Europaisches Patentamt (19) 3 European Patent Office Office europeen des brevets (11) EP 0 916 649 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) |nt Cl.e: C07C 245/16 19.05.1999 Bulletin 1999/20 (21) Application number: 98203801.0 (22) Date of filing: 11.11.1998 (84) Designated Contracting States: • Huang, Der-Shing AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU Folsom, California 95630 (US) MC NL PT SE • Pratton, Mark H. Designated Extension States: Gait, California 95632 (US) AL LT LV MK RO SI • Barnard, James C. Shingle Springs, California 95682 (US) (30) Priority: 13.11.1997 US 970035 (74) Representative: de Bruijn, Leendert C. et al (71) Applicant: AEROJET-GENERAL CORPORATION Nederlandsch Octrooibureau Rancho Cordova, CA 95670 (US) P.O. Box 29720 2502 LS Den Haag (NL) (72) Inventors: • Archibald, Thomas G. Fair Oaks, California 95628 (US) (54) Large scale batch process for diazomethane (57) Diazomethane is prepared in a batch process solvent, reagent concentrations, addition rate and reac- on a scale of at least 50 gram-moles per batch, from an tion temperature to cause codistillation of the product N-methyl-N-nitroso amine in an organic solvent and an and the organic solvent in such a manner that the con- inorganic base in an aqueous solution by the use of a centration of diazomethane in both liquid and vapor phase transfer catalyst and by controlling the choice of phases are controlled within limits that will prevent det- onation of the diazomethane. O) ^- CO CO O) o a. LU Printed by Jouve, 75001 PARIS (FR) EP 0 916 649 A1 Description BACKGROUND OF THE INVENTION 5 1. Field of the Invention [0001] This invention resides in the technology of diazomethane synthesis. 2. Description of the Prior Art 10 [0002] Diazomethane (CH2=N=N, also known as azimethylene or diazirine) has a wide range of utility in chemical syntheses. It is a common methylating agent for carboxylic acids, phenols, alcohols, enols, and heteroatoms such as nitrogen and sulfur. It is also used for the ring expansion or chain extension of ketones, and for the conversion of ketones to epoxides. A further example of its use is the conversion of acid chlorides to a-diazoketones which are is themselves useful intermediates. Still further examples are its use in cycloaddition reactions with olefins to produce cyclopropyl or nitrogen-containing heterocyclic rings. Still further examples involve the formation of viral protease in- hibitors including those used to combat HIV. A particularly important class of viral protease inhibitors are those that include structures known as amino acid isosteres which consist of a three-carbon moiety derived from a two-carbon amino acid by the addition of a functionalized carbon. An example is Saquinavir (Roche Laboratories). The addition 20 of the carbon must be done without compromising the chirality of the amino acid or affecting any portion of the remainder of the molecule. This is sucessfully achieved by the use of diazomethane in a modified Arndt-Eistert reaction. [0003] Despite its wide applicability in chemical synthesis, diazomethane is a hazardous reagent. It is a carcinogen and a powerful allergen and is poisonous. Its greatest problem however is that it is highly explosive. For this reason, the technical literature on the synthesis of diazomethane cautions against the use of ground-glass joints and any 25 glassware that has not been firepolished, and no syntheses other than laboratory bench-scale syntheses have been reported. Equipment specifically designed for diazomethane preparation, such as the DIAZALD® apparatus of Aldrich Chemical Company, Inc., Milwaukee, Wisconsin, USA, is designed for a maximum of 300 millimoles of diazomethane by single batch reaction. See Black, T.H., "The Preparation and Reactions of Diazomethane, ' 'Ala 'richimica Acta 16(1): 3-10 (1983). A preparation referred to as "large scale" is disclosed by Acevedo et al. in United States Patent No. 30 5,459,243, "Apparatus and Processes for the Large Scale Generation and Transfer of Diazomethane," issued October 17, 1995. The reactions disclosed in the patent however are performed in laboratory Erlenmeyer glassware on a 100-millimole (4.2 g) scale. [0004] In view of the versatility of diazomethane, a truly large-scale process, i.e., one that produces quantities well into the gram-mole range in a single batch, is needed. 35 SUMMARY OF THE INVENTION [0005] It has now been discovered that diazomethane can be synthesized in a batch reaction on a truly large scale with little or no danger of explosion. Batches of 50 gram-moles (2.1 kg) of diazomethane quantity or greater can now 40 be prepared, such as about 50 gram-moles to about 25,000 gram-moles (2. 1 kg to 21 0 kg), preferably about 1 00 gram- moles to about 15,000 gram-moles (4.2 kg to 126 kg), and more preferably about 300 gram-moles to about 10,000 gram-moles (1 2.6 kg to 42. 1 kg). As in the prior art, the synthesis includes the reaction between an N-methyl-N-nitroso amine and a strong base and is conducted in a two-phase aqueous-organic liquid reaction mixture with co-distillation of the organic solvent and the product diazomethane immediately as the latter is formed. According to the invention, 45 however, the reaction is conducted in the presence of a phase transfer catalyst, and the choice of organic solvent, the degree of dilution of the reagents in the solvent, and the reaction temperature are selected such that the concentration of diazomethane in both the liquid and vapor phases are maintained within prescribed limits of a maximum of about 3 weight percent in the liquid phase and a maximum of about 25 mole or volume percent in the vapor phase. Further insurance against spontaneous explosions is achieved by maintaining the reaction conditions steady, for example by so adding an organic solution of the N-methyl-N-nitroso amine at a gradual and steady rate to the aqueous base, and by maintaining controlled agitation of the reaction mixture during the addition to avoid localized variations in concentration and temperature within the reaction vessel. [0006] Further features, embodiments and advantages of the invention will become apparent from the description that follows. 55 DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS [0007] The phase transfer catalyst is any catalyst that will disoslve in the two-phase liquid system and enhance the 2 EP 0 916 649 A1 rate of reaction between a reactant in the aqueous phase and one in the organic phase. Any of the wide variety of known phase transfer catalysts will serve this purpose, although the preferred catalysts are those that will neither undergo a chemical decomposition nor vaporize into the gas phase under the conditions at which the reaction is per- formed. High-boiling phase transfer catalysts, preferably with boiling points above about 200°C, are preferred. 5 [0008] Examples of classes of phase transfer catalysts that can be used are quaternary ammonium or phosphonium salts, crown ethers and glycol ethers. Examples of quaternary ammonium salts are benzyltriethylammonium chloride, methyltrioctylammonium chloride, methyltrioctylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylam- monium bromide, and other such ammonium halides containing 15 or more carbon atoms. Examples of quaternary phosphonium salts are tetra-n-butylphosphonium chloride, tetra-n-butylphosphonium bromide, and others that are the 10 phosphonium counterparts to the quaternary ammonium salts. Note however that in preferred embodiments of this invention, the reaction is performed at a temperature in excess of 45° C and in very strong base. Under these conditions, quaternary amonium salts are often degraded to amines which would react with diazomethane. Hence, quaternary ammonium salts that degrade in this manner are less preferred than other phase transfer catalysts. [0009] Examples of crown ethers are hexaoxacyclooctodecane and its analogs with phenyl and cyclohexyl ring sub- 's stituents on the crown ether ring. Examples of glycols are diethylene glycol monomethyl ether, diethylene glycol mo- noethyl ether, triethylene glycol monomethyl ether, and triethylene glycol monoethyl ether. Glycols having a molecular weight of at least about 1 20 are preferred. One particularly effective glycol for this purpose is diethylene glycol monoe- thyl ether. [0010] The phase transfer catalyst is employed in a catalytic amount, which is generally a range of concentrations. 20 The optimum amount or preferred range in any particular system will vary with the particular catalyst or class of catalyst used, but the appropriate amount for any particular reaction system will be apparent to those skilled in the use of these catalysts. [0011] The N-methyl-N-nitroso amine used in the process of this invention is represented generically by the formula 25 NO R CH3 in which R is an electron-withdrawing radical, or a radical with an electron-withdrawing group in close proximity (pref- erably bonded directly) to the amine nitrogen at the center of the formula. Examples of electron-withdrawing groups 35 are sulfonyl groups ( — S02 — ), carbonyl groups ( — C(=0) — ), and iminomethylene groups ( — C(=NH) — ). Exam- ples of specific N-methyl-N-nitroso amines within the above formula are N-methyl-N'-nitro-N-nitrosoguanidine (com- monly known as "MNNG"), N-methyl-N-nitrosourea, N-methyl-N-nitrosocarbamate, N-methyl-N-nitrosourethane, and N-methyl-N-nitroso-p-toluenesulfonamide (available from Aldrich Chemical Company, Inc., Milwaukee, Wisconsin, USA, as "DIAZALD®"). 40 [0012] The choice of inorganic base is not critical to the invention, although the preferred inorganic base is potassium hydroxide. [0013] The organic solvent is selected as one that will co-distill with the diazomethane in a manner that will reduce or eliminate the risk of a high concentration of diazomethane in the vapor phase.