzyl-2-oxazolidinone).

[0600] 87. Load the filtrate (step 85) into a clean reactor at 25℃±5℃.

[0601] 88. Concentrate the filtrate under vacuum at a temperature below 50°C until no distillate is observed.

[0602] 89. Cool the reactants to 25℃±5℃.

[0603] 90. Send the sample to QC for GC to check the purity (I-1).

[0604] 91. Methyl tert-butyl ether (7.4 kg-10.0 kg, 7.4 w / w-10.0 w / w) was loaded into the reactor at 25 °C ± 5 °C.

[0605] 92. Cyclohexylamine (0.252 kg, 0.252 w / w) was slowly added to the reactants at 25 °C ± 5 °C.

[0606] 93. Stir the reactants at 25℃±5℃ for NLT 30 min.

[0607] 94. Raise the temperature of the reactants to 45℃±5℃.

[0608] 95. Stir the reactants at 45℃±5℃ for NLT 60 min.

[0609] 96. Cool the reactants to 25℃±5℃.

[0610] 97. Stir the reactants at 25℃±5℃ for NLT 60 min.

[0611] 98. Filter solids through a Nutsche filter under vacuum at 25℃±5℃.

[0612] 99. Blot the material dry for 30 minutes (NLT), and unload the wet material into a double-layer polyethylene bag and place it in an HDPE container.

[0613] 100. Send wet material samples to QC for inspection of (1) HPLC purity and chiral purity (by LCMS). Acceptance criteria: HPLC purity: NLT 91.0 w / w% and chiral purity (other isomers): NMT 1.0 w / w%.

[0614] 101. If the results meet the acceptance criteria, step 110 is the next step; otherwise, step 102 (MTBE purification) is the next step.

[0615] 102. Load methyl tert-butyl ether (10.0 w / w, based on the wet weight of step 99) into the reactor.

[0616] 103. Load the wet material (step 99) into the reactor at 25℃±5℃.

[0617] 104. Stir the wet material (step 103) at 25℃±5℃ for NLT 60 min.

[0618] 105. Filter solids through a Nutsche filter under vacuum at 25℃±5℃.

[0619] 106. Wash the bed with methyl tert-butyl ether (3.0 w / w, based on the wet weight of step 99).

[0620] 107. Blot the material dry for 30 minutes (NLT), and unload the wet material into a double-layer polyethylene bag and place it in an HDPE container.

[0621] 108. Send wet material samples to QC for inspection of (1) HPLC purity and chiral purity (by LCMS). Acceptance criteria: HPLC purity: NLT 91.0 w / w% and chiral purity (other isomers): NMT 1.0 w / w%.

[0622] 109. If the results meet the acceptance criteria, step 110 is the next step; otherwise, step 102 (MTBE purification) is the next step.

[0623] 110. Load the wet material from step 99 / 107 into a VTD (vacuum disc dryer) and dry it under vacuum (NLT 300 mm Hg) at 25°C ± 5°C for 2 hours.

[0624] 111. Raise the temperature of the vacuum dryer to 45℃±5℃.

[0625] 112. Dry the material in a vacuum (NLT-300mmHg) at 45℃±5℃ in a VTD until the residue content and water content of the sample meet the acceptance criteria.

[0626] Starting from the 8th hour, samples are sent to QC for water content every 4 hours until the residue content and water content meet the acceptance criteria.

[0627] Acceptance criteria: Water content: NMT 0.8% w / w.

[0628] Residual solvent (according to GC-HS)

[0629] Methyl tert-butyl ether (NMT) 4000ppm

[0630] Tetrahydrofuran - NMT 720ppm

[0631] Ethyl acetate - NMT 5000ppm

[0632] n-Heptane - not greater than NMT 5000ppm

[0633] 113. Cool the VTD to 25℃±5℃.

[0634] 114. Unload the dried product into a double-layer polyethylene bag placed in an HDPE container.

[0635] Yield: ~0.5kg

[0636] Theoretical yield: 1.17 kg

[0637] Yield %: ~42.73%

[0638] d. Preparation of (1 g⁻¹)

[0639]

[0640] 1. Dichloromethane (13.3 kg, 13.30 w / w) was loaded into the reactor at 25 °C ± 5 °C under a nitrogen atmosphere.

[0641] Dichloromethane samples were sent to QC for testing based on the water content of KF (acceptance criteria NMT (not greater than) 0.20% w / v).

[0642] 2. 3,3,3-trifluoro-1-propanol ((1g-11); 1.0kg, 1.0w / w) was loaded into the reactor at 25℃±5℃ under a nitrogen atmosphere.

[0643] 3. 2,6-Dimethylpyridine (1.42 kg, 1.42 w / w) was loaded into the reactants at 25 °C ± 5 °C under a nitrogen atmosphere.

[0644] 4. Stir the reactants at 25℃±5℃ under a nitrogen atmosphere for NLT 5 min.

[0645] 5. Cool the reactants to -25℃±5℃ under a nitrogen atmosphere.

[0646] 6. Under a nitrogen atmosphere at -25℃±5℃, trifluoromethanesulfonic anhydride (3.46 kg, 3.46 w / w) is slowly added to the reactants.

[0647] 7. Stir the reactants under a nitrogen atmosphere at -25℃±5℃ for NLT 120 min.

[0648] 8. Slowly raise the temperature of the reactants to 20℃±5℃ under a nitrogen atmosphere.

[0649] 9. Stir the reactants at 20℃±5℃ under a nitrogen atmosphere for 1 hour.

[0650] Starting from the first hour, samples are sent to QC every 2 hours for 3,3,3-trifluoro-1-propanol (1g-11) content according to GC, until the 3,3,3-trifluoro-1-propanol content is reduced to a sufficient level.

[0651] Acceptance criteria: 3,3,3-trifluoro-1-propanol content (NMT) 5.0%.

[0652] Note: Sampling procedure: Take approximately 5 mL of the reaction material and submit it to QC.

[0653] 10. Cool the reactants to 0℃±5℃ under a nitrogen atmosphere.

[0654] 11. Under a nitrogen atmosphere at 0℃±5℃, slowly add purified water (7.0 kg, 7.0 w / w) to the reactants.

[0655] 12. Stir the reactants at 0℃±5℃ for NLT 15 min.

[0656] 13. Slowly raise the temperature of the reactants to 20℃±5℃.

[0657] 14. Stir the reactants at 20℃±5℃ for NLT 15 min.

[0658] 15. Allow material settling to continue for NLT 15 min.

[0659] 16. Separate the bottom organic layer into the HDPE container and collect the aqueous layer in a separate container.

[0660] 17. Load the organic layer back into the reactor and add purified water (7.0 kg, 7.0 w / w) at 20 °C ± 5 °C.

[0661] 18. Stir the reactants at 20℃±5℃ for NLT 15 min.

[0662] 19. Allow material settling to continue for NLT 15 min.

[0663] 20. Separate the bottom organic layer into the HDPE container and collect the aqueous layer in a separate container.

[0664] 21. Load the organic layer back into the reactor and concentrate it completely under vacuum at below 30°C until ~2.5-4.0 volume of material remains in the reactor.

[0665] 22. Fractionally distill the crude product described above at a temperature below 40°C under high vacuum, and collect the different fractions.

[0666] (1g-1)

[0667] Yield: ~1.2kg

[0668] Theoretical yield: 2.15 kg

[0669] Yield %: ~55.81%

[0670] e. Preparation of (I-1), (2a) and (2b)

[0671]

[0672] 1) Load dichloromethane (18.10 kg, 18.10 w / w) into the reactor at a temperature below 30°C.

[0673] 2) Compound (1) (1.0 kg, 1.0 w / w) was loaded into the reactor at a temperature below 30 °C.

[0674] 3) Stir the reactants at 25℃±5℃ for NLT 10 min.

[0675] 4) Add 1.5N HCl solution (slowly add concentrated HCl (1.58 kg, 1.58 w / w) and mix it with purified water (8.42 kg, 8.42 w / w)), and add the resulting solution to the reactants at 25℃±5℃.

[0676] 5) Stir the reactants at 25℃±5℃ for NLT 10 min.

[0677] 6) Allow the material to settle at 25℃±5℃ for NLT 10 min.

[0678] 7) Separate the bottom organic layer into a clean HDPE container. Keep the aqueous layer in the reactor.

[0679] 8) Load dichloromethane (7.24 kg, 7.24 w / w) into the aquifer mentioned above at 25℃±5℃.

[0680] 9) Stir the reactants at 25℃±5℃ for NLT 10 min.

[0681] 10) Allow the material to settle at 25℃±5℃ for NLT 10 min.

[0682] 11) Separate the bottom organic layer into a clean HDPE container and the top aqueous layer into a clean HDPE drum.

[0683] 12) The combined organic layers (steps 7 and 11) are loaded back into the reactor at 25°C ± 5°C.

[0684] 13) Load purified water (9.0 kg, 9.0 w / w) into the organic layer above at 25 °C ± 5 °C.

[0685] 14) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0686] 15) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0687] 16) Separate the bottom organic layer into a clean HDPE drum and the top water-containing layer into a clean HDPE drum.

[0688] 17) Load the organic layer (step 16) from above back into the reactor at 25℃±5℃.

[0689] 18) At 25℃±5℃, a saturated salt solution (NaCl (2.17 kg, 2.17 w / w) loaded and dissolved in purified water (7.83 w / w)) was added to the organic layer above.

[0690] 19) Stir the reactants at 25℃±5℃ for NLT 10 min.

[0691] 20) Allow the material to settle at 25℃±5℃ for NLT 10 min.

[0692] 21) Separate the bottom organic layer into a clean HDPE drum and the top moisture layer into a clean HDPE drum.

[0693] 22) Load the organic layer (step 21) from above back into the reactor at 25℃±5℃.

[0694] 23) Sodium sulfate (2.0 kg, 2.0 w / w) was loaded into the organic layer above at 25 °C ± 5 °C.

[0695] 24) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0696] 25) Filter the reactants through a Nutsche filter and collect the filtrate into a clean HDPE container.

[0697] 26) Rinse the reactor with dichloromethane (4.0 kg, 4.0 w / w) and wash the wet filter cake, and collect the filtrate in an HDPE container.

[0698] 27) The combined organic layers from the above are loaded into a clean and dry reactor at 25°C ± 5°C.

[0699] 28) The reactants are completely concentrated under vacuum at a temperature below 45°C.

[0700] 29) Cool the reactants to 25℃±5℃ and unload them into HDPE containers. (Wt of (I-1): ~0.7kg).

[0701] Enter all raw materials based on the weight (I-1) in step 29.

[0702] 30) Dry tetrahydrofuran (6.23 kg, 8.90 w / w) was loaded into the reactor at 25 °C ± 5 °C under a nitrogen atmosphere.

[0703] THF samples were sent to QC for testing based on the water content of KF (acceptance criterion NMT 0.10% w / v).

[0704] 31) Diisopropylamine (0.682 kg to 0.76 kg, 0.974 w / w to 1.08 w / w) was added to the reactants at 25 °C ± 5 °C under a nitrogen atmosphere.

[0705] 32) Stir the reaction mixture under a nitrogen atmosphere at a temperature below 30°C for NLT 5 min.

[0706] 33) Cool the reactants to -45℃±10℃ and continue for NLT for 30 minutes.

[0707] 34) 2.5M n-butyllithium was slowly added to hexane (1.87 kg to 2.17 kg, 2.67 w / w to 3.10 w / w) at -45℃±10℃ under a nitrogen atmosphere and added to the reactants from a cylinder.

[0708] 35) Stir the reactants under a nitrogen atmosphere at -45℃±10℃ for NLT 5 min.

[0709] 36) Slowly raise the temperature of the reactants to 0℃±10℃ under a nitrogen atmosphere.

[0710] 37) Stir the reaction mixture under a nitrogen atmosphere at 0℃±10℃ for NLT 40 min.

[0711] 38) Cool the reactants to -75℃±8℃ under a nitrogen atmosphere for NLT 30 minutes.

[0712] 39) At 75℃±8℃ under a nitrogen atmosphere, the (I-1) solution (0.7 kg, 1.0 w / w) was slowly added to the reactants as a dry THF solution (3.11 kg, 4.45 w / w).

[0713] 40) Stir the reaction mixture under a nitrogen atmosphere at -75℃±8℃ for NLT 120 min.

[0714] 41) At -75℃±8℃ under a nitrogen atmosphere, (1g-1)(1.085kg, 1.55w / w) was slowly added to the reactants over a period of 30 minutes via NLT.

[0715] 42) Stir the reaction mixture under a nitrogen atmosphere at -75℃±8℃ for NLT 2 hours.

[0716] 43) Starting from the 2nd hour, samples are sent to QC at 2-hour intervals up to the 8th hour for (I-1) content (w / w%) to be checked by HPLC (acceptance criterion: (I-1) content NMT 25.0 w / w%).

[0717] Note: Sample procedure: Take 5 mL of sample from the reactants and quench with 20% ammonium chloride solution, and separate the organic layer and submit it as an IPC (in process control).

[0718] 44) Slowly raise the temperature of the reactants to -30℃±10℃ under a nitrogen atmosphere.

[0719] 45) At temperatures below 0°C, the 20% ammonium chloride solution prepared above (ammonium chloride (0.7 kg, 0.7 w / w) dissolved in purified water (3.5 kg, 5.0 w / w)) is slowly added to the reactants through a loading container.

[0720] 46) Raise the temperature of the reactants to 25℃±5℃.

[0721] 47) At 25°C ± 5°C, commercially available methyl tert-butyl ether (10.36 kg to 11.90 kg, 14.8 w / w to 17.0 w / w) was loaded into the reactor.

[0722] 48) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0723] 49) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0724] 50) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0725] 51) Load purified water (3.5 kg, 5.0 w / w) into the organic layer above at a temperature below 30°C.

[0726] 52) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0727] 53) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0728] 54) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0729] 55) Load purified water (3.5 kg, 5.0 w / w) into the organic layer above at a temperature below 30°C.

[0730] 56) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0731] 57) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0732] 58) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0733] 59) Load purified water (3.5 kg, 5.0 w / w) into the organic layer above at a temperature below 30°C.

[0734] 60) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0735] 61) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0736] 62) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0737] 63) Cool the organic layer to 20℃±5℃.

[0738] 64) At 20℃±10℃, the 1.5N HCl solution prepared above (concentrated HCl (1.12 kg to 1.68 kg, 1.60 w / w to 2.4 w / w) was slowly added and mixed in purified water (5.88 kg to 8.82 kg, 8.4 w / w to 12.6 w / w)) was added to the organic layer through a loading vessel, and the pH of the reactants was adjusted to below 3.0.

[0739] 65) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0740] 66) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0741] 67) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0742] 68) At a temperature below 30°C, 4.9 kg of purified water (7.0 w / w) was loaded into the organic layer above.

[0743] 69) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0744] 70) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0745] 71) Separate the bottom aquifer into a clean HDPE container and retain the organic layer in the reactor.

[0746] 72) Load purified water (4.9 kg, 7.0 w / w) into the organic layer above at a temperature below 30°C.

[0747] 73) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0748] 74) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0749] 75) Separate the bottom aqueous layer into a clean HDPE container and retain the organic layer in the reactor.

[0750] 76) Sodium sulfate (0.7 kg, 1.0 w / w) was loaded into the organic layer above at 25 °C ± 5 °C.

[0751] 77) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0752] 78) Filter the reactants through a Nutsche filter and collect the filtrate into an HDPE container.

[0753] 79) The reactor was rinsed and the wet filter cake was washed with methyl tert-butyl ether (1.4 kg to 2.8 kg, 2.0 w / w to 4.0 w / w), and the filtrate was collected in an HDPE container.

[0754] 80) Load the organic layer described above back into a clean and dry reactor and concentrate it completely under vacuum at a temperature below 55°C.

[0755] 81) Under a nitrogen atmosphere, the reactants were cooled to 25℃±5℃ and unloaded into an HDPE container (weight of (2a): ~0.77kg).

[0756] The sample was sent to QC for HPLC testing to check the (I-1) content (w / w%). Acceptance criteria: (I-1) content (according to HPLC): NMT 10.0 (w / w).

[0757] Enter all RMs based on the weight (2a) in step number 81.

[0758] 82) Dry tetrahydrofuran (6.85 kg, 8.90 w / w) was loaded into the reactor at 25 °C ± 5 °C under a nitrogen atmosphere.

[0759] THF samples were sent to QC for testing based on the water content of KF (acceptance criterion NMT 0.10% w / v).

[0760] 83) Diisopropylamine (0.53 kg to 0.60 kg, 0.69 w / w to 0.78 w / w) was added to the reactants at 25 °C ± 5 °C under a nitrogen atmosphere.

[0761] 84) Stir the reaction mixture under a nitrogen atmosphere at a temperature below 30°C for NLT 5 min.

[0762] 85) Cool the reactants to -45℃±10℃ for NLT for 30 minutes.

[0763] 86) 2.5M n-butyllithium (1.40 kg to 1.71 kg, 1.82 w / w to 2.22 w / w) in hexane is slowly added from a cylinder to the reactants at -45℃±10℃ under a nitrogen atmosphere.

[0764] 87) Stir the reactants under a nitrogen atmosphere at -45℃±10℃ for NLT 5 min.

[0765] 88) The temperature of the reactants is slowly increased to 0℃±10℃ under a nitrogen atmosphere.

[0766] 89) Stir the reaction mixture under a nitrogen atmosphere at 0℃±10℃ for NLT 30 min.

[0767] 90) Cool the reactants to -75℃±8℃ under a nitrogen atmosphere for NLT 30 minutes.

[0768] 91) At -75℃±8℃ under a nitrogen atmosphere, the solution (2a) (0.77 kg, 1.0 w / w) dissolved in dry THF (3.46 kg, 4.45 w / w) was slowly added to the reactants.

[0769] 92) Stir the reaction mixture under a nitrogen atmosphere at -75℃±8℃ for NLT 3 hours.

[0770] 93) Cool the reactants to -100℃±10℃ under a nitrogen atmosphere.

[0771] 94) Under a nitrogen atmosphere at -100℃±10℃, a 2,2,2-trifluoroacetamide solution (0.57 kg, 0.74 w / w, dissolved in dry THF (1.04 kg, 1.35 w / w)) was slowly added to the reactants through a loading container.

[0772] 95) Stir the reactants under a nitrogen atmosphere at -100℃±10℃ for NLT 120 min.

[0773] 96) Slowly raise the temperature of the reactants to -30℃±10℃ under a nitrogen atmosphere.

[0774] 97) At -30℃±10℃, a 20% ammonium chloride solution (ammonium chloride (0.46 kg, 0.6 w / w) dissolved in purified water (2.31 kg, 3.0 w / w)) is slowly added to the reactants through a loading container.

[0775] 98) Raise the temperature of the reactants to 20℃±10℃.

[0776] 99) At a temperature below 20°C ± 10°C, mix a 1.5N HCl solution (concentrated HCl (1.12 kg to 1.68 kg, 1.60 w / w to 2.4 w / w)) with purified water (5.88 kg to 8.82 kg, 8.40 w / w to 12.6 w / w) and slowly add it to the reactants through a loading vessel. Adjust the pH of the reactants to be acidic to below 3.

[0777] 100) Methyl tert-butyl ether (5.7 kg, 7.4 w / w) was loaded into the reactants described above at a temperature below 30°C.

[0778] 101) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0779] 102) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0780] 103) Separate the bottom aqueous layer into a clean HDPE container and the top organic layer into a clean HDPE container.

[0781] 104) Load the aquifer (step 103) back into the reactor at 25℃±5℃.

[0782] 105) Methyl tert-butyl ether (2.85 kg, 3.7 w / w) was loaded into the aquifer described above at a temperature below 30°C.

[0783] 106) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0784] 107) Allow the material to settle at 25℃±5℃ for NLT 15 min.

[0785] 108) Separate the bottom aquifer into a clean HDPE container and retain the organic layer in the reactor.

[0786] 109) At a temperature below 30°C, 7.7 kg of purified water (10.0 w / w) was loaded into the organic layer above.

[0787] 110) Stir the reactants at 25℃±5℃ for NLT 5 min.

[0788] 111) At 25℃±5℃, dissolve 0.5N NaOH solution (NaOH (0.015kg to 0.15kg, 0.02w / w to 0.20w / w)) in purified water (0.77kg to 7.7kg, 1.00w / w to 10.0w / w) and slowly add it to the reactants through a loading container.

[0789] 112) Stir the reactants at 25℃±5℃ for NLT 5 min.

[0790] 113) Allow the material to settle at 25℃±5℃ for NLT 5 min.

[0791] 114) Separate the bottom aquifer into a clean HDPE container and retain the organic layer in the reactor.

[0792] 115) Load purified water (7.7 kg, 10.0 w / w) into the organic layer above at a temperature below 30°C.

[0793] 116) Stir the reactants at 25℃±5℃ for NLT 5 min.

[0794] 117) Allow the material to settle at 25℃±5℃ for NLT 5 min.

[0795] 118) Separate the bottom aquifer into a clean HDPE container and retain the organic layer in the reactor.

[0796] 119) At a temperature below 30°C, 7.7 kg of purified water (10.0 w / w) was loaded into the organic layer above.

[0797] 120) Stir the reactants at 25℃±5℃ for NLT 5 min.

[0798] 121) Allow the material to settle at 25℃±5℃ for NLT 5 min.

[0799] 122) Separate the bottom aquifer into a clean HDPE container and collect the organic layer into a new HDPE container. Adjust the pH of the aquifer to 5-7.

[0800] 123) The organic layer (step 122) is loaded back into a clean and dry reactor and fully concentrated under vacuum at a temperature below 55°C.

[0801] 124) Cool the material to 30℃±5℃ and unload the material.

[0802] The sample was sent to QC for GC testing to check the content of (2a). Acceptance criteria: Content of (2a) (according to GC): NMT 35.0%.

[0803] 125) At a temperature below 30°C, the crude product (step 124) and methyl tert-butyl ether (1.89 kg to 3.43 kg, 2.45 w / w to 4.45 w / w) described above are loaded into a clean, dry reactor.

[0804] 126) Load n-heptane (2.63 kg, 3.42 w / w) into the reactants at a temperature below 30°C.

[0805] 127) Tert-butylamine (0.18 kg, 0.24 w / w) was slowly added to the reactants via GAV at 25 °C ± 5 °C.

[0806] 128) Stir the reactants at 25℃±5℃ for NLT 30 minutes.

[0807] 129) Add n-heptane (6.28 kg, 8.16 w / w) slowly to the reactants at a temperature below 30°C.

[0808] 130) Stir the reactants at 25℃±5℃ for NLT 60 minutes.

[0809] 131) Filter the material through a Nutsche filter and collect the filtrate in an HDPE container.

[0810] 132) The reactor was rinsed and washed with a mixture of methyl tert-butyl ether (1.83 kg, 2.38 w / w): n-heptane (1.83 kg, 2.38 w / w) and the wet filter cake was washed, and the filtrate was collected in an HDPE container.

[0811] 133) Unload the material into a double-layer LDPE bag and place it in an HDPE container.

[0812] 134) Load the wet material into a vacuum disc dryer and dry it at 25℃±5℃ under a vacuum of NLT-300mmHg until the water content meets the acceptance criteria.

[0813] Starting from the 8th hour, samples are sent to QC for water content testing every 4 hours until the water content meets the acceptance criteria. Acceptance criteria: Water content NMT 5.0% w / w.

[0814] 135) Unload the material into a double-layer LDPE bag and place it in an HDPE container.

[0815] The sample was sent to QC for HPLC and GC testing to check the content of (2b).

[0816] Acceptance criteria: Visual description: Dark brown to almost white.

[0817] According to HPLC, the content of RSM-002-ITM09A (RSM-002TBA salt) is: NLT 70.0%

[0818] Based on the GC's RSM-002-ITM09A (RSM-002TBA salt) content: NLT 80.0A%.

[0819] Yield: ~0.5kg

[0820] Theoretical yield: 1.19 kg

[0821] Yield %: ~42.01%

[0822] f.(2) Preparation

[0823]

[0824] 1) Methyl tert-butyl ether (7.40 kg, 7.40 w / w) was loaded into a clean and dry reactor at 30°C.

[0825] 2) Load (2b) (1.0 kg, 1.0 w / w) into the reactor described above at a temperature below 30°C.

[0826] 3) Stir the reactants at a temperature below 30°C for NLT 5 minutes.

[0827] 4) At 25℃±5℃, slowly add 0.5N HCl solution (concentrated HCl (0.42kg to 0.52kg, 0.42w / w to 0.52w / w) mixed with purified water (8.0kg to 10.0kg, 8.0w / w to 10.0w / w)) to the reactants.

[0828] 5) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0829] 6) Allow the reactants to settle at 25℃±5℃ for NLT 15 min.

[0830] 7) Separate and collect the bottom aquifer into an HDPE tank. Keep the top organic layer inside the reactor.

[0831] 8) Load purified water (5.0 kg, 5.0 w / w) into the organic layer above at 25℃±5℃.

[0832] 9) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0833] 10) Allow the reactants to settle at 25℃±5℃ for NLT 15 min.

[0834] 11) Separate and collect the bottom aquifer into an HDPE tank. Keep the top organic layer inside the reactor.

[0835] 12) Load purified water (5.0 kg, 5.0 w / w) into the organic layer above at 25℃±5℃.

[0836] 13) Stir the reactants at 25℃±5℃ for NLT 15 min.

[0837] 14) Allow the reactants to settle at 25℃±5℃ for NLT 15 min.

[0838] 15) Separate and collect the bottom water layer into an HDPE drum, and collect the top organic layer into a new HDPE container.

[0839] 16) Load the organic layer (step 15) back into the clean and dry reactor.

[0840] 17) The reactants are completely concentrated under vacuum at a temperature below 55°C.

[0841] 18) Cool the reactants to 30℃±5℃.

[0842] 19) Methyl tert-butyl ether (1.11 kg, 1.11 w / w) was loaded into the reactants and unloaded into an HDPE container.

[0843] 20) Load the above-mentioned reactants into a clean and dry reactor at a temperature below 30°C.

[0844] 21) Methyl tert-butyl ether (4.81 kg, 4.81 w / w) was loaded into the reactants at a temperature below 30°C under a nitrogen atmosphere.

[0845] 22) Under a nitrogen atmosphere at 25℃±5℃, a tert-butylamine solution (tert-butylamine (0.185 kg, 0.185 w / w) dissolved in methyl tert-butyl ether (1.48 kg, 1.48 w / w)) was slowly added to the reactants.

[0846] 23) Stir the reactants at 25℃±5℃ for NLT 10 min.

[0847] 24) At 25℃±5℃ under a nitrogen atmosphere, n-heptane (6.84 kg, 6.84 w / w) was slowly added to the reactants.

[0848] 25) Stir the reactants at 25℃±5℃ for NLT 10 minutes.

[0849] 26) Cool the reactants to 5℃±5℃.

[0850] 27) Stir the reactants at 5℃±5℃ for NLT 60 minutes.

[0851] 28) Filter the reactants through a Nutsche filter and collect the filtrate in an HDPE container.

[0852] 29) Wash the wet material above with a mixture of methyl tert-butyl ether (1.48 kg, 1.48 w / w): n-heptane (1.36 kg, 1.36 w / w).

[0853] 30) Vacuum dry the material under vacuum for NLT 60 minutes and unload the material into a new HDPE container.

[0854] 31) Samples were sent to QC to check the content of (2a: R,R isomer) according to GC and the purity of (2b) according to HPLC. Acceptance criteria: (2a: R,R isomer): NMT 1.0% area (isomer purity (according to GC)), (2b) (according to HPLC): NLT 95.0% area.

[0855] 32) Methyl tert-butyl ether (7.40 kg, 7.40 w / w) was loaded into a clean and dry reactor at a temperature below 30°C.

[0856] 33) Load the wet material (step 30) into the reactor described above at a temperature below 30°C.

[0857] 34) Stir the reactants at a temperature below 30°C for NLT 5 minutes.

[0858] 35) At 25℃±5℃, slowly add 0.5N HCl solution (concentrated HCl (0.42kg to 0.52kg, 0.42w / w to 0.52w / w) mixed with purified water (8.0kg to 10.0kg, 8.0w / w to 10.0w / w)) to the material.

[0859] 36) Stir the reactants at 25℃±5℃ for NLT 15 minutes.

[0860] 37) Allow reactants to settle for NLT 15 minutes.

[0861] 38) Separate and collect the bottom aquifer into an HDPE tank. The top organic layer remains inside the reactor.

[0862] 39) Load purified water (5.0 kg, 5.0 w / w) into the material at 25℃±5℃.

[0863] 40) Stir the reactants at 25℃±5℃ for NLT 15 minutes.

[0864] 41) Allow reactants to settle for NLT 15 minutes.

[0865] 42) Separate and collect the bottom aquifer into an HDPE tank. The top organic layer remains inside the reactor.

[0866] 43) Load purified water (5.0 kg, 5.0 w / w) into the material at 25℃±5℃.

[0867] 44) Stir the reactants at 25℃±5℃ for NLT 15 minutes.

[0868] 45) Allow reactants to settle for NLT 15 minutes.

[0869] 46) Separate and collect the bottom aqueous layer into an HDPE drum. Collect the top organic layer into a new HDPE container.

[0870] 47) Load the organic layer (step 46) back into the clean and dry reactor at 25℃±5℃.

[0871] 48) At 25℃±5℃, an activated carbon solution (activated carbon (0.10 kg, 0.10 w / w) mixed in methyl tert-butyl ether (0.7 kg, 0.7 w / w)) was loaded into the organic layer above.

[0872] 49) Raise the temperature of the reactants to 45℃±5℃.

[0873] 50) Stir the reactants at 45℃±5℃ for NLT 120 min.

[0874] 51) Cool the reactants to 25℃±5℃.

[0875] 52) Cool the reactants at 45℃±5℃ for NLT 60 min.

[0876] 53) Beds for Nutsche filters were prepared using diatomaceous earth (2.00 kg - 6.00 kg) and methyl tert-butyl ether (10.00 kg - 60.00 kg).

[0877] 54) Filter the material through a Nutsche filter and collect the filtrate in a new HDPE container.

[0878] 55) Rinse the reactor with methyl tert-butyl ether (3.7 kg to 5.0 kg, 3.7 w / w to 5.0 w / w).

[0879] 56) Wash the bed with the methyl tert-butyl ether rinsed above.

[0880] 57) Vacuum dry the washed bed for NLT for 10 minutes and collect the filtrate into a new HDPE container.

[0881] 58) Load the filtrate (step 57) from above into the reactor through the loading line connected to the cartridge filter.

[0882] 59) The reactants are completely concentrated under vacuum at a temperature below 55°C.

[0883] 60) Load n-heptane (3.42 kg, 3.42 w / w, filtered through a tube) into the reactants at a temperature below 55°C.

[0884] 61) The reactants are completely concentrated under vacuum at a temperature below 55°C.

[0885] 62) Load n-heptane (3.42 kg, 3.42 w / w, filtered through a tube) into the reactants at a temperature below 55°C.

[0886] 63) The reactants are completely concentrated under vacuum at a temperature below 55°C.

[0887] 64) Cool the reactants to 25℃±5℃.

[0888] 65) Load n-heptane (6.84 kg, 6.84 w / w, filtered through a tube) into the reactants at a temperature below 25 °C ± 5 °C.

[0889] 66) Slowly raise the temperature of the reactants to 50℃±5℃.

[0890] 67) Stir the reactants at 50℃±5℃ for NLT 10 minutes until the solution is clear.

[0891] 68) Slowly cool the temperature of the reactants to 10℃±5℃.

[0892] 69) Stir the reactants at 10℃±5℃ for NLT 60 min.

[0893] 70) Filter the material through the Nutsche filter described above and collect the filtrate in a new HDPE container.

[0894] 71) Rinse the reactor with n-heptane (1.37 kg to 3.7 kg, 1.37 w / w to 3.7 w / w, filtered through a tube).

[0895] 72) Wash the bed with the n-heptane that was rinsed above.

[0896] 73) The compound (2) was vacuum dried for NLT 60 min and then unloaded.

[0897] 74) The sample was sent to QC to check the purity (according to HPLC) and isomer purity (according to GC).

[0898] Acceptance criteria: (2) Purity: NLT 99.0% area (according to HPLC), (I-1) content: NMT 0.40% area, impurities at RRT ~ 0.98: NMT 0.25% area,

[0899] Unknown impurity: NMT 0.10%.

[0900] Based on the isomer purity of GC: (2a: S,R isomer): NMT 0.25% w / w, (2a: R,R isomer): NMT 0.45% w / w.

[0901] Yield: ~0.5kg

[0902] Theoretical yield: 0.83 kg

[0903] Yield %: ~60.0%

[0904] Example 6

[0905] Compound (3b) was synthesized from compounds (3-2) and (2).

[0906] Compound (3b-1): Compound (3-2) was prepared according to the details described in PCT Publication No. WO 2021 / 163676, which is incorporated herein by reference. Compound (3-2) (96.5%, 1.0 equivalent, 459.05 g) was suspended in DMF (2.75 volume, 819.97 g). The feed vessel was rinsed with DMF (0.50 volume, 149.48 g), and the rinse solution was transferred to a 10 L reactor. Compound (2) (1.00 equivalent, 314.99 g; prepared according to Example 5) was suspended in DMF (1.25 volume, 372.25 g). The feed vessel was rinsed with DMF (0.50 volume, 151.67 g), and the rinse solution was transferred to a reactor. TBTU (1.30 equivalent, 359.20 g) was transferred to the reactor as a solid. Use DMF (0.50 volume, 148.90 g) to flush the reactor walls.

[0907] The reaction mixture was cooled to 15.95 °C over 12 minutes. While maintaining the reaction temperature between 15.36 °C and 18.43 °C, triethylamine (2.55 equivalents, 222.03 g) was fed into the reactor over a period of 34 minutes. The feed funnel was rinsed with DMF (0.35 volume, 104.48 g), and the rinse solution was transferred into the reactor.

[0908] The temperature of the reaction mixture was set to 19.04°C over an 8-minute period, and then stirred at 20°C. After 63 minutes, IPC 1 (“Process Control 1”, i.e., the first process control performed in this process) indicated that the reaction was complete. Dichloromethane (7.00 volume, 2926.67 g) was added to the reaction mixture. The batch was quenched with water and the layers were separated. The dichloromethane-rich layer was washed twice with water ((7.00 volume, 2205.01 g) × 2) and used directly for the next step.

[0909] Dichloromethane (2.65 v / v, 1109.20 g) was added to the reactor. The batch temperature was lowered to 11.84 °C, and TFA (5.20 v / v, 2441.51 g) was fed over a 20-minute period at 11.53 °C–16.31 °C. The reaction mixture was heated to 21.43 °C over a 21-minute period and then stirred at 23 °C. IPC 2 shows that the reaction was complete after 4 hours.

[0910] The reaction mixture was concentrated in a jacket temperature range of 24.72°C–28.09°C until a vacuum of 180 mbar was reached and no more distillate was observed. MTBE (7.00 g / L, 1631.95 g) was fed into the reactor over a period of 26 minutes. A 10% w / w dipotassium hydrogen phosphate solution (17.60 w / w, 5544.37 g) was added to the reactor. The two-phase mixture was stirred, allowed to settle, and the phases were separated. The pH of the aqueous phase was measured to be 0.94, and this phase was then discarded. Another 10% w / w dipotassium hydrogen phosphate solution (17.60 w / w, 5543.73 g) was added to the reactor. The two-phase mixture was stirred, allowed to settle, and the phases were separated. The pH of the aqueous phase was measured to be 1.54, and this phase was then discarded. Another 10% w / w dipotassium hydrogen phosphate solution (17.60 w / w, 5546.54 g) was added to the reactor. Stir the two-phase mixture, allow it to settle, and separate the phases. Measure the pH in the aqueous phase to 5.70, then discard this aqueous phase.

[0911] Phosphoric acid (0.50 V, 268.12 g) was dissolved in water (3.30 V, 1040.91 g). Approximately 0.64 L of the phosphoric acid solution was fed into a portion of a 10% w / w dipotassium hydrogen phosphate solution (8.50 V, 2678.30 g) until pH 5.53 was reached. A portion of this buffer solution (8.50 V, 2679.25 g) was transferred to the reactor. The two-phase mixture was stirred, allowed to settle, and the phases were separated. The pH of the aqueous phase was measured to be 5.62, and this aqueous phase was then discarded.

[0912] Feed approximately 0.63 L of phosphoric acid solution into a portion (8.50 volume, 2679.30 g) of a 10% w / w dipotassium hydrogen phosphate solution until pH 5.55 is reached. Transfer a portion (8.50 volume, 2680.40 g) of this buffer solution to the reactor and discard the remainder. Stir the two-phase mixture, allow it to settle, and separate the phases. Measure the pH in the aqueous phase; it should be 5.57. Then discard this aqueous phase.

[0913] IPC 3 was performed, and a residual TFA level of 0.02 mg / mL was found in the organic phase.

[0914] Add water (8.00 g / L, 2520.85 g) to the reactor. Stir the two-phase mixture, allow it to settle, and separate the phases. Measure the pH of the aqueous phase; it is 5.36. Then discard this aqueous phase.

[0915] The organic phase was filtered into the reactor through a 10 μm filter at 20 °C, and the bottle was rinsed with MTBE (0.80 volume, 186.26 g).

[0916] A DABCO solution was prepared by dissolving DABCO (2.25 equivalents, 217.46 g) in isopropyl acetate (6.90 v / v, 1892.84 g) and MTBE (3.50 v / v, 816.52 g). The DABCO solution was fed into the reactor over a period of 37 min. The flask was rinsed with MTBE (0.4 v / v, 93.94 g). The suspension was stirred at 19.89 °C–20.00 °C for 121 min and then filtered through a 3 L sintered glass filter with a porosity of 3. The filter cake was rinsed twice with MTBE (2 × 4.40 v / v, 1028.54 g and 1026.48 g) and then dried at 25 °C for 5.5 days. A yield of 101% (597.6 g) was determined. Compound (3b-1) was obtained with an HPLC purity of 98.9% a / a.

[0917] #imgpt66#

[0918] Compound (3b): Compound (3b-1) (1.0 equivalent, 588.0 g) was transferred as a suspension in DMF (2.80 volume, 1555.70 g) to a reactor and then to a 30 L reactor. The feed vessel was rinsed with two portions of DMF (2.00 volume and 1.10 volume, 1114.61 g and 611.2 g), and the rinse solution was transferred to the reactor.

[0919] HOBt (2.50 equivalents, 327.1 g) was suspended in DMF (1.20 volume, 667.5 g) and transferred to the reactor. The feed vessel was rinsed with DMF (1.10 volume, 610.4 g), and the rinse solution was transferred to the reactor.

[0920] The temperature of the reaction mixture was set to 12.1°C over a period of 14 minutes, and then a 2.0M solution of ammonia in isopropanol (3.30 volumes, 1523.1 g) was transferred to the reactor.

[0921] EDC·HCl (2.50 equivalents, 410.1 g) was suspended in DMF (3.50 volume, 1954.2 g) and transferred to the reactor. The feed vessel was rinsed with DMF (3.15 volume, 1750.6 g), and the rinse solution was transferred to the reactor.

[0922] The reaction mixture was stirred between 11.9°C and 12.2°C for 43 minutes, heated to 19.2°C during the same period, and then stirred between 19.4°C and 20.3°C. After 21 hours and 23 minutes, IPC 1 (“Process Control 1”, i.e., the first process control performed in this process) indicated that the reaction was complete.

[0923] Water (30.00 volume, 17638.1 g) was added over 89 minutes while maintaining the temperature between 16.3 °C and 21.2 °C. The suspension was filtered through a 3 L P3 sintered glass filter. The filter cake was washed twice with water (2 × 5.00 volumes, 2940.3 g and 2940.3 g respectively) and then dried at 50 °C over 5 days. A yield of 88% (430.7 g) was determined on the filter. IPC 2 was performed for informational purposes, and an HPLC purity of 98.9% a / a was shown.

[0924] The crude product (3b) was dissolved in acetic acid (4.00 volume, 1772.16 g) and transferred to a 10 L reactor. The feed vessel was rinsed with acetic acid (1.00 volume, 443.11 g), and the rinse solution was transferred to the reactor. The temperature of the reaction mixture was set to 19.36 °C.

[0925] Water (5.50 volume, 2322.44 g) was transferred to the reactor over a period of 25 minutes while the temperature was maintained between 14.92 °C and 16.65 °C. The resulting suspension was stirred over a period of 15 minutes between 14.67 °C and 16.40 °C and then filtered through a 3 L P3 sintered glass filter. The filter cake was washed twice with water (2 × 5.00 volumes, 2110.18 g and 2112.32 g) and then dried under vacuum at 50 °C for 4 days. A yield of 82% (404.3 g) was determined on the filter. IPC 3 was performed, and an HPLC purity of 99.80% a / a and a residual acetic acid level of 0.10% w / w were shown.

[0926] Example 7

[0927] Compound (3a) was synthesized from compounds (3-1) and (2).

[0928] Compound (3-1) was prepared as detailed in Reider, PJ et al., J. Org. Chem., 52:955-957 (1987), which is incorporated herein by reference.

[0929] Compound (3a) was prepared from compounds (3-1) and (2) as detailed in PCT Publication No. WO2012 / 129353, which is incorporated herein by reference.

Claims

1. A salt represented by the structure of formula (I): Q is an ammonium cation.

2. The salt according to claim 1, wherein the ammonium cation is a primary ammonium cation, a secondary ammonium cation, or a tertiary ammonium cation.

3. The salt according to claim 2, wherein the primary ammonium cation comprises a cycloalkyl moiety.

4. The salt according to claim 2 or 3, wherein the primary ammonium cation is a cyclohexylammonium cation, a cyclopentylammonium cation, a cycloheptylammonium cation, or a cyclooctylammonium cation.

5. The salt according to claim 4, wherein the primary ammonium cation is a cyclohexylammonium cation.

6. The salt according to claim 2, wherein the secondary ammonium cation is a dicyclohexylammonium cation, a dicyclopentylammonium cation, a dicycloheptylammonium cation, or a dicyclooctylammonium cation.

7. The salt according to claim 2, wherein the tertiary ammonium cation is diisopropylethylammonium cation, diethylisopropylammonium cation, or N-methylmorpholine ammonium cation.

8. The salt according to any one of the preceding claims, wherein the salt is stable for 6-12 months.

9. The salt according to claim 8, wherein the salt remains stable for 6 months.

10. A method for preparing compound (3a) or compound (3b), comprising: Step A: From equation (I): Where Q is an ammonium cation; preparation of compound (2): as well as Step B: From compound (3-1): Compound (3a) was prepared from compound (2) in step A: or From compound (3-2): And the compound from step A (2) Preparation of compound (3b):

11. A method for preparing compound (2) from formula (I), comprising: From equation (I): Where Q is an ammonium cation; and Compound (1g-1): Preparation of mixture (2a): Compound (2b) was prepared from (2a): as well as Compound (2) was prepared from (2b).

12. The method according to claim 10 or 11, wherein formula (I) is prepared by a method comprising: From (1a): and (1a-1): Preparation of compound (1b): Compound (1c) was prepared from (1b): Compound (1d) was prepared from (1c): Compound (1e) was prepared from (1d): From (1e); and (1e-1): Preparation of compound (1f): Compound (1g) was prepared from (1f): And the preparation of formula (I) from compound (1g).

13. The method according to claim 12, wherein the step of preparing formula (I) from compound (1g) comprises: Compound (I-1) was prepared from compound (1g): as well as Formula (I) is prepared from compound (I-1).

14. The method according to any one of claims 10-13, wherein Q in formula (I) is a cyclohexylammonium cation.

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