[1]3 2 4 0 8 , 3 5 2 United States Patent Office l,tented Oct. 29, 1968 2 mary amino (-NH2); mono(lo wer)alky lamino; e.g. 3,408,352 methylamino and butylamino; or di (lower) alkylamino, 2H-BENZO(b) QUINOLIZINES e g. diethylamino; at most one of R5, R6, R7 and R8 Goetz E. Hardtmann, Florham Park, N.J., qssignor to b'ein.@ carbocyclic aryl, amino, halo, or trifluoromethyl; Sandoz Inc., Hanover, N.J. No Drawing.,Continuation-in-part of application Ser. No' 5 R9 is hydroxy (-OH); and 365,498, May 6, 1964. This application Apr. 11, 196'7, RIO is either lower alkyl, e.-. methyl, ethyl, propyl and Ser. No. 629,922 9 Claims. (C]. 260-288) 10 ABSTRACT OF THE DISCLOSURE The compounds are 1,3,4,6,1 1,1 la-hexahydro-2H-benzo(b) quinolizin-I 1-ones (A), I 1- hydroxy-derivatives (B) of said 11-ones and intermediates (C) in the preparation of (A). (A) is prepared by condensing a pipecolic acid with, 15 e.g., a benzyl halide and cyclizing the product (C) with polyphosphoric acid. (B) results from subjecting (A) to a Grignard reaction. Both (A) and (B) are useful as anal.-esics. 20 This is a continuation-in-part of application Serial No. 365,498 flied May 6, 1964, now abandoned. The present invention is dire,-ted to compounds of the formula 2 5 R 8 R I RT I I R2 9 "T'2 3 0 18, l@ 3 W\\6 I /N 4 RG 5\@' \R@ R5 RII R4 wherein R is either carbonyl (>C--O) or 35 RO R10 c 40 each of RI, R2, R3 and R4 iS either carboxyl (-COOH); a hydro-en atom (-H); or strai,@ht chain lower alkyl, e.@. methyl, ethyl, propyl and butyl; at most two of RI, R2, R3 and R4 being other than a hydrogen atom; and RI and R2 not bein carboxyl in the same cOm- 45 pound; each of R5 and R7 is either lower alkoxy, e.g. methoxy, ethoxy, propoxy and butoxy; a hydro.-en atom (-H); straight chain lower alkyl, e.g. methyl, ethyl, propyl butyl; carbocyclic aryl, e.g. phenyl, naphthyl and diphenyl; cycloalkyl with from three to seven carbon atoms, e..-. cyclopentyl and cyclohexyl; 1-(Iower)alkyl4-piperidyl, e.,-. 1- propyl-4-piperidyl; (lower)alkoxyphenyl, e.g. o-, ' m-, and p-methoxyphenyl; benzyl; - (CH,),CHR'-i'@H"R@', e.g. 1-dimethy laminopropyl-3- and 1-dimethylamino-lmethyl-propyl-3-; or -(CH3).-CH-NR' 1 L (C H2) e.g. @-(2'-N-methylpiperidyl)-ethyl-; R' is either a hydro,@en atom (-H); or lower alkyl, e.,-. methyl, ethyl, propyl and blityl; ach of R" and R* is, independently, either lower alkyl, e.g. methyl, ethyl, propyl and butyl; or cycloalkyl having from five to seven carbon atoms, e.,-. cyclopentyl @nd cycloheptyl; R is lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; n is one of the inte-ers, 1, 2 and 3; m is one of the inte@gers 3, 4 and 5; and RI' is either a hydro-en atom (-H); straight chain lower alkyl, e.g. methyl, ethyl, propyl, and butyl; phenyl or para-substituted phenyl, the substituent being either methoxy, trifluoromethyl (-CF3), chloro (-CI), fluoro (-F) or bromo (-Br); R" being pmethoxyphenyl only when at least two of R5, R7 and RB are methoxy; and bein.@ a hydrogen atom or lower alkyl when any of R5, R6, R7 and R8 is amino; and to a process for preparing said cornpounds. The process is a two-step reaction using readily available reactants. A piperidine-2-carboxylic acid of the formula RI 0 1 HO-C R2 TrN ii/@R3 y R4 wherein each of RI, R2, R3 and R4 has the above-ascribed and btityl; chloro (-CI); bromo (-Br); trifluoro- 5o meaning, is reacted with a benzyl halide or ester of the methyl (-CF3); aryl, e.g. phenyl; primary amino fo rmtila (-NH2); niono(lower)alkylamino; e.- methylamino R s and btitylamino; or di(lower)@lkylam'm@'o, e.g. diethylI amino; R R6 is eitber a hydrogen atom (-H); lower alkyl, e.g. 55 methyl, ethyl, propyl and butyl; chloro (-CI); bromo R CH-.X (-Br); triflooromethyl (-CF3); carbocyclic aryl, e.,-. phenyl; primary amino (-NH2); mono(lower)alkylamino, e.,-. methylamino and butylamino; or di(lower) N vherein alkylamino, e.g. diethylamino; 60 R8 is either lower alkoxy, e.g. methoxy, ethoxy, propoxy each of R5, R6, R7, and R8 and RI' has the above-ascribed and butoxy; a hydrogen ato ' m (-H); straight chain meaning, and lower alkyl, e.g. methyl, ethyl, propyl and butyl; chloro X is either chloro (-CI), bromo (@Br), iodo (-I), (- CI); bromo (-Br); trifluoromethyl (-CF3); pri- tosylate or mesylate, at from 80' to 100' C. in an
[2]3l4O8y352 3 aqueous alkali-metal hydroxide, e.g. sodium hydroxide, medium to produce compound (IV): R8 R' 0 1 11 R7- HO-C.5 R l R, (I V) wherein each of R' to R8 and R" has the aboveascribed 10 meaning. (The aqueous medium may, altematively, be a water/dioxane medium containing alkali-metal hydroxide.) When any of R5, R6, R7 and R8 is a primary, secondary or tertiary amino group (only one such group bein.- possible) in compound (1), the starting compound 15 (III) contains a nitro group, i.e. at most one, in its stead. The nitro group is converted to the amino group after the reaction of compound (11) with compound (Iff) and according to well-known procedures. 20 Compounds (II) and (111) are either available or are prepared accordin.- to established procedures from known compounds. To obtain compound (IV) from the first step of the two-step reaction, the amount of alkalimetal.hydroxide 25 in the medium is critical. There must be sufficient alkalimetal hydroxide to convert each carboxyl (-COOH) group @of compound (II) to the corresponding alkali-metal salt group, e.g. (-COONa) and (-COOK), so as to avoid ester formation, but the concentration of alkali- 30 metal hydroxide must be below that which would lead to saponification of compound (III) before it alkylates the nitrogen atom of compound (II). Since at most two of R' to R4 can be carboxyl -roups, the actual amount of alkali-metal hydroxide depends upon the actual number of such groups, i.e. in addition to the carboxyl group in the 2-position of compound (11). It is essential that each acid function (carboxyl group) be present in the form of its alkali-metal salt, and sufficient alkali-metal hydroxide must be present in the medium for this purpose. 40 The first step of the two-step reaction is thus accomplished by dissolvin,@ 1 mole of compound (11) in the aqueous solvent with an equivalent (for each carboxyl group) amount of alkali-metal hydroxide and thereafter adding, simultaneously and at reaction temperature, to 4,- the resultin.- solution I mole of compound (III) and an 0 additional equivalent of alkali-metal hydroxide. The second step of the two-step process is the cyclization of cornpound (IV) to produce compound (V): Rs 0 RI 50 R7 R2 R P,3 55 3 (V) wherein each of R' to R8 and R" has the above-ascribed meaning. Critical to this step is the use of polyphosphoric acid for ring closure. Other cyclization reagents, such as C)o sulfuric acid and trifluoro-acetic anhydride, and cyclization of the acid chloride with stannous chloride are materially inferior and result in yields which are negligible compared to that obtained with polyphosphoric acid. In addition to the preparation of compounds (V), this 65 two-step process is also useful for producing compounds for formula (V) wherein each @of RI to RB, R7, R8 and RI' have the above-ascribed meanin,-S, and R6 iS Iower alkoxy, e.g. methoxy, ethoxy, propoxy and butoxy. Compound (V) is useful as an antidepressant, an anal70 gesic, an analeptic and an anti-inflammatory. It can be administered to mammals either orally or parenterally in either a single daily dose or in divided doses from two to four times a day. Daily dosa,-es are from 0.5 to 3 m.@./k.@. of body weight. 75 4 Each of the pharmaceutically active compounds of this invention, may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from I to 3 percent binder, e.g. tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosa,@e of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by wei,-ht. Tablets are prepared according to standard tabletting techniques, which are wellknown in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compounds is: Parts Title compound of Example 2 ------------------ 40 Tra.-acanth --------------------------------- 2 Lactose ------------------------------------ 49.5 Corn starch --------------------------------- 5 Talcum ------------------------------------- 3 Magnesium --------------------------------- 0.5 Alcohol SD-30 quantity sufficient. Purified water In addition compound (V) is useful as an intermediate in the preparation of compound (VI): Rg R10 R- RI P,7 R2 R6 5 11 R4 Ra (VI) wherein each of RI to R" has the above-ascribed meaning and wherein, in addition, R6 is alternatively lower alkoxy, e.g. methoxy, ethoxy, propoxy and butoxy. (R" can be pmethoxyphenyl when R6 is the -only one of R5 to Rg which is methoxy.) Compound (VI), which is useful for mammals as an antihypertensive and an analgesic in the same manner as compound (V), is prepared by reacting (standard Grignard Reaction) compound (V) with a Grignard Reagent, @RI(I-Mg-Y, wherein R'O has the above-ascribed meaning, and Y is either chloro (-CI), bromo (-Br) or iodo (-I). Alternatively, in place of R'O-Mg-Y, RI(-Li can be used to obtain similar results. Therapeutically acceptable acid addition salts of both compound (V) and compound (VI) are similarly useful. Exemplary of such salts are salts of organic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloric acid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. an alkylsulfonic acid, such as methanesulfonic acid (H3C-SO3H); dibasic acids, e.g. tartaric acid and succinic acid; tribasic acids, e.g. phosphoric acid and citric acid; saturated acids, e.g. acetic acid; ethylenically unsaturated acids, e.g. maleic acid and fumaric acid; and aroniatic acids, e.g. salicyclic acid and arylsulf6nic acids, such as benzenestilfonic acid. The only limitation on the acid selected is that the resulting acid addition salt be pharmaceutically acceptable; the acid does not nullify the therapeutic properties. The foilowin.- examples illustrate the invention, the parts and percentages being by weight unless otherwise stated, and the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter. AM temperatures are in de.-rees centigrade.
[3]2)4081352 5 EXAMPLE 1 N-benzylpipecolic acid-The first step of the two-step process 0 0 5 no + CH2-Br Nn (a) (b) 1 0 Dissolve in 100 parts by volume of water 25 parts of pipecolic acid (b) and 12.75 parts of potassium bydroxide (85% KOH). Heat the resulting solution to a temperature of 80'. Concurrently add (from two dropping funnels) to the 15' heated solution (while stirring same) over a period of thirty minutes 12.6 parts of potassium hydroxide (85% KOH) in 60 parts by volume of water and 24.1 parts by volume of m-bromotoluene (a). After the addition is complt-ted, continue stirring the resulting reaction mixture for 20 one hour at 80' before coolin.- same to room temperature (20'). There is thus obtained a slightly yellow solution. Extract the sli.-htly yellow solution twice with 50 parts by volume of diethylether to remove any benzyl ester 25 which may have been formed. Thereafter add 2 N (normal) sulfuric acid to the slightly yellow solution to adjust its pH to 3. A precipitate is thus forined. Filter off the precipitate (10.5 parts), and extract the filtrate 6 times with 50 parts by volume (each) of chloro- 30 form. Filter off precipitate formed during the extractions. Then dry the chloroform extract over sodium sulfate, and evaporate the solvent from the dried extract. Place the residue in a refrigerator at about O', where crystallization takes place slowly. 35 6 Add concentrated ammonia to the above-noted filtrate to adjust the pH thereof to 8. Evaporate the resultant to about 50 parts by volume, whereby a precipitate is formed. Filter the precipitate. Combine all obtained precipitates and crystals, and extract (Soxhlet) the combination with chloroform for 48 hours. Thereafter evaporate thechloroform extract to dryness. There are thus obtained 30 parts of N-benzylpipecolic acid (c). Recrystallize compound (c) twice from acetone to obtain very fine white crystals, melting point (M.P.) 223' to 2281. In place of compound (a) a-chlorotoluene or a-iodotoluene is employed with comparable results. Likewise, under the same conditions as d.-scribed fully hereinabove, every compound (II) is reacted with every compound (111) to produce every compound (IV), except: where any of R5 to R8 is a primary or secondary amino group, a nitro group is present in its stead durin- the reaction. The nitro group is subseqtiently reduced according to wellknown procedures. The only change in procedure occurs when one or two of R' to R4 is a carboxyl -roup. For each of R' to R4 which is a carboxyl group,@an additional 12.75 parts of potassium hydroxide (85%) is dissolved in the aqueous solution in which compound (II) is initially dissolved. Also the potassium hydroxide is replaced either wholly or partially by an equivalent amount of sodium hydroxide without otherwise altering the procedure or result. Following the procedure of Example 1 (with the noted exception when one to two of RI to R' is a carboxyl -roup) react equivalents of each of the following compounds (II) and (III) to prepare the corresponding compound (IV): (III) (IV) Piperidine-2,3-dicarboxylic acid ----- 2-bromomethyldiphenyl ---------- N-(ophenylbenzyl)piperidine-@9,3- dicarboxylic acid. Pipecolic acid ----------------------- 3-phenyl-2,4',5-trimethoxy- N[2,5-dimethoxy-3-phenyl-adiphen yliodomethane. (p-methoxyphenyl)benzyl]pipecolic acid. 2-pipecoline-4,6-dicarboxylic acid ---- wbromotoluene ------------------- N-benzyl-2- pipecoline-4,6- di carboxylic acid. Piperidine-2,5-dicarboxylic acid -- --- a@ethyl-3-nitro-4-phenyl--tosyl- N (.-ethyl-3-nitro-,'-phenylbenzyl)- toluene. pi peridine-2,5-dicarboxylic acid. Piperidine-2,6-dicarboxylic acid -- --- p-ethoxy-benzylmesylate ---------- N-[4-ethoxybenyllpiperidine-2,6- di carboxylic acid. Piperidine-2,3,5-tricarboxylic acid--- 2-(Iehlorobutyl)-toluene ---------- N-[.-propyl-9-- methyl-benzyll piperi dine-2,3,5-tricarboxylic acid. Pipecolic acid ----------------------- 1-(I-bromopentyl)-3-ethyl-5- N [@-butyl-3-ethyl-5-propoxypropoxybenzene. benzyl]pipecolic acid. Do ----------------------------- 4-propyl-di phenyliodomethane ---- N-[2-phenyl-.- phenyl-4- propylbenzyllpipecolic acid. 5-ethyIpipecolic acid ---------------- 5-butyl-2-ethoxy-4'-trifluoro- N-[5- butyl-2-ethoxy-3-phenyl-.-(pinethyl benzhydryl tosylate. trifluoromethylphenyl)benzyl]-5- ethylpipecolic acid. 4-propylpiperidine-2-carboxylic acid- -(p-chlorophenyl)--mesyl-4- N-E.-(P-chlorophenyl)-4:-phenylphenyl toluene. benzyl]-4-propylpipecolic acid. Piperidine-2-carboxylic acid -- ------- 2-chloro-4@-fluoro-4-propoxydiN-[2-chloro--fluorophenyl)-4- phenylehloroniethane. propoxybenzyl]pipecolic acid. 3-butyl-piperidine-2-carboxylic acid- 3,4'-dibromo-2-propyl-diphenyl N-[3-broino--( p-bromophenyl)-2- broiiao-methane. propylbenzyl]-3-butyl pipecolic acid. Pipecolic acid ----------------------- 4- fluoro-3-methoxydiphenyl- N-(fluoro-5-methoxy-@phenyliodomethane. benzyl)pipecolic acid. Do ----------------------------- 4- methyl-.-tosyl--(P-trifluoro- N-[4-methyl-w(p-trifluoromethylm ethyl phenyl) toluene. p henyl)benzyl]pipecolic acid. Do ----------------------------- @mesyl--@p-methoxyphenyl)-2,4- N-[2,4-dimethoxy-.-(p-inethoxydi methoxy-2-trifluoromethylp henyl)-2-trifluoromethylbeiizyljto luene. pi pecolic acid. Do ----------------------------- 4- chloro-3'-trifluoromethyl- N-[.-(p-chlorophenyl)-3-trifluorodi phonylchloromethane. m ethylbenzyl]pipecolic acid. Do ------------------------------ 3- ethoxy-4-trifluoromethyl- N-[5-othoxy-4-trifluoromethylb enzylbromide. b enzyl]pipecolic acid. 5-methylpipecolic acid -------------- 4- bromo-3-methyl-5-trifluoro- N-[-(P-bromophenyl)-3-methyl-5- m ethyl diphonyl-bromotr ifluoromethylbenzyll-5-inethylin ethane. pi pecolic acid. Pipecolic acid ----------------------- 3- butyl-2-nitrobenzyltosylate ------ N-(3-butyl-9-- nitrobenzyl)pipecolic acid. 3-methylpipecolic acid -------------- a,5-dimethyI-3-nitro-2-propoxy- N-(.-5- dimethyl-3-nitro-2-propoxybenzyl mesylate. benzyl)-3-methylpipecolic acid. Pipecolic acid ----------------------- wethyl-4-riitrobenzyl chloride- ---- N-(-ethyl-4- n i t r o b e n z y l ) p i p e c o l i c a c i d . 5-propyl-pipecolic acid --------- ----- 2-methoxy-5-nitro@propylbenzyl N-(2-methoxy-5-nitro-.-propylbromi de. benzyl)-5-propylpipecolic acid. Pipecolic acid ------------------------ 2,5-dimethoxy-.-(pmethoxy- N[4-ethyl-2,5-dimethoxY-a-(Pphenyl )-4-ethylbenzyl chloride. methoxyphenyl)benzyl]4-pipecolic acid 4-methylpipecolic acid -------------- @bromo-4-eth oxy-5-propyltoluene - N-(4-ethoxy-5- p r o p y l b e i i z y l ) - 4 @ m e t h y l p i p e c o l i c a c i d .
[4]7 EXAMPLE 2 1,3,4,6,1 1,1 la-hexahydro-2H-benzo(b)quinotizin-I 1one-The second step of the two-step process 0 11 C\ PPA (d) Maintain und,-r stirring and at a temperature of from 145' to 150' 250 parts by volume of polyphosphoric acid (PPA). To the PPA under these conditions add (in I-part portions) 10 parts of (c), uniformly admixing each part with the PPA prior to the addition of each successive part. After all of the (c) has been added, maintain the resulting reaction mixture at 150' under stirring for 30 minutes before coolin.- said reaction mixture to room temperature. Pour the thus-cooled reaction mixture onto 500 parts of ice and neutralize (wbile maintainin.- the entire reaction mixture at below O', as with Dry Ice/methanol) with 50% (aq) potassium hydroxide solution. Extract the neutralized solution five times with 300 parts by volume (each) of diethyl etber. Wash the combined ether extracts twice with 150 parts by volume (each) of water. Dry the washed extract over sodium sulfate, and evaporate the solvent in vacuo. There are thus produced 6.8 parts of li.-ht yellow oil which crystallizes on standing at room temperature. Filter the crystals, wash same with 50 parts by volume of diethyether ether and sublime the thus-washed crystals at 65' in vacuo (0.1 mm.). 5.2 parts of white crystals M.P. 74' to 76', are thus obtained. The yield is 52 percent based on the starting wei-.ht of (c). In this example every compound (IV) produces results comparable with those illustrated. For example, each compound (IV) identified following Example 1 (any nitro group is converted to an amino 'substituent prior to rinclosure) is subjected to rin.@ closure in strict accord with the method of Example 2 with comparable results. To prepare a secondary or tertiary amino substituent, the primary amino group obtained by reducing a nitro substituent is appropriately alkylated prior to ring closure by standard procedures well known to the artskilled. EXAMPLE 3 1,3,4,6,11,lla-hexahydro-11-hydroxy - It - p - meth oxyphenyl-2H-benzo(b)quinolizineThe use of compound (V) as @an intermediate O-CH3 O-CE[3 I-Algo ]E[20 (d) + O-CH3 HO (g) 3;408)352 8 Bring 17.8 parts of p-iodoeinisole into intimate contact with 1.7 parts of magnesium as in standard preparation for Grignard reagents, whereby p-meihoxyp-henyl magnesium iodide (e) is formed. Admix 15 parts of compound (d) dissolved in 50 parts by volume of diethyl ether with the thus-formed compound (e) at room,tem@ perature to form a reaction mixture. Reflux the reaction mixture for thirty'minutes and then cool same to room temperature. Admix 100 parts 10 by volume of concentrated (aq) ammonium chloride solution wi',h the cooled reaction mixture. Separate the ether phase from the water phase in a separatory funnel. Wash ether phase with water, and combine the washwater with the water phase. Extract the combin-ed wa:ter 1 layers twice with 150 parts by volume (each) of chloroform. Combine the chloroforrft extracts, and wash same with water. Dry the washed chloroform extract over sodium sulfate, and combine with the ether phase. Evaporate the 6ombined chloroform and ether phases 20 in vacuo to dryness to obtain 9 parts of grey-white cr@stals. Recrystallize said crystals twice from chloroform to obtain 6 parts of the title compound (g), M.P. 210.5' to 211.5'. For the Grignard Reac-tion none of RI, R2, R3 and R4 iscarboxyl. In place of compound (e) each of the followinGrignard rea,-ents is employed with comparable results@: methylmagriesiuni chloride, propyl magnesium bromide, phenyl magnesium iodide, cycloheptylma.-nesium bro30 mide, m-ethoxy phenylmagnesium iodide, benzylmagnesium chloride, 1-methyl-4-piperidylmagnesium chloride, 3-dimethylamino-l-propyl-ma,- nesium chloride, 2-(Nmethyl-2-piperidyl)ethyl magnesium chloride, 2-(Ncyclohexyl-Nmethyl-amino)-ethyl magnesium chloride. 3,5 In addition, in place of the enumerated magnesium halides the correspondina organolithium compound, e.g. methyl lithium, is emplooyed according to the procedure of Example 3 with comparableresults. In the same as described in detail in the procedural 40 presentation of Example 3, the example is repeated with comparable results with each compound (V) produced accordin.- to Example 2. The product (VI) obtained depends only upon the specific reactants selected. EXAMPLE4 45 Methanesulfonate of 1,3,4,6,11,lla-hexahydro - 11 - hydroxy - 11 - p - methoxyphenyl-2H-benzo(b)quinolizine-Acid-addition salt preparation 50 o-cll3 55 Io Hac-soz(D 60 Dissolve 7 parts of (g) in 175 parts by volume of methylene chloride. Admix with the resulting 'solution 65 1.5 parts by volume of methanesulfonic acid. The color of the obtained solution tums yellow. Heat the said obtained solution with 0.1 part of charcoal at 40' for 5 minutes. Filter off the charcoal. Evaporate the filtrate on a steam bath to about 50 parts by 70 volume, whereupon the salt (title compound) starts to crystallize. Collect the crystals on a Buechner funnel and wash with diethyl ether. A yield of 6.5 parts is thus obtained. Recrystallize from ethanol to obtain title compound 75 having a meltiii.-Ipoint of 221' to 223'.
[5]9 EXAMPLE 5 1,3,4,6,11,lla-hexahydro-11-hydroxy-ll(,ydimethylaminopropyl)-2H-benzo(b) quinolizine-The use of compound (V) as an intermediate CH3 HO CHr-CH2-CH2-N C113 Admix 0.948 part of (d) in 10 parts of tetrahydrofuran with a solution of ydimethylaminopropyl-ma.-nesium chloride (prepared from 0.55 part of magnesium and 2.85 parts of 3-chloro-N-dimethylpropylamine by standard procedures) in 10 parts of tetrahydrofuran. After the vi.-orous reaction which follows, reflux the reaction mixture for 10 minutes. Cool the resultant to room temperature (20'), and pour same into 50 parts of saturated (aq) ammonium chloride solution. Extract the obtained mixture four times with 50 parts (each) of methylene chloride. Extract twice with 20 parts of water (each) the combined methylene chloride extracts. Dry the water-extracted methylene chloride extract over sodium sulfate, and evaporate the dried extract to dryness. Add 10 parts of diethylether to the residue to obtain 1.05 parts of white crystals, M.P. 113' to 114', of the title compound. It is thouaht that the invention and its advanta-es will be understood from the fore.-oin.- description. It is apparent that various changes may be made in the procedures, the intermediates and the final products without departina from the spirit and scope of the invention or sacrificing its material advantages. The processes', intermediates and final products hereinbefore described are merely illustrativeembodiments of the invention. What is
