3,590,077 United States Patent Office Patented June 29, 1971 2 propane-1,3-diol and L(--)-threo-1-p-nitrophenyl-2-N,N- 3,590,077 dimethylamino-propane-1,3-diol and their acid addition SALTS OF CHRYSANTHEMIC ACID WITH 1-p- NITROPHENYL - 2-N,N - DIMETHYL-AMINO salts. The said diastereoisomers are unexpectedly excel PROPANE-1,3-DIOLS lent agents for the resolution of racemic acids since they Georges Muller, Nogent-sur-Marne, Gaston Amiard, form salts of greater stability and better crystallizability Thorigny, Andre Poittevin, Les Lilas, and Vesperto and the bases are less soluble in aqueous media than Torelli, Maisons Alfort, France, assignors to Roussel known resolving agents such as ephedrine or L(--)- UCLAF, Paris, France threo-1-p-nitrophenyl-2-amino-propane-1,3-diol. No Drawing. Continuation-in-part of application Ser. No. The disastereoisomers of the invention are particu 610,219, Jan. 19, 1967. This application July 5, 1968, O larly useful for the resolution of racemic mixtures of Ser. No. 742,485 Claims priority, application France, Jan. 26, 1966, 1,5-dioxo - 7a - lower alkyl-5,6,7,7a-tetrahydroindane-4- 47,305; July 7, 1967, 113,580 acetic acids which have been difficult to separate with The portion of the term of the patent subsequent to known resolution agents due to the very slight solubility Mar. 9, 1987, has been disclaimed differences and poor stability of diastereoisomeric salts Int, C. C07c 91/20 formed therewith, such as with L(--)-threo-1-p-nitro U.S. C. 260-501.7 4 Claims phenyl-2-amino-propane-1,3-diol. Other racemic acids may be resolved with the novel compounds of the inven tion and examples of said acids are polyhydronaph ABSTRACT OF THE DISCLOSURE thalenic acids, tetrahydroindane acids and ox-amino acids. Optical isomers of 1-p-nitrophenyl-2-N,N-dimethyl 20 1,5-dioxo - 7a - methyl - 5,6,7,7a - tetrahydroindane-4- amino-propane-1,3-diol and acid addition salts thereof, acetic acid, which is described in French Pat. No. useful for the separation of racemic compounds and 1,384,854, is useful as an intermediate for the prepara preparation thereof. tion of various steroids, such as B-nor-steroids and estra diol derivatives. To resolve a racemic mixture of the 25 said acid, D(-)-threo-1-p-nitrophenyl-2-N,N-dimethyl amino-propane-1,3-diol can be added to a solution of PRIOR APPLICATION the racemic acid in an ethyl acetate-ethanol-water solvent The present application is a continuation-in-part of to crystallize the dextrorotatory salt of D(-)-threo-1-p- our commonly assigned, copending U.S. patent appli nitrophenyl-2-N,N-dimethylamino-propane-1,3-diol with cation Ser. No. 610,219, filed Jan. 19, 1967 now U.S. 30 dextrorotatory 1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroin Pat. No. 3,499,929. dane-4-acetic acid, separating the said crystals from the PRIOR ART mother liquor, treating the crystals with first alkaline conditions and then acid conditions to recover (--) 1,5- The importance of the separation of racemic com dioxo-7a-methyl-5,6,7,7a-tetrahydroindane - 4 - acetic acid pounds such as racemic acids, which are formed in the having a melting point of 129° C. and a specific rotation synthesis of natural products of which only one isomer of fox 20=225-1 (0.5% in water), evaporating the is active, is well known. The resolution of racemic acids mother liquor taking up in water the residue, treating is currently effected by combining the acid with an the aqueous solution with alkaline conditions, separating optically active base to form a mixture of two diastereo the crystals formed, acidifying the filtrate, then purifying isomeric salts which can be separately recovered and 40 the reaction mixture, extracting with an organic solvent, purified and then decomposed into the corresponding evaporating the extracts and treating the residue with dextrorotatory or levorotatory acid. Optically active bases L(--)-threo-1-p-nitrophenyl-2-N,N-dimethylamino-pro such as brucine, morphine, quinine, L(--)-threo-1-p- pane-1,3-diol to form the corresponding levorotatory salt nitrophenyl-2-amino-propane-1,3-diol, etc., have been which can be subjected to alkaline and then acid treat used as resolution agents. 45 ment to obtain (-)-1,5-dioxo-7a-methyl-5,6,7,7a-tetra However, tests have shown that the resolution of an hydroindane-4-acetic acid with a melting point of 129° C. acid very often runs into great difficulties of a technical and a specific rotation of oil0=-225-1 (0.5% in nature which cannot be predicted. The base should form water). Of course, the order of addition of the optically easily crystallizable stable salts with one of the diastereo active isomers of the invention may be reversed with isomeric salts being distinctly less soluble than the other 50 the levorotatory salt being recovered first. in order to facilitate the separation of the salts. Also, Another valuable use for the diastereoisomers of the the base to be separated should preferably be slightly invention is the resolution of dl-trans chrysanthemic acid soluble in aqueous media so that it may be recovered into its optically active isomers. This process is charac without great difficulty after decomposition of its salt. terized in the addition of D(-) or L(--) threo-1-p-nitro 55 phenyl-2-N,N-dimethylaminopropane-1,3-diol to a solu OBJECTS OF THE INVENTION tion of dl-trans chrysanthemic acid in an organic solvent It is an object of the invention to provide novel, to form the corresponding crystalline diastereoisomeric optically active isomers of 1-p-nitrophenyl-2-N,N-di salt in a mother liquor, separating the crystalline salt and methylaminopropane-1,3-diol and its acid addition salts. subjecting the latter to acid hydrolysis to get the optical It is another object of the invention to provide a 60 isomer of trans chrysanthemic acid and recovering the novel process for the preparation of the optically active other optical isomer of trans chrysanthemic acid from isomers of 1-p-nitrophenyl-2-N,N-dimethylamino-pro the mother liquor. pane-1,3-diol and its acid addition salts. The organic solvent may be an aliphatic ether such It is a further object of the invention to provide novel as ethyl ether, isopropyl ether, etc.; an aromatic hydro salts of the said optically active diol. 65 carbon such as benzene or toluene; an aliphatic alcohol These and other objects and advantages of the inven Such as methanol; an aliphatic acid ester such as ethyl tion will become obvious from the following detailed acetate. Particularly preferred is isopropyl ether contain description. ing up to 15% of methanol. The acid hydrolysis is preferably effected with a strong mineral acid such as THE INVENTION 70 hydrochloric acid. The novel compounds of the invention consist of The process of the invention for the preparation of the D(-)-threo-1-p-nitrophenyl - 2 - N,N-dimethylamino threo-1-p-nitrophenyl-2-N,N-dimethylamino-propane-1,3- 3,590,077 3 4. diols comprises subjecting a diastereoisomer of threo-1-p- in water). The product was soluble in water and in alco nitrophenyl-2-amino-propane-1,3-diol to reductive alkyla hols and slightly soluble in ethyl acetate. tion with a mixture of formaldehyde and formic acid to This compound is not described in the literature. form the corresponding N,N-dimethylamino compound, Step B-Preparation of dextrorotatory 1,5-dioxo-7a which can be converted into an acid addition salt with an methyl-5,6,7,7a-tetrahydroindane-4-acetic acid: 24 gm. of organic or inorganic acid. the dextrorotatory salt of D(-)-threo-1-p-nitrophenyl-2- In the following examples, there are described several N,N-dimethylamino-propane-1,3-diol with dextrorotatory preferred embodiments to illustrate the invention. How 1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindane - 4 - acetic ever, it should be understood that the invention is not acid were introduced into 100 cc. of ice water under an intended to be limited to the specific embodiments. O atmosphere of nitrogen. Then 50 cc. of N-sodium hydrox ide were very slowly and under agitation added to the EXAMPLE I reaction mixture. The reaction mixture was then filtered Preparation of D(-) and L(--)-threo-1-p-nitrophenyl and the filtrate was recovered, washed repeatedly with 2-N,N-dimethylamino-propane-1,3-diols ethyl acetate, then acidified with concentrated hydrochlo A reaction mixture of 50gm. of D(-)-threo-1-p-nitro 5 ric acid. Ammonium sulfate was added until saturation phenyl-2-amino-propane-1,3-diol, 50 cc. of 30% formol Was attained, and finally, the reaction mixture was ex and 50 cc. of 98% formic acid was heated for about 3 tracted several times with methylene chloride. The ex hours in a steam bath after which it was distilled to dry tracts were combined, dried over magnesium sulfate, ness under vacuum. The oily residue obtained was dis treated with animal black and evaporated to dryness under solved in 150 cc. of water and after 40 cc. of 22 Béam 20 WaCLEllin. monium hydroxide were added, the mixture was main The residue was taken up in 20 cc. of toluene and tained for about 15 minutes at a temperature of about allowed to stand for crystallization. The crystals formed 80° C. Then 60 cc. of ammonium hydroxide were again were vacuum filtered, washed with iced toluene and dried added at a high temperature and the entire mixture was to obtain.