Europaisches Patentamt J European Patent Office Publication number: 0 205 583 Office europeen des brevets B1 EUROPEAN PATENT SPECIFICATION (45) Date of publication of patent specification: 30.01.91 Intel.5: C 07 C 211/65 (3) Application number: 86900522.3 @ Date of filing: 17.12.85 (8) International application number: PCT/US85/02509 ® International publication number: WO 86/03744 03.07.86 Gazette 86/14 STABLE LITHIUM DIISOPROPYLAMIDE AND METHOD OF PREPARATION. (M) Priority: 24.12.84 US 685318 Proprietor: LITHIUM CORPORATION OF AMERICA, INC. Post Office Box 795 Date of publication of application: Bessemer City, NC 28016 (US) 30.12.86 Bulletin 86/52 Inventor: MORRISON, Robert, Charles Publication of the grant of the patent: 1946 Elmwood Drive 30.01.91 Bulletin 91/05 Gastonia, NC 28054 (US) Inventor: HALL, Randy, Winf red Route 4 Box 697 (M) Designated Contracting States: Kings Mountain, NC 28086 (US) AT BE CH DE FR GB IT LI LU NL SE Inventor: RATHMAN, Terry, Lee 3843 Gardner Park Drive Gastonia, NC 28054 (US) References cited: US-A-3197 516 US-A-3 694516 US-A-3388178 US-A-4 006187 Representative: Gore, Peter Manson et al US-A-3446 860 US-A-4399 078 W.P. THOMPSON & CO. Coopers Building Church Street JOURNAL OF ORGANOMETALLIC CHEMISTRY, Liverpool L1 3AB (GB) vol. 4, 1965; GILMAN et al.: "Stabilities of some n-alkyllithium compounds in mixed solvent CO I References cited: 00 systems", pp. 483-487 JOURNAL OF ORGANOMETTALIC CHEMISTRY, m JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 29, 1971; HONEYCUTT: "Kinetics of the in vol. 22, 1957; GILMAN et al.: "Preparation and cleavage of tetrahydrofuran by n-butyllithium in o stability of some organolithium compounds in hydrocarbon solvent", pp. 1-5 CM tetra hydrofuran", pp. 483-487 Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall Q. be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been LU paid. (Art. 99(1) European patent convention). Courier Press, Leamington Spa, England. EP 0 205 583 B1 D References cited: JOURNAL OF ORGANIC CHEMISTRY, vol. 37, no. 4, 1972; BATES et al.: "Cycloreversions of anions from tetrahydrofurans. A convenient synthesis of lithium enolates of aldehydes", pp. 560-562 LIEBIGs ANNALEN DER CHEMIE, vol. 10, 1980; REETZ et al.: "Einfache Darstellung von Lithiumdiisopropylamid in molarem Massstab" pp. 1471-1473 SYNTHESIS, June 1979; GAUDEMAR- BARDONE et al.: "A convenient preparation and utilization of lithium dialkylamides", pp. 463-465 JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 36, 1972; ELLISON et al.: "A method for accurate titration of alkyllithium reagents in ether solutions", pp. 209-213 CHEMICAL ABSTRACTS, vol. 70, no. 23, 09 June 1969, Columbus, OH (US); NORMANT et al.: "Metal alkylamides. Metallation of aliphatic amines", p. 271, no. 105864h CHEMICAL ABSTRACTS, vol. 55, no. 19, 18 Sep 1961, Columbus, OH (US); NORMANT et al.: "Metallation in tetrahydrofuran by sodium in the presence of naphtalene", no. 18549g EP 0 205 583 B1 Description This invention relates to a stable lithium diisopropylamide (LDA) composition, and a method of its preparation. 5 Lithium diisopropylamide (LDA) is widely used as a reagent in the preparation of Pharmaceuticals and speciality chemicals. LDA has a low solubility and irreversibly precipitates in hydrocarbon solvents. Consequently, LDA is not commercially available in solution form. The only commercially available LDA has been as a pyrophoric solid or slurry in hydrocarbon, and this has been available only in low volumes. The safety hazard in the shipment and handling of the pyrophoric LDA solid or slurry, as well as the 10 difficulty in using these forms of LDA in reactions, severely limit the usefulness of these LDA forms in commercial applications. Users of LDA generally prefer an LDA solution. Although LDA is soluble in ethers, it is quite unstable in this medium and quickly decomposes at room temperatures. Therefore, large volume users of LDA must synthesize their own LDA as it is needed, typically by reacting n-butyl-lithium with diisopropylamine in cold is tetrahydrofuran (THF). This reaction is fairly easy to carry out, but may present safety hazards for those users umfamiliar in the handling of pyrophoric n-butyllithium. Accordingly, the need exists for a stable and nonpyrophoric form of lithium diisopropylamide which could be produced and shipped in quantity and which presents fewer handling problems than the currently available forms of lithium diisopropylamide. 20 In accordance with the present invention, there is provided a composition comprising lithium diisopropylamide and a limited amount of tetrahydrofuran that forms a lithium diisopropylamide composition which is thermally stable at mild temperatures for several months. Furthermore, the composition is non-pyrophoric and thus fewer precautions are required to ensure safe shipping and handling. 25 Tetrahydrofuran (THF) is the preferred liquid ether for use in the present invention, since LDA is quite soluble in THF. However, as earlier noted, the currently available forms of LDA are unstable in the presence of THF. It has been found that by limiting the amount of THF to no more than about 1 mole of THF for each mole of LDA present, an LDA/THF composition is obtained which exhibits enhanced thermal stability. 30 Preferably, the mole ratio of THF to LDA is within the range of 0.5:1 to 1:1, and most desirably within the range of 0.8:1 to 1:1. Surprisingly, while not critical to the present invention, the presence in the LDA composition of small amounts of excess diisopropylamine, one of the reactants in the preparation of the LDA, and/or the presence of other amines, such as non-metalable triethylamine (TEA) for example, has a significant 35 stabilizing effect on the decomposition of the LDA. As little as one mole percent excess amine has a stabilizing effect but an excess of 4 or more mole percent is preferred. Excesses of up to 100 mole percent can be utilized. The most preferred molar excess of amine is about 10 to 11 moles of amine per mole of lithium diisopropylamide. Thus, in accordance with one broad aspect of the present invention, there is provided a stable, non- 40 pyrophoric form of lithium diisopropylamide comprising lithium diisopropylamide, and tetrahydrofuran in an amount not exceeding about one mole of tetrahydrofuran per mole of lithium diisopropylamide. For added stability, the composition may also include at least one C2 to C18 amine, preferably a tertiary amine. In its preferred and more limited aspects, the present invention provides a stable, nonpyrophoric lithium diisopropylamide solution which comprises a 1 to 3 molar solution of lithium diisopropylamide in a 45 mixture of tetrahydrofuran, at least one amine selected from the group consisting of diisopropylamine and triethylamine, and an inert liquid hydrocarbon cosolvent, the tetrahydrofuran being present in an amount not exceeding about 1 mole of tetrahydrofuran per mole of lithium diisopropylamide. While the soluble, stable LDA composition of the present invention can be produced by any of several different methods, including the conventional method involving the reaction of n-butyllithium with so diisopropylamine, as well as by reacting other organolithiums and organodilithiums, such as methyllithium, ethyllithium, phenyilithium, cyclohexyllithium, dilithiobutane for example, the preferred method of preparation in accordance with the present invention involves the preparation of lithium diisopropylamide directly from lithium metal. This approach has very significant economic advantage over the traditional method of preparation, since one mole of lithium metal will produce one mole of LDA, while 55 two moles of lithium metal are required when producing LDA from an alkyllithium compound. In accordance with the preferred method of the present invention, the lithium diisopropylamide is produced directly from lithium metal with the use of an electron carrier such as styrene or isoprene. The reaction is carried out in tetrahydrofuran (THF), with the amount of the THF being limited to no more than two moles per mole of electron carrier. Limiting the amount of THF results in a stable product, as earlier 6o noted, and also advantageously avoids sticking together of the lithium metal during the reaction. An inert liquid hydrocarbon cosolvent may also be employed to adjust the final LDA concentration as desired. The stable LDA composition produced by this method will also include as part of the hydrocarbon cosolvent system, the reduced electron carrier, e.g. ethylbenzene (b.p. = 136°C) where styrene was used as the electron carrier and 2-methyl-2-butene (b.p. = 36°C) where isoprene was used. Since the boiling points of 65 these two byproducts differ widely, the particular electron carier which is used may be selected to facilitate EP 0 205 583 B1 of the recovery user's end product from the reduced electron carrier. Thus, for example, where the end product is a liquid, if the user is preparing a high boiling compound, an LDA solution containing the low boiling 2-methyl-2-butene would be selected, whereas the choice for a low boiling LDA solution compound would be an containing ethylbenzene. For those instances where the butene or ethylbenzene not 5 suitable, other electron are carriers may be used, such as butadiene, divinylbenzene, and naphthalene for example