Method for synthesizing anhydrous lactic acid

Abstract

Provided is a method for synthesizing anhydrous lactic acid, the method comprising reacting a compound of formula (Ia): #imgabs0# with a compound of formula H n The acid compound of formula (Ib) and the lactic acid compound of formula (I) are reacted in a first solvent to produce a reaction mixture comprising a compound of formula (Ib) and a lactic acid compound of formula (I) in a solution containing the first solvent and / or water. #imgabs1#n is an integer other than 0, x is 0 or an integer other than 0, M is an alkali metal or an alkaline earth metal, and X is the formula H n The conjugate base of the acid compound of X. The resulting reaction mixture is filtered to produce a filtrate containing lactic acid in solution. The filtrate is crystallized from a second solvent to produce anhydrous lactic acid.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 USC §119(e) to U.S. Provisional Application No. 63 / 019,870, filed May 4, 2020, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present application and disclosed embodiments relate to improved methods, reactants, and reagents for synthesizing lactic acid. More specifically, the present application and disclosed embodiments relate to improved methods, reactants, and reagents for synthesizing anhydrous lactic acid. Background Art

[0004] Lactic acid is a naturally occurring hydroxycarboxylic acid used in a variety of applications across various industries. For example, it is used as a food additive, detergent, and flavoring agent. Lactic acid is also a precursor for the chemical and polymer synthesis of biodegradable and biocompatible polymers. In cosmetics and personal care products, lactic acid is used to moisturize the skin, prevent acne, and increase dermal collagen thickness. (Philipp, Babilas; Ulrich, Knie; Christoph, Abels, “Cosmetic and dermatologic use of alpha hydroxy acids” Journal of German Society of Dermatology, 10(7):488–49, 2012).

[0005] Global demand for lactic acid has been growing steadily since 2013. In 2018, economic reports valued the global lactic acid market at $2.64 billion and predicted an expected annual growth rate (CAGR) of 18.6% from 2019 to 2025. (Komesu, A., Oliveira, J.A. R., Martins, L.H. D., Wolf Maciel, M.R., and Maciel Filho, R., "Lactic acid production to purification: A review," BioResources. 12(2). 4364-4383, 2017); see also (Grand View Research, "Lactic Acid Market Size, Share & Trend Analysis Report," Report ID: 978-1-68038-126-9, 2019).

[0006] Lactic acid is a chiral molecule composed of two enantiomers: L-(+)-lactic acid, or (S)-lactic acid, and its mirror image, D-(-)-lactic acid, or (R)-lactic acid. In the pharmaceutical industry, the purity and chemical structure of reactants and reagents can greatly affect the resulting properties and therapeutic effectiveness of the active pharmaceutical ingredient (API). There are few suppliers of high-quality lactic acid (especially anhydrous lactic acid) suitable for manufacturing APIs. Most suppliers provide lactic acid in approximately 80%-95% aqueous solutions (e.g., approximately 90% aqueous solutions). Aqueous lactic acid solutions contain a large number of impurities that are unsuitable for manufacturing APIs.

[0007] The main methods for producing L-lactic acid involve fermentation of carbohydrates followed by recovery and purification. Some of these methods are described in U.S. Patent No. 2,232,554 and other publications. (Borsook, H., Huffman, HM and Liu, Y.-P., J. Biol. Chem., "The Preparation of Crystalline Lactic Acid," 102,449, 1933). For example, a lactic acid solution can be produced by converting crude lactic acid into calcium lactate by fermentation, crystallizing the calcium lactate, neutralizing the calcium lactate with an inorganic acid (sulfuric acid), and filtering to obtain a lactic acid solution. (Sidney Hsin-Huai Chow "Lactic Acid Review," A Master's Thesis, 1957). Other methods for producing lactic acid involve fractionating mixed ethers (diethyl ether and isopropyl ether) in a commercial syrup greater than 50%, followed by crystallization. (Borsook, H., Huffman, HM, and Liu, Y.-P., J. Biol. Chem., “The Preparation of Crystalline Lactic Acid,” 102, 449, 1933). These solvent extraction methods for extracting lactic acid from aqueous solutions are inefficient. PCT / EP2015 / 067258 describes converting crude lactic acid into solid magnesium lactate, which is then acidified with hydrochloric acid gas to produce a lactic acid solution from which the lactic acid can be recovered using additional separation and purification steps.

[0008] The production of anhydrous lactic acid typically requires laborious and complex post-fermentation steps, which typically include derivatization to a Ca- / Zn- / NH4-salt, isolation of the corresponding salt, acid treatment of the salt, distillation, crystallization, and additional separation steps. One such method utilizes vacuum distillation to obtain monomeric lactic acid, which is then subjected to adiabatic crystallization to obtain dry lactic acid crystals. See, for example, U.S. Patent No. 6,630,603; European Patent No. 1317408; and U.S. Patent Publication No. 2011 / 0319660.

[0009] There is no known reliable process for isolating anhydrous lactic acid directly into a non-aqueous solvent without involving an aqueous lactic acid solution. There is also no known process for chemically synthesizing anhydrous lactic acid on an industrial scale without employing multiple, complex, and inefficient steps that ultimately produce a water-containing or low-purity product. Therefore, there is a need for improved methods for synthesizing anhydrous lactic acid that address the purity, complexity, and yield deficiencies of available conventional processes. Summary of the Invention

[0010] The present application and disclosed embodiments relate to improved methods, reactants and reagents for synthesizing lactic acid on an industrial scale for use in all applications. More specifically, the present application and disclosed embodiments relate to improved methods, reactants and reagents for synthesizing anhydrous lactic acid for use in pharmaceutical applications.

[0011] In an exemplary embodiment, a method for synthesizing anhydrous lactic acid is provided, the method comprising reacting a compound of formula (Ia):

[0012]

[0013] With formula H n The acid compound of X is reacted in a first solvent to produce a reaction mixture comprising a compound of formula (Ib) and a lactic acid compound of formula (I) in a solution comprising the first solvent and / or water.

[0014]

[0015] wherein each n is independently an integer other than 0, x is 0 or an integer other than 0, M is an alkali metal or an alkaline earth metal, and X is the formula H n The conjugate base of the acid compound of X.

[0016] In an exemplary embodiment, the lactic acid compound of formula (I) is soluble in the first solvent, and the compound of formula (Ib) is insoluble in the first solvent. The resulting reaction mixture is filtered to produce a filtrate containing lactic acid in solution. The filtrate is crystallized from a second solvent to produce anhydrous lactic acid.

[0017] The above and other objects, features and advantages of the present disclosure will become more apparent from the following detailed description of exemplary embodiments as disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Embodiments of the present application are described, by way of example only, with reference to the accompanying drawings, in which:

[0019] FIG1 depicts an exemplary reaction scheme for synthesizing anhydrous lactic acid;

[0020] FIG2 depicts anhydrous lactic acid crystals produced using an exemplary synthesis scheme;

[0021] FIG3 depicts an exemplary equipment layout for synthesizing anhydrous lactic acid; and

[0022] FIG4 depicts the structure of the L-(+)-lactic acid final product synthesized using the exemplary synthesis scheme. 1 HNMR results.

[0023] Figure 5 depicts representative chromatograms of standard solutions of D-lactic acid and L-lactic acid using the chiral HPLC protocol described herein. DETAILED DESCRIPTION

[0024] The following examples and embodiments disclosed and described in this application are illustrative. Those skilled in the art will understand that various changes to the embodiments may be made without departing from the scope or intent of the present application or the disclosed exemplary embodiments, including changes in the synthetic methods, processes, reactants, reagents, parameters, and conditions described herein. This application relates to improved methods, reactants, and reagents for synthesizing anhydrous lactic acid for use in industrial processes, including but not limited to petrochemical processes; chemical and polymer synthesis; processes for producing cosmetics and personal care products; processes for producing food additives, detergents, and flavorings; and processes for producing pharmaceuticals and active pharmaceutical ingredients.

[0025] In an exemplary embodiment, an anhydrous lactic acid compound of formula (I) is produced by the synthesis and process steps depicted in Figure 1. The exemplary synthesis of Figure 1 can be used to produce anhydrous lactic acid, particularly L-(+)-lactic acid, D-(-)-lactic acid, and DL-lactic acid.

[0026] For the synthesis of anhydrous lactic acid depicted in Figure 1 , n is an integer other than 0, and x is 0 or an integer other than 0. In an exemplary embodiment, n is 1 or 2, and x is 0 to 6.

[0027] M is an alkali metal or an alkaline earth metal. Suitable alkali metals and alkaline earth metals include, but are not limited to, calcium, sodium, potassium, magnesium, lithium, cesium, barium, beryllium, or strontium. In one exemplary embodiment, M is calcium, and the compound of formula (Ia) is calcium lactate hydrate. In another exemplary embodiment, the compound of formula (Ia) is calcium L-lactate pentahydrate.

[0028] H n X is an acid. Suitable inorganic acids include, but are not limited to, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, chloric acid, hydrofluoric acid, and nitric acid. Suitable organic acids include, but are not limited to, malonic acid, glutaric acid, citric acid, malic acid, tartaric acid, oxalic acid, or formic acid. In an exemplary embodiment, the acid is sulfuric acid or oxalic acid.

[0029] X is the conjugate base of the acid used in the synthesis of Figure 1. Depending on the acid used in the synthesis of Figure 1, the conjugate base may vary. Suitable examples of conjugate bases include, but are not limited to, HSO4- 1 、Cl- 1 Br- 1 、F- 1 、I- 1 、ClO4- 1 、ClO3- 1 、NO3- 1 、C2O2- 4 、C3H3O4- 1 、C5H6O4- 2 、C6H5O7- 3 、C4H5O5- 1 、C4H4O6- 2 、H2PO4- 1 or HCO2-.

[0030] In the exemplary steps of the synthesis of FIG1 , a compound of formula (Ia) is reacted with a compound of formula H n The acid compound of X is reacted in a first solvent.

[0031]

[0032] The first solvent can be one or more ester solvents, includes but not limited to methyl acetate, ethyl acetate, isopropyl acetate or n-propyl acetate.Other suitable solvents comprise acetone, toluene, acetonitrile, methyl tertiary butyl ether (MTBE), Virahol, ethanol, methanol, tetrahydrofuran (THF), butanols, butyl acetate, tetracol phenixin, ethylene dichloride, methylene dichloride, ether, diisopropyl ether, dimethyl sulfoxide (DMSO), heptane, hexane, methyl acetate, ethyl ketone, methyl tertiary butyl ether or methyl isobutyl ketone.Can select the first solvent based on the end use of final anhydrous lactic acid product.In exemplary embodiments, the first solvent is methyl acetate, ethyl acetate, isopropyl acetate and / or toluene.

[0033] The compound of formula (Ia) and formula H n The reaction of the acid compound of X in the first solvent produces a reaction mixture comprising the compound of formula (Ib) and lactic acid (I) in a solution comprising the first solvent and / or water.

[0034]

[0035] (I) (Lactic acid in solution) (Ib)

[0036] Each n described herein is independently an integer other than 0. By way of example only, when the acid is HCl, H nn in X is 1; when the acid is sulfuric acid, H n n in X is 2. By way of example only, when calcium lactate hydrate is used as the compound of formula (Ia) and reacted with HCl, M n+ n is 2, H n n in X is 1, and Where n is 2. By way of example only, when calcium chloride is used as the compound of formula (Ib), MX n Where n is 2. In some embodiments, based on stoichiometry, each n in the above equation has the same value. For those skilled in the art, the stoichiometry and / or value of each n will become clear.

[0037] In an exemplary embodiment, the compound of formula (Ib) is at least partially insoluble in the first solvent, and lactic acid (I) is at least partially soluble in the first solvent. In an exemplary embodiment, the compound of formula (Ib) is insoluble in the first solvent, and lactic acid (I) is soluble in the first solvent.

[0038] In the next step of the synthesis of Figure 1, the reaction mixture containing lactic acid (I) and the compound of formula (Ib) in a solution containing the first solvent is filtered to concentrate a first filtrate containing lactic acid (I) in a solution containing the first solvent and / or water. The first filtrate containing lactic acid can be further processed, separated, recovered, filtered, concentrated, distilled, decanted, crystallized, dried and / or dehydrated to produce anhydrous lactic acid.

[0039] Suitable filtration techniques include vacuum filtration, gravity filtration, cold filtration, hot filtration, Nutsche agitation filtration, centrifugal filtration, and robofiltration. In one exemplary embodiment, gravity filtration is performed using a Buchner funnel. In another exemplary embodiment, gravity filtration is performed using a Hirsch funnel. Buchner and Hirsch funnels can be equipped with filter paper and filter cloth to facilitate filtration.

[0040] In an exemplary embodiment after the first filtration, the first filtrate containing lactic acid in a solution containing the first solvent and / or water can be distilled to remove the water and / or the first solvent and concentrate the lactic acid in the first filtrate. Maximizing the removal of the first solvent and water from the first filtrate by distillation maximizes the yield of anhydrous lactic acid.

[0041] After the initial filtration and distillation steps, the first filtrate containing lactic acid (I) can be separated and then crystallized by combining the lactic acid (I) with a second crystallization solvent and cooling the solution to produce purified crystals of anhydrous L-lactic acid (I). Optionally, seed crystals of lactic acid can be added to the solution to initiate and accelerate crystallization.

[0042] In order to maximize the recovery and productivity of the final product, lactic acid is only partially dissolved in the second recrystallization solvent. The second recrystallization solvent can be one or more solvents, including but not limited to toluene and heptane. An additional filtration step can be adopted to separate and purify the anhydrous lactic acid product obtained.

[0043] After the first filtering step, other treatment steps can be adopted to improve the productive rate of anhydrous lactic acid. For example, residual water can be removed from the first filtrate of separation to produce anhydrous lactic acid by azeotropically removing water. In an exemplary embodiment, azeotropic removal can be achieved by azeotropic distillation. A distillation solvent (such as toluene) can be used to form an azeotrope with water to achieve azeotropic distillation. In an exemplary embodiment, a Dean-Stark water trap can be used to azeotropically remove water from the first filtrate of separation that contains lactic acid in solution to produce dry / anhydrous lactic acid.

[0044] The degree of crystallization and the degree of purification of the anhydrous lactic acid obtained from the solution containing crystallization solvent and lactic acid depend to a great extent on the water content of the filtrate and the elimination of water from the first filtrate produced after the initial filtration. In addition to the exemplary synthesis steps disclosed herein, the water content of the filtrate can also be monitored using Karl Fischer titration, and residual water can be removed azeotropically as described herein to improve the yield and purity of the anhydrous lactic acid product. In an exemplary embodiment, the filtrate can also be dried over a desiccant (such as anhydrous Na2SO4) to remove water. Molecular sieves and drying ovens can also be used to remove water from the first filtrate.

[0045] The exemplary method of synthesizing anhydrous lactic acid disclosed herein can produce such anhydrous lactic acid product, the anhydrous lactic acid product having less than 0.1% water by weight and less than 1% polylactic acid impurities (such as lactide, oligomers of lactic acid and mixtures thereof) by weight. In some embodiments, the anhydrous lactic acid obtained is substantially free of water and does not contain polylactic acid, and can be used for high-precision, high-purity industrial processes such as the production of API. The anhydrous lactic acid obtained is substantially free of water and substantially free of polylactic acid, and can be used for high-precision, high-purity industrial processes such as the production of API. As used herein, "substantially free of water and substantially free of polylactic acid" means that the product has less than about 5%, about 4%, about 3%, about 2%, about 1% or about 0.5% water and / or polylactic acid.

[0046] In one exemplary embodiment of the synthesis of anhydrous lactic acid depicted in FIG1 , reaction scheme 1 can be used to neutralize calcium lactate hydrate in methyl acetate with concentrated sulfuric acid.

[0047]

[0048] Reaction Scheme 1

[0049] Based on the ultimate use of the anhydrous lactic acid final product in the synthesis of active pharmaceutical ingredients (APIs), calcium lactate hydrate was used and methyl acetate (MeOAc) was selected as the solvent in Reaction Scheme 1. After the calcium lactate hydrate was reacted with concentrated sulfuric acid in methyl acetate, the resulting lactic acid-containing slurry was filtered and concentrated. Residual water was removed by absorption with calcium sulfate and azeotropic removal of the residual water using vacuum distillation (including rotary evaporators or direct vacuum distillation) to produce an anhydrous lactic acid final product.

[0050] In an exemplary embodiment of the synthesis of anhydrous lactic acid of FIG. 1 , calcium lactate hydrate can be neutralized with hydrochloric acid in methyl acetate using Reaction Scheme 2.

[0051]

[0052] Reaction Scheme 2

[0053] After the calcium lactate hydrate reacts with hydrochloric acid, the calcium chloride produced forms a hydrated insoluble material in MeOAc that can be filtered off. The filtrate containing lactic acid can be further processed by separating, recovering, filtering, concentrating, decanting, distilling, crystallizing and / or dehydrating the filtrate to produce high-purity anhydrous lactic acid.

[0054] In one exemplary embodiment of the synthesis of anhydrous lactic acid of FIG. 1 , calcium lactate hydrate can be neutralized with oxalic acid in methyl acetate using Reaction Scheme 3 below.

[0055]

[0056] Reaction Scheme 3

[0057] Calcium lactate hydrate can be neutralized with oxalic acid, which has a pKa lower than that of lactic acid. Reaction Scheme 3 utilizes a slurry in methyl acetate to react with the slurry. Calcium oxalate is insoluble in methyl acetate and can be filtered off to produce a pure lactic acid filtrate. The pure lactic acid filtrate can be further processed by separating, recovering, filtering, concentrating, decanting, distilling, crystallizing, and / or dehydrating the filtrate to produce high-purity anhydrous lactic acid.

[0058] The anhydrous lactic acid end product produced by Reaction Scheme 1-3 can be used to convert a compound of Formula (XXII) (i.e., 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one (IUPAC name) or 1 -(6-(4-Fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (name generated by ChemDraw Professional Edition 17.1.0.105 (19))) is reacted with anhydrous lactic acid in an ethyl acetate solution to produce the API compound of formula (XXIII).

[0059]

[0060] Thus, provided herein are methods for preparing compounds of formula (XXIII):

[0061]

[0062] The method comprises making a compound of formula (XXII)

[0063]

[0064] Contact with anhydrous lactic acid as described herein provides a compound of formula (XXIII).

[0065] The examples below describe exemplary reaction conditions, parameters and reagents to carry out the exemplary steps in the synthesis of anhydrous lactic acid. The following examples illustrate some embodiments as described herein. Those of ordinary skill in the art will appreciate that, without departing from the scope or intention of the present application or disclosed exemplary embodiments, there may be various changes to the embodiments, including variations on synthetic methods, techniques, reactants, reagents, parameters and conditions as described herein. The examples below can produce anhydrous lactic acid products having less than 0.1% water by weight and less than 1% polylactate impurities (such as lactide, lactic acid oligomers and mixtures thereof) by weight. The embodiments can also be used to produce anhydrous lactic acid, particularly L-(+)-lactic acid, D-(-)-lactic acid and DL-lactic acid.

[0066] abbreviation

[0067] AcOH acetic acid

[0068] EtOAc

[0069] h hour

[0070] IPAC or iPrOAc Isopropyl acetate

[0071] min

[0072] Me methyl

[0073] MeOAc methyl acetate

[0074] ROI Residue on Ignition

[0075] Tol Toluene

[0076] Example

[0077] General procedures:

[0078] The examples described below can be used to prepare high-purity anhydrous lactic acid, including L-(+)-lactic acid, D-(-)-lactic acid and / or DL-lactic acid. The following examples are for illustrative purposes only and are not intended to limit the scope of the embodiments and / or claims herein.

[0079] The chiral purity of the product was measured by an isocratic HPLC method (using a chiral column with UV detection at 254 nm). The method was used for release testing of L-calcium lactate to determine the chiral purity and content of D-calcium lactate. The chemical structures of L-calcium lactate and D-calcium lactate are shown below.

[0080]

[0081] Column: Phenomenex Chirex 3126(D)-Penicillamine, 4.6 mm ID x 250 mm L, 5 μm, Product No. 00G-3126-E0

[0082] Instrument: Agilent 1260 HPLC system with UV detector.

[0083] Mobile phase: 2mmol / L CuSO4:IPA (98:2) in water

[0084] Column temperature: 30℃.

[0085] Flow rate: 0.7 mL / min

[0086] Injection volume: 10 μL

[0087] Detector: 254 nm

[0088] Needle washing solvent: diluent

[0089] Run time: 40 minutes

[0090] The relative retention times (RRT) of D-lactic acid and L-lactic acid using this method are as follows.

[0091]

[0092] Integration and calculation were performed by integrating only the peaks of L-lactic acid and D-lactic acid in the chromatogram.

[0093] D-Calcium lactate % = [A D-乳酸 / (A L-乳酸 +A D-乳酸 )]x 100

[0094] Chiral purity (%) = 100 (%) - D-calcium lactate %*

[0095] *D-Lactic acid peak is only considered in the calculation if it is ≥ 0.45%.

[0096] Figure 5 shows a representative chromatogram of the standard solution.

[0097] Obtained on a Varian Mercury 400 MHz machine 1 HNMR data (including QNMR data).

[0098] Reaction Scheme 1: Using concentrated H2SO4 as the inorganic acid

[0099] Example 1

[0100] In an exemplary embodiment of Reaction Scheme 1, concentrated H2SO4 (1.14 mL, 20.61 mmol, 0.9 eq) was added dropwise under nitrogen to a cold (-14°C) slurry of calcium lactate hydrate (5 g, 22.9 mmol anhydrous, 1.0 eq) and MeOAc (100 mL) in a flask. The slurry was stirred at a temperature of -12°C for 30 minutes and at room temperature for an additional 2 hours. The resulting free-flowing slurry was then filtered, and the filtrate was concentrated to produce 3.79 g (quantitative) of a viscous liquid. The filtrate of Example 1 can be further processed to produce anhydrous lactic acid by separating, recovering, filtering, concentrating, decanting, distilling, crystallizing, and / or dehydrating the filtrate.

[0101] Example 2:

[0102] In an exemplary embodiment of reaction scheme 1, concentrated H2SO4 (1.27mmol, 22.9mmol, 1.0 equivalent) is added dropwise under nitrogen to a cold (-14°C) slurry of calcium lactate hydrate (10g, 34.45mmol 4H2O base, 1.5 equivalents) and MeOAc (100mL) in a flask. The reaction mixture is stirred for 3h at a temperature of -12°C to -14°C and stirred for another 2 hours at room temperature. The resulting slurry is then filtered through a sinter funnel and concentrated to approximately 3 volumes on a rotary evaporator. 5 volumes of heptane are then slowly added to form an oily immiscible bottom layer in the reaction mixture. The reaction mixture is then concentrated to 3 volumes. 5 volumes of heptane are added to obtain a similar oily bottom layer. The reaction mixture is then completely concentrated into a viscous oil, dissolved in 50mL MeOAc and dried over anhydrous Na2SO4. The mixture is then concentrated to 2 volumes. 2 volumes of heptane are added, followed by lactic acid seed crystals. Commercially available anhydrous lactic acid was used as seed in the initial experiments, and the material from Example 2 or commercially available anhydrous lactic acid was used as seed in subsequent experiments. The reaction mixture was then cooled in an ice bath while stirring, yielding a semisolid precipitate with some white crystals. The semisolid precipitate was then completely concentrated and subjected to high vacuum filtration to yield 3.57 g of anhydrous lactic acid as a hygroscopic white solid. This synthesis yielded 86.5% anhydrous lactic acid by weight.

[0103] Example 3:

[0104] In an exemplary embodiment of reaction scheme 1, concentrated H2SO4 (3.06mL, 55.12mmol, 1.0 equivalent) is added dropwise under nitrogen to a cold (-13°C) slurry of calcium lactate hydrate (20g, 68.9mmol based on 4H2O base, 1.25 equivalent) and MeOAc (200mL) in a flask. The slurry is stirred for 3h at a temperature of -10°C to -14°C, and stirred for another 2 hours at room temperature. The free-flowing slurry is then filtered through a short pad of anhydrous Na2SO4 in a sintered funnel and concentrated to approximately 2 volumes on a rotary evaporator. The solution is then cooled to 0°C and 1.5 volumes of heptane are then slowly added while stirring. At this point, L-lactic acid seed crystals and another 4.5 volumes of heptane (6 volumes in total) are added. The double layer of the resulting product is then completely concentrated into a semi-solid precipitate. The semi-solid is dissolved in 2 volumes of MeOAc, and 10 volumes of heptane are slowly added. An immiscible layer formed at the bottom of the mixture. The mixture was then concentrated to 2 volumes, and 10 volumes of heptane were added, followed by additional lactic acid seed crystals. A bulk slurry formed, which was completely concentrated to obtain white, hygroscopic, solid crystals of anhydrous L-lactic acid. The synthesis yielded 9.47 grams of anhydrous L-lactic acid at 95.4% by weight.

[0105] Example 4:

[0106] In an exemplary embodiment of reaction scheme 1, concentrated H2SO4 (275.6mmol, 1.0 equivalent) is added dropwise to a cold (-13°C) slurry of calcium lactate hydrate (100g, 344.56mmol based on 4H2O base, 1.25 equivalent) and MeOAc (800mL) in a flask under nitrogen over 15 minutes. The slurry is stirred for 6h at a temperature of -12°C to -14°C. The slurry is then filtered through a Buchner funnel equipped with filter paper and filter cloth. The filter cake is washed with MeOAc (50mL x 2) and a filtrate having a total volume of 1000mL is produced. The filtrate is then divided into the following parts by measuring in a graduated cylinder:

[0107] 1. Part A: 300 mL of the filtrate was used for crystallization from heptane / MeOAc.

[0108] 2. Part B: 300 mL of the filtrate was used for crystallization from toluene / MeOAc.

[0109] 3. Part C: 300 mL of the filtrate was used for crystallization from aqueous solution.

[0110] 4. Part D: 95 mL unused.

[0111] Part A:

[0112] The filtrate from Part A in aqueous solution was concentrated to 30 mL, cooled to a temperature of 0°C to 5°C with an ice bath, and 60 mL of heptane was added dropwise to form an oily immiscible layer. At this point, 30 mg of anhydrous lactic acid crystals were added, which dissolved immediately. The entire solution was then concentrated to 30 mL. 60 mL of heptane was added and concentrated to 30 mL, and this was repeated three times. 60 mL of heptane was then added, cooled in an ice bath, and then 30 mg of anhydrous lactic acid was added as seed crystals to form a slurry. The slurry was not free-flowing or filterable. The slurry was completely concentrated again on a rotary evaporator, dissolved in 10 mL of MeOAc, cooled in an ice bath, and then seed crystals and 60 mL of heptane were added to produce a slurry with better filtering properties. The slurry was then completely concentrated to obtain anhydrous L-lactic acid as a white solid stuck to the wall. The synthesis yielded 12.2 grams of 82% anhydrous L-lactic acid by weight.

[0113] Part B:

[0114] The filtrate in aqueous solution of Part B was concentrated to 30 mL, cooled to a temperature of 0°C to 5°C in an ice bath, and then 60 mL of toluene was added dropwise over 15 minutes. An oil-immiscible layer was formed after the addition of 60 mL of toluene. The double layer was then concentrated to 30 mL. 60 mL of toluene was added to this solution and concentrated to 30 mL at 30°C, and this was repeated three times. Finally, 60 mL of toluene was added, the solution was cooled to a temperature of 0°C to 5°C in an ice bath, and then 30 mg of anhydrous lactic acid seed crystals were added. The solution quickly formed free-floating crystals with large chunks of anhydrous lactic acid. The solution was stirred until the large chunks of anhydrous lactic acid broke up and became a free-flowing filterable slurry. The slurry was then filtered under nitrogen to produce white crystals of anhydrous lactic acid. The synthesis formed 11.6 grams of 78% by weight anhydrous lactic acid.

[0115] Part C:

[0116] The filtrate of Part C in aqueous solution is completely concentrated into a viscous liquid and divided into two parts of 6 g (each in a 15 mL centrifuge tube). Then 600 μL H2O is added to both to prepare an approximately 90% aqueous solution. The solution is then cooled to 15 ° C and anhydrous lactic acid seeds are added. The seeds dissolve at this temperature. The solution is then gradually cooled to 10 ° C and additional anhydrous lactic acid seeds are added to obtain a slurry. The slurry is left to stand in a refrigerator at a temperature of 6 ° C, and the seeds grow into larger crystals. The slurry is then centrifuged at a temperature of 5 ° C and 3000 rpm for 15 minutes. The resulting solid with crystals is then collected by decantation and dried in a vacuum oven at room temperature. A total of 3.9 g (29% yield) of solid is collected. The crystals are difficult to transfer and dry relative to Part B-Part C. The supernatant present in the wet crystals is azeotroped with toluene (20 mL x 4). The resulting double-layer suspension containing 20 mL of toluene is cooled to a temperature of 0 ° C, and then lactic acid seeds are added. A slurry was formed which was distilled twice with 20 mL of toluene.The resulting free-flowing slurry was filtered under nitrogen to obtain 9.1 grams of 61% by weight anhydrous lactic acid in the form of white crystals.

[0117] Example 5:

[0118] In an exemplary embodiment of reaction scheme 1, concentrated H2SO4 (15mL, 275.6mmol, 1.0 equivalent) is added dropwise to a cold (-15°C) slurry of calcium lactate hydrate (100g, 344.56mmol based on 4H2O base, 1.25 equivalent) and MeOAc (800mL) in a flask under nitrogen for 30 minutes. The slurry is stirred at a temperature of -12°C to -14°C for 6 hours. The slurry is then filtered through a Buchner funnel equipped with filter paper and filter cloth. The filter cake is washed with 100mL MeOAc. The filtrate is concentrated to 300mL. 200mL toluene is added, and the slurry is concentrated to 300mL at a temperature of 30°C. This step is repeated 3 times. Along with adding anhydrous lactic acid crystals (50mg) as seeds, the double layer of the gained is cooled to a temperature of 4°C in an ice bath and centrifuged at 400rpm. Form bulk solid immediately. The suspension was stirred at room temperature for 15 hours. A viscous slurry was formed that was not free-flowing or filterable. 2 volumes of MeOAc were added to dissolve all solids, and the solution was concentrated on a rotary evaporator until it became a viscous oil. 1 volume of MeOAc and 2 volumes of toluene were added to the solution and concentrated to 2 volumes. Another 2 volumes of toluene were added and concentrated to 3 volumes. A free-flowing slurry was now formed, which was filtered under vacuum and dried under high vacuum for 4 hours to produce 37.2 grams of anhydrous lactic acid in the form of a white crystalline solid, 75% by weight. As determined by Karl Fischer titration, the water content of the anhydrous lactic acid product was 0.562% by weight. Figure 2 depicts the synthesized anhydrous lactic acid product.

[0119] Example 6:

[0120] In an exemplary embodiment of reaction scheme 1, concentrated H2SO4 (15.0mL, 275.6mmol, 1.0 equivalent) is added dropwise to a cold (-13°C) slurry of calcium lactate hydrate (100g, 344.56mmol based on 4H2O base, 1.25 equivalent) and MeOAc (800mL) in a flask under nitrogen over 30 minutes. The slurry is stirred at a temperature of -10°C to -12°C for 6 hours. The slurry is then filtered through a Buchner funnel equipped with filter paper and filter cloth. The filter cake is washed with 100mL MeOAc. The filtrate is concentrated to 100mL. 200mL MeOAc is added and concentrated to 100mL, and repeated. 200mL toluene is added, concentrated to 300mL at a temperature of 30°C, and repeated 3 times. 200mL toluene is added. The double layer of the obtained is stirred at room temperature, and anhydrous lactic acid crystals (50mg) are added as seed crystals. A precipitate-like slurry formed that was not free-flowing or filterable. The slurry was concentrated to 100 mL at 30°C. 200 mL of toluene was added and concentrated to 100 mL, and this was repeated twice. A free-flowing slurry was formed, which was filtered under vacuum and dried under high vacuum at room temperature for 24 hours to obtain 40.8 grams of 82% by weight anhydrous lactic acid as a white crystalline solid.

[0121] Reaction Scheme 1 and the use of sulfuric acid produce high-grade, high-purity, and high-yield anhydrous lactic acid from a slurry of calcium lactate hydrate. The slurry produced by Reaction Scheme 1 is easily filtered, and the lactic acid is isolated in high yield as a purified final product. Exemplary Reaction Scheme 1 can produce anhydrous lactic acid of high purity and high yield.

[0122] Reaction Scheme 3: Using solid oxalic acid as the neutralizing acid

[0123] Example 7

[0124] In an exemplary embodiment of Reaction Scheme 3, solid anhydrous oxalic acid (1.39 g, 15.5 mmol, 0.9 eq) is added to a cold (-10° C.) slurry of L-lactate calcium hydrate (5 g, 1.0 eq, x mmol based on 4H 2 O) in MeOAc (100 mL). The resulting slurry is stirred at a temperature of -10° C. for 40 minutes and then at room temperature for 46 hours. The slurry is then filtered through a sintered funnel and concentrated on a rotary evaporator to produce 2.63 grams of 94% by weight lactic acid in the form of a highly viscous liquid. The filtrate containing lactic acid can be further processed by separating, recovering, filtering, concentrating, decanting, distilling, crystallizing and / or dehydrating the filtrate to produce high-purity anhydrous lactic acid.

[0125] Example 8

[0126] In an exemplary embodiment of reaction scheme 3, solid anhydrous oxalic acid (2.48g, 27.54mmol, 0.8 equivalent) is added to a cold (-10°C) slurry of L-lactate calcium hydrate (10g, 1.0 equivalent, 17.22mmol based on 4H2O) in MeOAc (200mL). The resulting slurry is warmed to room temperature and stirred at room temperature for 18 hours. The slurry is then filtered through a sintered funnel and concentrated to 5 volumes on a rotary evaporator to produce a filtrate. 5 volumes of heptane are added to the filtrate, followed by the addition of lactic acid seed crystals. A precipitate is formed, which is completely concentrated and maintained in a high vacuum to produce 3.86g of 79% by weight of anhydrous L-lactic acid in the form of a white crystalline solid.

[0127] Exemplary Reaction Scheme 3 can produce high-purity anhydrous lactic acid in high yield, including L-(+)-lactic acid, D-(-)-lactic acid and / or DL-lactic acid.

[0128] Exemplary large-scale synthetic route (II) can be used to produce anhydrous L-lactic acid having less than 0.1% by weight of water and less than 1% by weight of polylactate impurities (such as lactide, oligomers of lactic acid, and mixtures thereof).

[0129]

[0130] Synthetic Route II

[0131] FIG3 depicts an exemplary equipment layout for synthesizing anhydrous lactic acid using Synthesis Route II.

[0132] The equipment used in Figure 3 includes two 80 L glass reactors (Reactor 1 and Reactor 2) and a tray dryer. The reactors are equipped with a stirrer. A filter flask is used for filtration. Vacuum filtration or pressure filtration can also be used.

[0133] Typical reactants, solvents, and materials used to carry out Synthesis Scheme II are summarized in Table 1.

[0134] Table 1: Summary of material distribution for synthetic route (II)

[0135]

[0136] In Synthesis Route II, the oxygen content in the reactor is reduced to ≤ 1% (by volume) before charging the reactants into the reactor 1. In an exemplary embodiment, the oxygen content in the reactor is 0.7% before initiating the reaction.

[0137] Reactor 1 was charged with 34.7 kg of isopropyl acetate and the stirring device was started. 7.5 kg of anhydrous calcium L-lactate was then charged to the reactor. The reaction mixture was maintained at a temperature of 0° C. to 10° C. In an exemplary embodiment, the reaction mixture was cooled and maintained at 7.3° C.

[0138] Then 2.8 kg of sulfuric acid was added to the reactor at a temperature of 0°C to 10°C. The reaction temperature was maintained at 0°C to 10°C during the reaction. After 3 hours, a sample of the mixture was used 1 H-NMR spectroscopy was performed every 1–4 h until the 1 The assay was greater than or equal to 11.5 or the difference between two consecutive samples was ≤ 0.5%.

[0139] In an exemplary embodiment, the reaction was carried out for 7 h 10 min and the results were analyzed by QNMR. 1 8.8% was determined by QNMR 2 The assay yielded 8.5% and the difference between two consecutive samples was 0.3%. The peak area of ​​the lactic acid peak at 4.07 ppm was monitored for quantitative NMR analysis. QNMR stands for quantitative 1 HNMR, in which the amount of test material is quantified (determined) relative to an internal reference standard. In this case, the internal reference standard is 1,3,5-trimethoxybenzene.

[0140] The reaction mixture is then filtered in a first filtration using a filter flask and a filter cake is produced. Vacuum filtration can be used.

[0141] Reactor 1 is charged with a second charge of 13.9 kg of isopropyl acetate at a temperature between 0° C. and 30° C. In an exemplary embodiment, reactor 1 is charged with a second charge of isopropyl acetate at a temperature between 3.7° C. and 6.4° C. The isopropyl acetate is cooled to a temperature between 0° C. and 10° C. In an exemplary embodiment, the mixture is cooled to a temperature between 6.3° C.

[0142] The filter cake from the first filtration is added to Reactor 1 at a temperature of 1° C. to 10° C. In an exemplary embodiment, the filter cake is added to Reactor 1 at a temperature of 6.3° C. to 6.4° C. The reaction mixture is stirred at a temperature of 0° C. to 10° C. for 1-2 hours. In an exemplary embodiment, the reaction mixture is stirred at a temperature of 6.4° C. to 8.7° C. for 1 hour and 3 minutes.

[0143] The reaction mixture was filtered in a second filtration using a filter bottle. The filtrate from the first filtration and the filtrate from the second filtration were added to the reactor 2 in batches through a capsule filter.

[0144] The mixture in the reactor 2 is concentrated to ≤ 45°C under reduced pressure (P≤-0.08 MPa) until 0.5-1.0 volume remains. In an exemplary embodiment, the mixture is concentrated at a temperature of 16.5-32°C and a pressure of -0.08 MPa.

[0145] Reactor 2 is charged with an additional 6.9 kg of isopropyl acetate and stirred until completely dissolved. The mixture is sampled using Karl Fisher titration to determine the water content. The mixture is cooled to a temperature of 20° C. to 25° C. In an exemplary embodiment, the mixture is cooled to a temperature of 24.3° C.

[0146] Anhydrous L-lactic acid seed crystals are added to the mixture. In an exemplary embodiment, 30.0 g of anhydrous L-lactic acid seed crystals are added to the mixture at a temperature of 20°C to 25°C over a period of 1-2 hours. The mixture is stirred at a temperature of 20°C to 25°C for 1-2 hours. In an exemplary embodiment, the mixture is stirred at a temperature of 21.4°C to 24.2°C for 1-2 hours.

[0147] The mixture is cooled to a temperature of 0° C. to 10° C. In an exemplary embodiment, the mixture is cooled to a temperature of 9.5° C. The mixture is stirred at a temperature of 0° C. to 10° C. for 1-2 h. In an exemplary embodiment, the mixture is stirred at a temperature of 2.3° C. to 9.5° C.

[0148] Toluene is added to the mixture through a capsule filter at a temperature of 0° C. to 10° C. In an exemplary embodiment, 52.2 kg of toluene is added to the mixture through a capsule filter at a temperature of 0° C. to 10° C.

[0149] The mixture is stirred at a temperature of 0° C. to 10° C. for 2-3 h. In an exemplary embodiment, the mixture is stirred at a temperature of 1° C. to 2.8° C. for 2-3 h.

[0150] The mixture was filtered through a filter flask. The filter cake was rinsed twice with 6.3 kg of toluene. The solids from the filter were placed in a tray dryer and dried at 15°C-25°C for 12 hours. In an exemplary embodiment, the drying temperature was 20°C-21°C. The solids were sampled every 4-12 hours for residual solvent analysis until the residual isopropyl acetate was ≤5000 ppm and the residual toluene was ≤890 ppm. In an exemplary embodiment, the product contained 563 ppm of isopropyl acetate and 277 ppm of toluene.

[0151] The resulting product is anhydrous L-lactic acid. In an exemplary embodiment, the resulting product is 6.0 kg of 99.3% by weight anhydrous L-lactic acid (based on 1H-NMR spectroscopy). The yield of Synthesis Route II is at least 47% and the chiral purity is 100%.

[0152] The reaction scale and yield of two batches of anhydrous L-lactic acid produced by Synthesis Route II are provided in Table 2.

[0153] Table 2: Results of Synthesis Route II

[0154]

[0155] Tables 3 and 4 summarize the chemical characteristics of the anhydrous lactic acid final products of Batch 1 and Batch 2.

[0156] Table 3: Chemical properties of the anhydrous lactic acid final product

[0157]

[0158] Table 4: Chemical properties of the anhydrous lactic acid final product

[0159]

[0160] Figure 4 depicts the final product of L-(+)-lactic acid synthesized using Synthesis Route II. 1 HNMR results.

[0161] The exemplary syntheses and reaction schemes disclosed herein can be used to produce anhydrous lactic acid, particularly L-(+)-lactic acid, D-(-)-lactic acid, and DL-lactic acid, for use in industrial processes, including but not limited to petrochemical processes; chemical and polymer syntheses; processes for producing cosmetics and personal care products; processes for producing food additives, detergents, and flavorings; and processes for producing pharmaceuticals and active pharmaceutical ingredients.

Claims

1. A method for synthesizing anhydrous lactic acid, the method comprising: The compound of formula (Ia): With formula H n The acid compound of X is reacted in a first solvent to form a reaction mixture comprising a compound of formula (Ib) and a lactic acid compound of formula (I) in a solution containing the first solvent: wherein each n is independently an integer other than 0, x is 0 or an integer other than 0, M is an alkali metal or an alkaline earth metal, and X is the formula H n the conjugate base of the acid compound of X; as well as The reaction mixture is filtered to produce a filtrate containing the lactic acid compound of formula (I) in solution.

2. The method according to claim 1, further comprising concentrating the filtrate.

3. The method of claim 2, wherein concentrating the filtrate comprises distilling the filtrate.

4. The method of claim 2, further comprising crystallizing the filtrate from a second solvent to produce a crystalline product. The method according to claim 1 , wherein the lactic acid compound of formula (I) is soluble in the first solvent. The method according to claim 1 , wherein the compound of formula (Ib) is insoluble in the first solvent.

7. The method of claim 1, wherein M is calcium.

8. The method of claim 1, wherein M is selected from the group consisting of sodium, potassium, magnesium, lithium, barium, beryllium, cesium, and strontium.

9. The method according to claim 1, wherein the formula H n The acid compound of X is sulfuric acid, and X is a sulfate group.

10. The method according to claim 1, wherein the formula H n The acid compound of X is oxalic acid, and X is oxalate.

11. The method according to claim 1, wherein the formula H n The acid compound of X is hydrochloric acid, and X is chloride.

12. The method of claim 1, wherein the compound of formula (Ia) is calcium L-lactate hydrate.

13. The method of claim 1, wherein the first solvent is an ester solvent.

14. The method of claim 13, wherein the ester solvent is methyl acetate.

15. The method of claim 13, wherein the ester solvent is ethyl acetate.

16. The method of claim 13, wherein the ester solvent is isopropyl acetate.

17. The method of claim 13, wherein the ester solvent is n-propyl acetate.

18. The method of claim 1, wherein the first solvent is selected from the group consisting of acetone, toluene, acetonitrile, MTBE, isopropanol, ethanol, methanol, and tetrahydrofuran.

19. The method of claim 4, wherein the second solvent is toluene.

20. The method of claim 4, wherein the second solvent is heptane.

21. The method of claim 4, further comprising introducing seed crystals of anhydrous lactic acid into the second solvent during crystallization.

22. The method of claim 1, further comprising azeotropically removing water from the filtrate.

23. The method of claim 4, further comprising vacuum drying the crystallized product.

24. The method of claim 1, further comprising drying the filtrate with a drying agent.

25. The method of claim 24, wherein the desiccant is Na2SO4.

26. The method of claim 4, wherein the anhydrous lactic acid is anhydrous L-(+)-lactic acid.

27. The method of claim 4, wherein the anhydrous lactic acid is D-(-)-lactic acid or DL-lactic acid.

28. A method for synthesizing anhydrous lactic acid, the method comprising reacting anhydrous calcium lactate with an acid in an ester solvent.

29. The method of claim 28, wherein the acid is sulfuric acid.

30. The method of claim 28, wherein the ester solvent is isopropyl acetate.

31. The method of claim 28, wherein the anhydrous lactic acid is anhydrous L-(+)-lactic acid.

32. The method of claim 28, wherein the anhydrous lactic acid is D-(-)-lactic acid or DL-lactic acid.

33. The method of claim 4, wherein the anhydrous lactic acid comprises less than 1% by weight of polylactate impurities.

34. The method of claim 28, wherein the anhydrous lactic acid comprises less than 0.1% by weight water.

35. The method of claim 28, wherein the anhydrous lactic acid comprises less than 1% by weight of polylactate impurities.

36. A method for preparing a compound of formula (XXIII): The method comprises: Synthesizing anhydrous lactic acid according to the method of claim 1; The compound of formula (XXII) contacting with anhydrous lactic acid according to claim 1 to provide said compound of formula (XXIII).

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