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WO 2018/200881 Al 01 November 2018 (01.11.2018) W !P O PCT

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WO 2018/200881 Al 01 November 2018 (01.11.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/200881 Al 01 November 2018 (01.11.2018) W !P O PCT (51) International Patent Classification: B01J 23/06 (2006.01) B01J 29/24 (2006.01) 5 0 . 2 / 72 (2006.01) (21) International Application Number: PCT/US2018/029658 (22) International Filing Date: 26 April 2018 (26.04.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/491,185 27 April 2017 (27.04.2017) US (71) Applicant: DEUTERIA BEVERAGES, LLC [US/US]; 15025 Broili Dr, Renoq, Nevada 8951 1 (US). (72) Inventors: LEFORT, Laurent; Wycker Grachtstraat 22A2, 622 1CW Maastricht (NL). SCHMITKAMP, Mike; Maria-Montessori Strasse 77, 52134 Herzogenrath (DE). (74) Agent: VANCE, David; P.O. Box 1224, Crozet, Virginia 22932 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) 00 0 o0 00 (54) Title: PROCESS FOR THE PREPARATION OF DEUTERATED ETHANOL FROM D20 (57) Abstract: The invention relates to a process for the preparation of a deuterated ethanol from ethanol, D O, a ruthenium catalyst, and a co-solvent. PROCESS FOR THE PREPARATION OF DEUTERATED ETHANOL FROM FIELD OF THE INVENTION [0001] The present invention relates to a process for the preparation of a deuterated ethanol from D2O. BACKGROUND OF THE INVENTION [0002] Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen. Deuterium-enriched organic compounds such as a deuterated ethanol are known. US Patent No. 8,658,236 describes an alcoholic beverage of water and ethanol, wherein at least 5 mole percent of the ethanol is a deuterated ethanol. This alcoholic beverage is believed to diminish the negative side effects associated with the consumption of ethanol. [0003] The production of a deuterated-ethanol containing alcoholic beverage requires the preparation of a deuterated ethanol in an efficient, safe, and cost-effective manner. A known process for the preparation of a deuterated alcohol (e.g., deuterated ethanol) involves an H/D exchange reaction between a non-deuterated alcohol and D2O. Depending on the process, the resulting deuterated alcohol may comprise deuterium in different positions. Examples of such processes can be found in Chemistry Letters 34, No.2 (2005), p.192- 193 "Ruthenium catalyzed deuterium labelling of a-carbon in primary alcohol and primary/secondary amine in D2O"; Adv. Synth. Catal. 2008, 350, p. 2215 - 2218 "A method for the regioselective deuteration of alcohols"; Org. Lett. 2015, 17, p. 4794-4797 "Ruthenium Catalyzed Selective a- and α,β-Deuteration of Alcohols Using D20 " and Catalysis Communications 84 (2016) p. 67-70 "Efficient deuterium labelling of alcohols in deuterated water catalyzed by ruthenium pincer complexes". [0004] Other routes to produce a deuterated alcohol involve several consecutive reactions requiring expensive and/or hazardous material. For each of these transformations, purification and isolation of the intermediates are necessary. [0005] In view of the above, it is desirable to be able to synthesize deuterated ethanol in an efficient, safe and cost-effective manner. It is further desirable to synthesize deuterated ethanol with deuteration substantially only at a desired position(s). SUMMARY OF THE INVENTION [0006] In an aspect, the present invention provides a process for the preparation of a deuterated ethanol from ethanol, D2O, a ruthenium catalyst, and a co-solvent. [0007] These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery of a new process of making deuterated ethanol. DETAILED DESCRIPTION OF THE INVENTION [0008] It has now surprisingly been found that the combination of D2O, a ruthenium catalyst, and co-solvent allows for the effective and selective deuteration of ethanol. [0009] Catalysis Communications 2016, 84, 67-70 (CC), mentions the deuteration of alcohol catalyzed by Ru-MACHO ®-BH and Ru-MACHO ®, but fails to mention the use of a co-solvent. Ru-MACHO ®-BH was used only for the deuteration of 1-butanol and not ethanol. It has now been found that no deuteration of ethanol occurs when 1-butanol is replaced by ethanol in the system described in CC where the catalyst is Ru- MACHO ®-BH. [0010] CC also mentions the deuteration of ethanol catalyzed by Ru-MACHO ® using 20 mol of NaOH. It has now been found that deuteration of ethanol is not possible when NaOH is replaced by another base in the system described in CC where the catalyst is Ru-MACHO ®. However, it has surprisingly been discovered that the addition of a co-solvent to dissolve the catalyst results in an efficient deuteration of ethanol, in particular without the presence NaOH. [0011] Thus, in an aspect, the present invention provides a novel process for the preparation of a deuterated ethanol of formula (I): CR R^CR^OH (I) comprising: reacting ethanol and D2O in the presence of a ruthenium catalyst of formula (II) and a co-solvent: (Π) whererin: R^R are independently H or D, provided that the abundance of D in R4 and R5 is at least 70%; each R6 is independently selected from: H, a Ci-io alkyl group, a substituted Ci-10 alkyl group, a C6 -i8 aromatic ring group, and a substituted C6 -i8 aromatic ring group; each Ar is independently selected from a C6 -i8 aromatic ring group and a substituted C6 -i8 aromatic ring group; each n is independently 1 or 2; L is a ligand; X is a counterion; and, the catalyst is soluble in the mixture of ethanol, D2O, and the co-colvent. [0012] In another aspect, the process is performed in the absence of a base. [0013] In another aspect, the process is performed in the absence of NaOH. 4 5 1 2 3 [0014] The abundance of D in R and R (the CH2 position) and in R , R , and R (the CH3 position) can be measured by ¾ NMR. The 70% abundance of D in R4 and R5 means that 70% of all R4 and R5 present are D (as opposed to the natural abundance of 0.01%). [0015] In another aspect, the abundance of D in R4 and R5 is at least 80%. Additional examples of the abundance of D in R4 and R5 include at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 99.5%. [0016] In another aspect, the incorporation of D occurs preferentially in R4 and R5 over R^R . In another aspect, the abundance of D in R^R is at most 50%. Additional examples of the abundance of D in R^R include at most 45, 40, 35, 30, 25, 20, 15, 10, 5, and 1%. [0017] In another aspect, the abundance of D in R4 and R5 is at least 90% and the abundance of D in R^R is at most 5%. Additional examples include (a) at least 95% and at most 1%, and (b) at least 99% and at most 1%. [0018] The conversion of ethanol to deuterated ethanol in the present process can be determined by ¾ NMR. The conversion is the molar ratio of deuterated ethanol formed divided by the initial amount of starting ethanol (un-enriched ethanol). In an aspect, the conversion percentage (molar ratio x 100) is at least 90%. Additional examples of the conversion percentage include at least 95%, at least 98%, and at least 99%. The co-solvent forms a mixture together with ethanol and D2O, which solubilizes the catalyst. Examples of co-solvents include tetrahydrofuran (THF), 2- methyltetrahydrofuran, methyl tert-butyl ether (MTBE), diisopropyl ether, 1,2- dimethoxyethane, toluene (tol), benzene, xylenes, 1,4-dioxane, diglyme (diethylene glycol diethyl ether), cyclopentyl methyl ether (CPME), ethyl acetate, 1,2- dichloroethane, dimethylacetamide, dimethylformamide, and dimethyl sulfoxide [0019] . The co-solvent may also be deuterated, wherein one or more H atoms of the co- solvent are replaced by D. Examples of deuterated co-solvents include ds- tetrahydrofuran, ds-toluene, and ds- 1,4-dioxane. [0020] The reaction mixture may be monophasic or biphasic. For example, in the case where the co-solvent is toluene or cyclopentyl methyl ether, the mixture is biphasic. [0021] For increasing the loading of the reactor and therefore the productivity, the amount of the co-solvent is typically not too high.
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