IL32239A - 4-(3-amino-2-hydroxypropoxy)-1,2,5-thiadiazoles,their preparation and pharmaceutical compositions containing them - Google Patents

Description

~('DpiRano*opiκ *n-2- 3 »BK-3)-4 4-(3^amino-2-h droxypropo-s )-l,2,5-Thiadiazoles , their preparation and pharmaoeutical compositions containing them 32239/2 This Invention is concerned with 4-/5-(substituted aralno)-2-hydroxypropoxy/ 1,2,5-thiadiazole compounds which are optionally substituted in the 3-position of the thiadiazole nucleus. These compounds exhibit β-adrenergic blocking properties and have the marked advantages of having a long duration of action and being effective at very low dosage levels. Those compounds which are additionally substituted in the 3-position of the 1,2,5-thiadiazole nucleus, exhibit especially desirable β-adrenergic blocking properties and generally, though not necessarily, those having a non-bulky substituent attached to the 3-position exhibit potent but short-acting β-adrenergic properties whereas those having a bulky substituen attached In this position generally exhibit potent and long-acting β-adrenergic blocking properties.

The novel β-adrenergic blocking agents of this invention have the structure and pharmacologically acceptable salts thereof, wherein R represents (l) hydrogen, (2) halogen, preferably chloro or brorao, (3) lower alkyl having from 1 to 5 ca_rbon atoms and either a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, lso-, secondary- or tert-butyl and amyl including all of its branched chain configurations, (4) a lower alkoxy having from 1 to 5 carbon atoms and being either a straight or branched chain and including methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy, the latter groups 32239/2 existing in either straight or branched configuration, (5) phenyl, (6) phenyl-lower alkyl wherein the lower alkyl moiety is either a straight or branched chain and has from 1 to 3 earbons, (7) an amino having the 7 ft 7 structure -NR'R wherein R represents hydrogen and a represents a lower alkyl having from 1 to 4 carbon 7 8 atoms, or R and R can be joined together either directly to form with the nitrogen atom to which they 32239/2 saturated heterocyclic are attached a 3 to 7 membered/ ring, such as pyrrolidino or piperidino, said 3 to 7 membered rings being optionally substituted with one or more lower alkyl haying from 7 1 to 5 carbons or hydroxy groups, or alternatively R' o and can be joined through an oxygen, nitrogen or sulfur atom to form with the nitrogen atom to which they are saturated heterocyclic attached a 5 or 6 membered/ring, advantageously a morpholino or piperaElno, optionally substituted by lower alkyl O^^ i (θ) a carbamoyl group having the structure HW'CO wherein is lower alkyl, having from 1 to 5 carbons,j R represents hydrogen or lower alkyl having a straight or branched chain containing from 1 to 5 carbons } represents an aliphatic hydrocarbon radical optionally g hydroxy-substituted, or and R can be Joined together 32239/2 either directly or through an oxygen atom to form with the nitrogen to which they are attached a 4 to 6 membered, saturated heterocyclic /ring, for example, pyrrolidine, plperidino or morpholino.

Suitable pharmacologically acceptable salts of product X are acid addition salts derived from inorganic acids, for example, hydrochlorides, hydrobromldes, phosphates or sulfates or salts derived from organic acids, for example, oxalates, lactates, malates, maleates, formates, acetates, succinates, tartrates, salicylates, citrates, phenylacetates, benzoates, p-toluenesulfonates and other salts such as those that provide relatively insoluble products that afford a slow release of the active material, for example, a l,l'-methylene-bis(2- hydroxy-3-naphthoate) and the like. 32259/2 can be separated into its optically active isomers by knov/n metnods such as described above. Resolution of certain representative intermediate and end products will be described in the detailed examples.. All products can be similarly resolved and the claims will be understood to embrace the products in the form, of raeemic - compounds or di- B , astereoisomers as .well as in the form of the optically active isomers where appropriate. ·. .. ., . in particular This invention xs/concerned with a novel and commercially feasible method for preparing the biologically. ^ active, S-enantiomer of a 3-R-4- (3-substituted amino-2- hydroxypropoxy) -1 , 2 , 5-thiadiazole product. Substantially all of the biological activit of these products resides in the S-enantiomer which was obtained by other workers by the resolution of the raeemic product or by the resolution of intermediates employed in their synthesis. These prior methods offer several disadvantages, principally the need to use' ;'". cyanogen, for the synthesis of the intermediate 3-chloro-4- hydroxy-1, 2, 5-thiadiazole, an important intermediate, as well as the need . to resolve the 3-R-4- (3-substituted amino-2- hydroxypropoxy) -1 , 2 , 5-thiadiazole derivative thereof, it is well known that resolutibn procedures are uneconomical as - they provide low yields of active material because .half of : the yield of raeemic product formed 'is of no value, and at least some of the desired isomer is not recoverable by., feasible large scale procedures. · ;' .' · 32239/2 f non-bulky group such as hydrogen, halogen, lower alkyl, and lower- alkoxy generally are short acting β-adrenergic blocking agents whereas when the substituent R is a more bulky substituent such as the .phenyl, phexjklk l* or the -NR7R8 group and especially when R7 and R8 are joined together either directly or through an oxygen, nitrogen or sulfurjj I' atom to form a saturated heterocyclic ring with the nitrogen to which ij they are attached, the products generally exhibit long-acting β- j j adrenergic blocking properties, and are substantially devoid of j j sympathomimetic properties. j Both the short-acting and long-acting β-adrenergic blocking agents are of value in therapy and each serves the need of certain patients requiring treatment with agents possessing this property.

The potential of a product as a β-adrenergic block- . ing agent conventionally is evaluated by the protocol which i is for the control of tachycardia that may be drug induced "(as by isoproterenol) or brought about by physiological conditions. In view of the considerable amount of- literature 'that has accumulated concerning the use of β-adrenergic blocking agents, physicians would employ the products of this invention in any of the known conditions where a short-acting or long-acting, agent is .needed, such as in the . management of .angina pectoris. * The invention further pr'ovides pharmaceutical ' '.... compositions comprising, as active ingredient, at least one , of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds may be presented in a form suitable for oral, rectal or parenteral administration." Thus, for example,- compositions for oral administration may.be solid or liquid and may take the form of capsules, tablets, coated tablets, suspensions, etc., such compositions comprising carriers or excipients corv veniently used in the pharmaceutical art. Thus suitable ■■ tabletting excipients include lactose, potato and maize . starches, talc, gelatine, stearic acid, magnesium stearate, ·' polyvinyl pyrrolidone, or other knbv/n tabletting substances.' For parenteral administration, the carrier or excipient may be a sterile, parenterally acceptable liquid, ■e.g. > .pyrogen-free water or an aqueous solution of polyvinyl pyrrolidone, or. parenterally acceptable oil, e.g., arachis ■ oil, contained in ampoules.

In compositions for-rectal administration, the /'. carrier may comprise a suppository base, e.g., cocoa butte or a glyceride.

The above procedure also can be employed. to replace the 3-chloro substituent by the ( 3 S ' -dihydroxy) diethylamino group which then can be cyclized to the desired, morpholino: substituent by^reaction with less than an equivalent of any sulfonylhalide followed by treatment with a base either at ambient temperature or by heating up to. about steam bath temperature. Any known sulfonylhalide can be employed for this purpose, preferred ones being of the type hereinbefore · described in relation to the preparation of the sulfonyloxy- alkamines. Bases recommended are substantially any basic , substance though Organic nitrogen bases such as pyridine, lutidine and similar organic bases have been found, to be quite suitable'; The 3-morpholino group can be similarly . formed' in the end product S-III when R is chloro.

To prepare the thiadiazole starting substance '.Ά" wherein Q. is hydroxyl, 3t-R-4-chloro-l , 2 , 5-thiadiazole is combined with aqueous sodium hydroxide or sodium hydroxide in- an organic solvent such as a lower Ci_s alkanol or aqueous alkanol containing up to 50% of H20 or D SO. Heating be- tween about 50° C. to . about 100°C. or up to reflux temperature facilitates the reaction. Upon cooling and acidifying the solution with concentrated mineral acid the 3-R-4 -hydroxy-. . 1 , 2 , 5-thiadiazole precipitates and can be collected by conventional methods.

These novel methods for the preparation' of 3-';. morphcilino- (piperidmy* or piperazxnyl) -4-chlorp-l , 2 , 5r.;- . thiadiazole and 3-R-4-hydroxy-1, 2 , 5-thiadiazole1. provide··■ the ·. . ; desired compound in very high yield. ·...·, For example, the' compounds of formula I can be prepared by. the following routes: ROUTE I.

Oil I-b "E" 3 The 3-R-^~hydroxy~l,2 , 5-thiadiazole (A) is treated with epi- chlorhydrin or epibromhydrin (B ) to provide product " c" v/hich can be separated from the reaction mixture by extraction with 6 ether. Ideally, the epih'alohydrin is used in excess for its ■ 7 solvent properties and the reaction proceeds at room tempera- 8 ture or with heating up to about 90° C. with optimum results 9 being obtained by heating at a temperature between about 55-. 10, ,^70 C The rea'ct on- of , ''A",..and. " B'V is additionally facili- 11 tate.d by the. presence of a trace of base which serves as a .12 catalyst, preferred catalysts being pipe'ridine, plperidine 13 hydrochloride, pyridine or other heterocyclic bases. After l extraction the intermediate product "C" is shaken with aqueous alkali to afford the epoxide (D) . Aqueous sodium 16 or potassium hydroxide are preferred at a concentration of 17 about 20^ for best yields. Treatment of the epoxide "D" 18 with the amine "E" provides the desired thiadiazole product 19 I-b. Advantageously an excess of the amine is employed for Larger quantities of course can be employed if so desired* This step can be carried out at a temperature between about ambient temperature and 90°C. although it is preferred to use temperatures between abou 60-70°C. It has also been found that certain amines, particularly branched chain monoalkyl amines, as neo ent laminefr can be refluxed with the intermediate product "C" to give the desired product l-b directly* The products of formula I can be prepared alternatively b the reaction of starting substance "A" with an a-haloacetic acid of the structure halo-CH_-COOH 2 to provide 3-B.--4'-carbbiiie1ihoxy^l,2,5-t{tladiazole which is converted by conventional methods o the acid chloride. Reaction of the acid chloride with diazomethane of the structure OE^-VS^ gives the 3-R-4"-(3-ohioro-2-oxo-l-propoxy)*1, 2 , 5-thiadiazole which upon reduction, preferably with sodium borohydride, affords the intermediate "G", which is converted to the thiadiazole of the formula I-b above by the procedures described above.

"P" I-d Ι-Θ " ' In the second route, treatment of the thiadiazole, I-d, (prepared by the method described in Route I) with an amine, "F" , affords the appropriately 3-substituted product I-e. When the amine "F" is a primary or secondary amine, the . reaction! advantageously is carried out under pressure; however, when the amine is a heterocycle of the type defined hereinabove the reaction readily takes place without . pressure ..by heating the reactants at a temperature betwee about 100- 150° C. but preferably at a temperature betwee about 125- 135° C. A slight excess of the amine "p" generally is used for its solvent properties and from about 3 to 5 moles of .amine have been found to give optimum yields. Larger quantities can, of course be .employed, if desired.

Various modifications can be made in the above preferred methods for preparing the products, of this invention. ; For example, when starting material "A1 in Route I is the 3-. chloro(or bromo)- -hydroxy-l,2,5-thiadiazole, it can be re- • acted with product MF" (see Route II ) thereby introducing the ;. desired -NR7Ra group in the 3-position of the thiadiazole ; nucleus. ,-Also, when R in product UD" (see Route I) is- chloro or bromo,, product "D" can be reacted with the amine "P" . whereupon the. amine will first react with the epoxide portion j , of the; product and then, by. increasing the temperature, it :' ; will replace the chloro or bromo group thereb formin a '.. product of. the structure: . (·. bient temperature. As the reaction is exothermic, the reaction mixture is cooled to maintain the temperature from · slightly below to slightly above ambient temperature for best results. Esterification can be effected with any alcohol/ advantageously methanol or other lower alkanols having advantageously from 1 to 4 carbons or a phenyl-lower alkanol. such as, for example, phenylethanol, and the reaction temperature preferably is maintained at a range from below to slight¬ ,Y is preferably a saturated or unsaturated lower' .. .. alkyl (Ci_5), hydrojy-lower alkyl (Ca_5). lower '.' ' cycloalkyl (C3_e) or phenyl; , · ;' ., Z is lower alkyl (Ci_5) . and . when .,' .. ·. Y and Z are each, lower alkyl they can be linked together to form a 3- to 6-membered carbocycl'ic ring with the carbon to which they are attached: ■■' R' haa the meaning hereinbefore assigned.

As catalyst, palladium on charcoal .or lithium aluminum hydride as reducing agent, advantageously is employed.

Yet another process of this invention comprises the reduction of a 3-R-4- (3-substituted amino-2-oxopropoxy) -1,2,5- . thiadiazole. Reduction of the ketonic function can be effected chemically with sodium borohydride or aluminum alkoxide. or reduction can be effected by fermentation with . a reductase of bacterial, ■ actinomycetales or fungal origin. In the latter system ' (i.e. , a reductase) the sinister isomer of- the desired 3-:fi-4- (3-substituted amino-2-hydroxypropoxy) -1,2 , 5—thiadiazole is obtained. ;·.' Chemical reduction advantageously is effected ϊη· ' the presence of an organic solvent such as a. lower alkanol .or' other polar aprotic organic solvents such as dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , tetrahydrofuran (THF) , hexa-methylphosphoramide (HMP) and tbie like. When sodium borohy- , dride is employed as " the reducing agent, it is preferred that' it be added portion-wise as the reaction is exothermic. Ex- · cess sodium borohydride subsequently is destroyed by the ■ addition of concentrated mineral acid, . advantageousl hydro- . chloric , acid; the end point for the addition of. acid Is ·., reached when the mixture remains acidic.

Reduction with a reductase is accomplished by inoculating the proper culture medium with the selected organism' and permitting the culture to stand, at 28° C. until 'good . growth is observed to have occurred. . For the fungi and actinomycetales this will take about five days and for the bacterial reductase from about two to three days. The 3-R-4-; (3-substituted amino-2-oxopropoxy) -1,2 , 5-thiadiazole then is added, preferably in the form of a salt, and the medium maintained at the same temperature for an additional 1 to 3 days, preferably about .48 hours. The solid material, then is removed by conventional methods, such as centrifugation or filtration, and the desired product obtained from the clarified.' filtrate by evaporation or other methods for removing the ■ water.

Organisms suitable for the reduction of ' 3-R-4- (3- substituted amino-2-oxopropoxy) -1 , 2 , 5-thiadiazole are (1) bacterial reductase selected, from Clostridium butylicum, Bacillus megaterium, C. lentoputrescens, Cornebacterium simplex, ■ ' Escherichia coli,' Salmonella paratyphi , E. freundii, ' ( Leuconostoc mesenteroides , Aerobacter aerogenes , Acetobacter ascendens, and • Mycobacterium lacticola, ' Lactobacillus delbrueckii (2) actinomycetales reductase selected from Streptomyces lavendulae and S. coelicolor and (3) fungal reductase selected from Saccharomyces Cerevisiae Geotrichum candidum Curvularia falcata and C. lunata. As media suitable to support the growth of each of these organisms is described in the literature and are well known to those skilled in the fermentation art, those teachings, are relied upon herein; by reference · in lieu of a detailed disclo-, sure of each of them.

In the above reaction' scheme is a' straight or branched chain alkyl having from 1 to 5 car'bon atoms which is optionally hydroxy substituted; ^is the alkyl or benzene moiety of the sulfonyl halide reactant hereinafter defined; and R represents chloro, lower alkyl having from 1 to 3 carbon atoms, lower alkoxy having from 1 to 3 carbon atoms, phenyl, benzyl , morph-olino, i eridy^ hydroxypiperidjfrQand N-lower alkyl-pipera-zinyl. ■ .· In the preparation of the sulfonyloxy compounds , any; sulfonyl halide can be employed as the sulfonyl moiety sub- . sequently is removed. For practical purposes,, commercially available and inexpensive sulfonyl halides could be employed and these would fall into, the class of alkylsulfonyl halides and benzenesulfonyl halides where the benzene moiety can optionally be substituted with one or more similar or dissimilar substituents selected from lower alkyl , lower alkoxy, halo, amino and nitro substituents. Among the commercially available sulfonyl halides that can be employed for this purpose . there can be mentioned methanesulfonyl chloride, benzene- - sulfonyl chloride, nitrobenzenesulfonyl chloride, bromobenzene- sulfonyl chloride, chlorobenzenesulfonyl chloride, toluene- · sulfonyl chloride, toluenesulfonyl fluoride, trichlorobenzene- sulfonyl chloride, tribromobenzenesulfonyl' chloride, fluoro- benzenesulfori'yl chloride, 4-chloro-2 (or 3) -nitrobenzenesulfonyl chloride, 1ιβχ3άβθ3ηβ3μ1ίonyl chloride, 2-mesitylenesulfonyl chloride, meth.oxybehsenesulfonyl chloride ,. and the like ."· ; According to '. -' Ά . .further ' process of this invention a 1,2,5-thiadiazole, structure "A1,1 is reacted with -an . optically active alkamine . of the sinister (S) configuration, structure II,· to provide product III in the sinister con-, figuration. Either structure "A"compound or structure. II com¬ 1 strong base. The reaction preferably is carried out at am- 2 bi.ent temperature although the reaction mixture either can . 3 be heated up to reflux temperature if desired, or cooled to 4 0° C. A solvent for the reactants is desirable and any con- 5 ventional solvent can be employed for this purpose; suitable 6 ones being polar aprotic solvents such as dimethylformamide 7 (DMF) , dimethyl, sulfoxide (D SO) , tetrahydrofuran ' (THF) , . 8 hexamethylphosphoramide (HMP) ,, lower alkanols and ..the ..like . 9 The readily available and relatively inexpensive tert-butanol " 0 . has been found to be a quite suitable, general purpose sol- 1 vent for these intermediates. . Strong bases that are recom- 2 mended for use. in the reaction are alkali metal alkoxides or 3 alkali metal hydroxides preferably the . sodium or potassium 4 alkoxides or hydroxides, or sodium hydride. When product S-III in the form of the free base is obtained as an oil, . 6 crystalline material can be prepared by forming the salt by 7 known methods . Suitable salts are those formed with mineral 8 acids or organic acids such as for example the hydrochloride 9 salt., the sulfate salt, the hydrogen maleate salt or other 0 desired mineral or organic acid salt. . . reaction with any known and particularly any commercially available sulfonyl halide.. ' As. any' .sulfonyl halide ■ will' ί :. · activate the hydroxyl group and as the sulfonyl moiety is . ,' subsequently removed it is not critical that any particular sulfonyl halide be employed to form the ' sulfonyloxy derivative of the S-l ,2-dihydroxy-3-amino(or substituted amino) -. propane. ■ For practical purpose's, commercially available and, inexpensive sulfonyl halide^' would, be employed' for . this., pur— pose and ^ these would'1 fall into the class : of alkylsulfonyl ; halides and benzenesulfonyl halides as mentioned in. the "second !'-" ■'· " · - - ' ·' '-paragraph of page 2/.

The S-oxazolidines are, prepared by the reaction- of S-l,2-dihydroxy-3-amino (or substituted amino) propane or the S-l-su,lfonyloxy-2-hydrox'y-3-amino (or substituted 'amino') -, propane with any aldehyde, ZCHO, to .provide,, an S-oxazolidine of the structure. wherein R^- is hydrogen or the sulfonyl group. The aldehyde ' used in the preparation of the. oxazolidine is not critical as any aldehyde can be used in the formation of the cyclic struc ture. which subsequently is cleaved by hydrolysis . to remove the NsCH/ grouping, provided by the aldehyde. For practical purposes any commercially available and inexpensive, aldehyde can be employed and among these there can be mentioned · aliphatic, aldehydes alicyclic> aromatic or heterocylic- aldehydes such as lower alkyl aldehydes, benzaldehyde , phenyl-lower . alkyl aldehydes, and the like, the phenyl moiet of eithe of the latter 'aldehydes optionally having .one or more similar or dissimilar substituents selected from halogen, lower alkyl, halo alkyl, amino) acylamino, mono- o di-alkylamino , nitro, alkbxy, phenalkoxy, haloalkoxy and hydroxy, a heterocyclic aldehyde optionally having substituents as halogen; lower alkyl, phenalkyl and the like. Among the many aldehydes that can be employed there can be mentioned. acetaldehyde , propionaldehyde , butyraldehyde, phenylacetaldehyde, anis-aldehyde, benzaldehyde, mesitaldehyde , tolualdehyde , furfural and the like. As mentioned above, R1 can be hydrogen or an' alkyl-, aryl- or, aralkyl-sulfonate of the type hereinabove described as suitable for preparing the sulfonyl derivatives of S-l > 2-dihydroxy-3-amino (or substituted amino) propane . When is hydrogen , the sulfonate of the 5-hydroxymethyloxazoli- . dine can be prepared by reaction with the desired sulfonyl halide in substantially the same manner as described/above.' . The S-2 , 3-epoxy-l-amino (or substituted amino) - ! .propanes are prepared by treating a l-sulfonyloxy-2-hydroxy-3-amino(or substituted. amino) propane with a strong base. The epoxide either in the form of its free base or as a' salt · ·■' thereof can be reacted with the 1 , 2 , 5-thiadiazole to give \ proaucc b-iu.-. ' ne narure or the salt is again not critical.

Inorganic acids or organic acids can be employed to: prepare the salt of the epoxide compound, usually hydrochloric, sulfuric, maleic, D-10-camphor sulfonic acids and the like are used for this purpose.

, . · , · .■■ The"following Examples will; illustrate this invention: _ 'EXAMPLE 1 ' ' · _ ,i 3-Chloro-4- (3-tert-butylamino-2-hydroxy- propoxy) -1 , 2 , 5-thiadiazo1e ' % · ·'-. ' - ' ' Step ¾; Preparation of 3-chloro-4- (2 , 3-epoxypropoxy) - ; 1 , 2 5-'thiadiazo'le ■ ■;·■ ■ A mixture of 30 g. (0.22 moles) of 3-chl6ro-4r hydroxy-l^^-thiadiazo.le, 71 g. (0.77 moles) of epichloro-hydrin, and 0.6 ml. of piperidine is maintained at 65-70°C. for two hours. Excess epichlorohydrin is removed at about 95°C. using water-pump vacuum. The residual viscous gum, 55.5 g., is dissolved in diethyl ether and refrigerated.

The supernatant ethereal liquor' is drawn off and evaporated to 'dryness giving '20.2 g. of a viscous oil that is then stirred for about one-half hour with 150 ml. of 10% sodium hydroxide solution. The mixture warms up slightly during this treatment. The mixture, then ' is extracted with diethyl ether , washed with water, and evaporated to yield 20.2 g. of crude 3-chloro-4- (2, 3-epoxypropoxy) -1,2, 5-thiadiazoie.

Step B: Preparation of 3-chloro-4-('3-tert-butylamino-2- · · hydroxypropoxy)-1,2, 5-thiadiazole hydrochloride A mixture of 40.2 g. (0.21 mole) of 3-chloro-4~ (2, 3-epoxypropoxy) -1,2, 5-thiadiazole and 76 g. (1.05 moles) o tert-butylamine is heated and stirred at 60-70° C. for two and one-half hours. Excess ert-butylamine is removed in vacuo giving 42.4 g. of residual crude product. The latter is dissolved by shaking with a mixture of diethyl ether and water containing 2.5 g. of sodium hydroxide. The ethereal phase is separated and the aqueous phase is extracted with several portions of diethyl ether. The ethereal extracts are combined/ washed with small volumes of water and .then treated with excess 3N hydrochloric acid. The aqueous: layer is separated, evaporated to dryness, and the resulting resi- due is dried by azeotropic distillation of benzene ethanol. The crystalline solid is recrystallized from ethanol diethyl ether giving 31.3 g. (^9·5#) of 3-chloro-4-(3-tert-butylamino- 2-hydroxypropoxy) -1,2, 5-thiadiazole hydrochloride, m.p. -l6l° C. Recrystallizations from the same solvent mix- ' ture gives product melting at I6I-I630 C. (ED50 = 0.093 mg./kg. ) .

' Analysis calculated for CQHIYC12 O02S: C, 35.77; H, 5.67; CI, 23.46; N, 13.90;; . '' * Found: C, 36.11; H, 5-37; CI, 23.33; N, 13.82.

-Step C: Preparation of 3-chloro-4- (3-tert-butylamino-2- hydroxypronoxy)-!,2, -thiadiazole The 3-chloro-4-(3-tert-butylamino-2-hydroxypropoxy)- 1,2, 5-thiadiazole hydrochloride obtained in Step B is neutra- lized with aqueous sodium carbonate and the. free base ex- the: residue is recrystallized from di-isopropyl ether giving the free base as colorless prisms, m.p. 78-790 C.

Analysis calculated for CeHieClNaOaS: C, 40.66; H, 6.07, CI, 13.3 ; , 15.81 s, 12 .07; Found: C, 0.80j H, 6.18; CI, 13.8O5 N, 16.00 ; * ■ s, 11.80.

In the following Sections describing methods of resolving certain 6f the racemic products of- this invention, no attempt has been made to assign an absolute configuration to the compounds. The [-)- and (+) -isomers of the resolving agents refer to the optical rotation of the parent (-) or " (+) agent employed. All (-) and (+) values given throughout for the compounds refer to the actual rotation of the free base, i.e., in referring to the ievorotatory salt, (+) -3- morphollno-4-( 3- ert-butylamino-2-hydroxypropoxy)- 1 , , - thiadiazole hydrogen maleate, the (+)- sign refers to the sign of rotation of the free base, (+) -3-morpholino-4- ( 3- tert-butylamlno-2-hydroxypropoxy)-l,2 , 5-thiadiazole.

RESOLUTION OF EXAMPLE 1 PRODUCT · Section 1 Isolation of (+)-3-chloro- -(3-tert-butylamino- 2-hydroxypropoxy) -1,2, 5-thiadiazole via the 0,0- di-p-toluoyl- ( - ) -tartrate Step A: A warmed solution of 26.5 g. (O.l mole) of racemic 3-chloro-4- (3-tLejrt-butylamino-2-hydroxypropoxy)-l,2 , - thiadiazole from Example 1, Step C, in 100 ml, of ethanol is added to a wa med solution of 38.6 g. (O.l mole) of 0, 0- di-p-toluoyl- (-)-tartaric acid in 225 nil. of ethanol and the .8 g. of crystalline product, m.p. l6o-2° .C. (dec), ([α] β2° + 77 5% c = 2.9 in CH3OH)A. The crude salt is recrystallized five times from five volumes by weight of ethanol affording 21.0 g. of enriched (+) -3-chloro-4-(3- tert-butylamino^-hydroxypropoxy)-!^, 5-thiadiazole hydrogen 0,0-di-p-toluoy'l-(-) -tartrate, m.p. 166.5-7.0° C. (dec), ( [a]^2°+ 80.6°, c= 2.5 in CHQOH) . ' Step B: The above salt (21.0 g., 0.0323 mole); is shaken with a mixture of 100 ml. of water, 14 ml. (0.07 mole) of sodium hydroxide solution, and 100 ml. of diethyl ether. Two further ether extractions (2 x 50 ml.) are performed and the combined ethereal extract is extracted once with 30 ml. (ca. 0.04 mole) of 1. 38N hydrochloric. acid. The acid layer is extracted once with a small amount of diethyl ether, and then basified with 10 ml. (0.05 mole) of 5N sodium hydroxide solution. The liberated base is extracted v/ith 100 ml. of diethyl ether, followed by two 25 ml. portions of ether.

The ethereal extracts are combined and washed with 20 ml. (2 x 10 ml.) of water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give 7.9 g. of syrupy (+)-3-chloro-4- ( 3-tert-butylamino-2-hydroxy- propoxy)-1,2, 5-thiadiazole -([a¾ + 6·5% c = 2. 4 in CHoOH) . The syrup (7.9 g.) is dissolved in II5 ml.' of warm "Skellysolve B" (essentially, n-hexane, b\ 60-68°) the solution allowed Λ The legends employed here ,ahd. throughout0the- specif cation ·,·'. have the following significance', "[a].22 + 77.5" signifies the specific rotation at 22°. C. (or otter given tempe ature), • at the "D" line of sodium. !'c = 2.9 in CH3OH" signifies the concentration of the- • product (2. or other given concentration) in methanol (or other specified solvent). . ; :-'\ .-r".r to cool to room temperature, seeded with a trace of racemic base, and left 18 hours at room temperature. The crystalline solids are collected, washed with a small volume of "Skellysolve D", and dried to give 0.92 g. of (-)-3-chloro-^-(3-terfc-butylamino-2-hydroxypropoxy)-l,2, 5-thiadiazole contaminated with a small amount of. the (-l-)-e antiomer, m.p. 59-68° C. The filtrate afforded 5.6 g. of (+)-3-chloro-4-(3"tert-butylamino-2-hydroxypropoxy)-l,2 ,5-thiadiazole, m.p. 58. -62. ° C. ([α]β°° + 6.7°, c = 2.5 in CH3OI-1) . Further crystallization of the- latter from "Skellysolve B" afforded the product melting at 58.5-6Ο.Ο0 C, {{^]^0° + 7.22°, c = 2. in CH3OH), (EDso = 0.023 mg./kg. tested as HC1 salt).

Analysis calculated for C9HiSCl 302S: C,.40.68; H, 6.07; CI, 13.34; N, 15.8l; S, 12.06; Found: C, 41.15; H, 6.08; CI, 13.76; N, 16.13; S, 12.04.

Section 2 Preparation of (+)-3-chloro-4-(3-tert-butylamino- ■ ■ 2-hydroxypropoxy-l, , 5-thiadiazole hydrochloride A solution of (-i-)-3-chloro-4-(3-tert-butylamlno-2-hydroxypropoxyrly2, -thiadiazole (1.45 ., m.p. 59~60° C.) in 20 ml. of anhydrous diethyl ether is treated with an ex-cess of ethanolic hydrogen chloride solution. The precipi-tated solid is collected and washed with anhydrous diethyl ether to give 1.43 g. of (+)-3-chloro-4-(3-tert-butylamino- . ■ 2-hydroxypropoxy)-1,2, 5-thiadiazole hydrochloride, m.p. 148-51° C. Precipitation of this material in ethanol with diethyl ether affords the product with m.p. 148-9.5° c, ([ ]ρ2°' -7. 5 c = 2.75 in CH3OH) . 1. Analysis Calculated for CQH_.GC1N302S .HC1: 2 c, 35.77; H, 5.67; Cl, 23.46; N, 13.90; 3 S, 10.60. 4. Found: C, 35.88; Ή, 5-7^5 CI, 23.61; N, l4.06; ' .. . . . . S, 10.34. · Section 3 7 Isolation of ( - ) -3-chloro-4- (3-tert-butylamino- 8 2-hydroxypropoxy) -1 , 2 , 5-fniadiazolG . 9 All liquors and washes resulting from the isolation 10 of. (+)~3-chloro-4- ( -tert-butylamino-2-hydroxypropoxy)- 11 1,2, -thiadiazole hydrogen 0,0-di-p-toluoyl-(-)-tartrate (see 12 Section l) are combined, evaporated to dryness, and the 13 ' residue treated with 5N sodium hydroxide solution as des-l4..cribed in Section 1. The. mixture then is extracted three times with diethyl ether. The combined ethereal extracts are 16 washed with water, dried, and evaporated to dryness to give. 17 14.3 g. of enriched (-)-3-chloro- -(3-tert-butylamino-2- 18 hydroxypropoxy)-l,2,5-thiadiazole, m.p. 58-76° C. The crude 19 material (14.3 g.) is dissolved in 210 ml. of "Slcellysolve 0 B", allowed to cool to room temperature, seeded with a trace 1 of racemic base, and left at room temperature for 24 hours. 2 The crystals are collected and dried to give 5.9 g. of (ΐ)-3~ 3 . chloro-4-(3-tert-butylamino-2-hydroxypropoxy)-l,2, -thiadia- 4 zole, m.p. 78.5-9.5° C. ([a]^°°0e)j and. the mother liquors afford further crops, of crystalline racemic material.. ' The 6. remaining mother liquors upon eyap0l'ation.,t,he¾'"affo.r.ds a ,'.· ·.... 7 total of 6.9 g. of (-)-3-chloro-4-(3-tert-butylamino-2- 8 hydroxypropoxy)-l,2,5-thiadiazole, m.p. 57-60° C, ( [a]D 9 -7.31°, c = 2.5 in CH3OK). Further purification gives (-)- 0 3-chloro-4-(3-tert-butylamino-2-hydroxypropoxy)-l,2,5-thia- ' 1 hydrochloride salt . ) 2 ■ Analysis calculated for CaHioCl aOaS: 3 . cy 40.68; H, 6.07; Cl, 13.3^; N, 15.81; 4 , ... S, 12.06.

Pound:' C, 40.46; H, 6.21; CI, 13- 31; N, 15-96; S, 11.90. 7 - Section 4 8 Preparation of ( - ) -3-chloro-4- (3-tert-butylamino- 9 . 2-hydroxypropoxy)-l, , ~'bhladiazole hydrochloride A slight excess of ethanolic hydrogen chloride 11 solution is added slowly to a stirred solution of (-)-3- 12 chloro-4-(3-tert-butylamino-2-hydroxypropoxy)-l,2, -thia-13, diazole (1.66 g., 6.26 millimoles, m.p. 59-60° C.,- obtained 14 as, in Section 3) in 50 ml.. of..dry diethyl ether.. The. re- .. suiting precipitated solid is collected, washed v/ith anhy-l6. drous diethyl. ether, and dried to give 1.8 g. of (-)-3~ 17 chloro-4-(3-tert-butylamino-2-hydroxypropoxy)-lJ2 ,5-thiadia- 18 zole hydrochloride, m.p. 146-7° C. ([α]ρ0° +7-9°, c = 2.8 19 . in CH30H) . 0 ' Section 5 1 Isolation of (-)-3-chloro-4-(3-tert-butylamino- 2 2-hydroxypropoxy)-l,2,5-thiadia!-ole 3 Step A: The procedure set forth in Section 1 is repeated 4. with the exception that 0,0-di-p-toluoyl-(-)-t.artaric acid 5 is replaced by 0,0-di-p-toluoyl)-(+)-tartaric acid. Thus 6 solutions of 25.75 g. .(0.0972 mole) of (i)-3-chloro-4- (3- . 7 tert-butylamino-2-hydroxypropoxy)-l,2 ,5-thiadiazole in 100 8 ml. of anhydrous ethanol and' 37-5 g. (0.0972 mole) of 0,0- 9 di-p-toluoyl-(+)-tartaric acid in 225 ml. of anhydrous 0 ethanol are mixed and chilled for two hours at 5° C. to. give to give 24 g, of highly enriched (-)-3-chloro- -(3-tcrt- butylamino-2-hydroxypropoxy)-l,2, 5-thiadiazole hydrogen pp 0 0,0-di~p-toluoyl-(+)-tartrate, m.p. I65-60 C. ([a]" -80.I0, c 3 in CH3OII) .

Analysis calculated. for CoHieClNaOaS . C20H10O0 : C 53.3; H, 5.25; Cl, 5·^; N, 6.44; · . S, ,91.

. . Pound: c, 53.1; H, .99; ci, 5-86; N, 6.94; .' S,.4.93.· Step B: The procedure set forth in Step B of Section 1, is followed for the treatment of the sal to afford the free base. Thus treatment of (-)-3-chloro-4-(3-,tert-butylamino-- 2-hydroxypropoxy)-l, , -thiadiazole hydrogen 0, O-di-p-toluoyl- (+)-tartrate, followed by extraction with diethyl ether, gave a free base that upon fractional crystallization from "Skellysolve B" to remove small amounts of racemic base affords 7 g. of (-)-3-chloro^4-(3-tert-butylamino-2-hydroxy-- propoxy)-!,2, 5-thiadiazole, m.p. 59-60° C.

Analysis calculated for C0H1GCIN3O2S : C, 40.68; H, 6.07; CI, 13.34; N, 15.8l; S, 12.06.

• Pound: C, 40.50; H, 6.21; Cl, 13.30; N, . I6..OO; 1 S, 11.90.

Section 6 Isolation of (+)-3-chloro-4-(3-tert-butylamino-2- . hydroxypropoxy)-l,2 , 5-thiadiazole pollowing».the procedure of Section 3, the mother liquors and washings from the isolation of (- )-3-chi rq-4» . (3-t r-butylamino-2-hydroxypropoxy)-l,2,5-thiadiazole hy- drogen 0,0-di-p-toluoyl-(+)-tartrate (from Step A, Section 2-hyd'roxypro oxy)-l,2 , 5-thiadiazole . Careful fractional crystallization of this crude base from "Slcellysolve D" removes (-)-3-chloro- -(3-tert-butylainino-2-hydroxypropoxy)- 1,2, 5-thiadiazole, m.p. 78-9° C. The remaining fractions are combined and recrystallized to afford (+)-3-chloro- - (3-ter_t-butylamino-2-hydroxypropoxy)1-l, 2, 5-thiadiazole, m.p. 59-60° C. ' Section 7 Isolation of ( - ) -3-chloro-ii— (3-tert-butylamino- 2-hydroxypropoxy)-l, , 5-thiadiazole The procedure set forth in Section 1 is repeated with the exception that 0,0-di-p-toluoyl-(-) -tartaric acid is replaced b (-)-tartaric acid. The resulting salt is recrystallized repeatedly from ethanol to give di-[(+)-3- chloro-1(--(3-tert-butylamino-2-hydroxypropoxy)-l,2,5-thia- diazole]-(-) -tartrate, m.p. 130-2° C. ([a]p2° -15-3°, c = 2.6 in CH3OH) . The tartrate is converted by the method described in Step B of Section 1 to the free base and the base subjected to fractional crystallization to afford (+)-3-chloro-4-(3-tert_-butyla lno-2-hydroxypropoxy)-l,2, 5- thiadiazole. Work up of the v;ashings and. mother liquors from di- [(+)-3-chloro- -(3-t rt-butylamino-2-hydroxypropoxy)-· 1,2, 5-thiadiazole ]-(-) -tart ate by the procedure given in ' Section 3 affords (- )-3-chloro-4-(3-tert-butylamino-2- hydroxypropoxy) -1,2, -thiadiazole.

":' Section^'8 — · ............. ..... ' · Isolation of (•l-)-3-chloi,-o-4-(3-iLQ t-butylamino- 2-hydroxypropoxy) -1,2 , 5-thiadiazole · Step A; The procedure set forth in Section 1 is repeated ' w.ith the exceptions that 0, 0-di-p-toluoyl- (- j-tartaric acid repeated recrystallization affords di-[(-)-3~chloro-4-(3- tcrt-butylamino-2-hydroxypropoxy)-1.2 , 5-thiadiazole -(-!·)- pp 0 tartrate, m.p. 130-2° C. . ( [ ]^ + 15.6% c = 2.3 in CH3- OH). , ' .

. , Analysis calculated for (CQHioClN302S )2. C4H0O0 : c, 38.7; H, 6.51J ci, 10.4; N, 12.3;' · s, g.39. · Found: C, 38.5; H, 5-70; CI, 10.7; N, 12.2; S,; 9.18 Step B; The tartrate is converted by the procedure of Section 1, Step B, to the free base and the base re'crystallized to afford (-)-3-chloro-4-(3-tert-butylarnino-2-hydroxypropoxy)-' 1,2, -thiadiazole, m.p. 58-βθ0 C.

Step C: Work up of the mother liquors and washings from di- [ (-) -3-chloro-4- (3-tert-b tylamino-2-hydroxyprόpoxy)- 1,2, -thiadiazole ]-(+) -tartrate by the procedure described , in Section 3 affords (-t-)-3-chloro-4-(3-tert-butylamino-2- hydroxypropoxy) -1,2, 5-thiadiazole.

Section Isolation of (-) and (+)-3-chloro- -(3-tert- butylamino-2-hydroxypropoxy) -1,2, -thiadiazole via 0, 0-dibenzoyl- (-Q-tartaric acid ' Step A: The procedure set forth in Section 1 is repeated v/ith the exception that 0,0-di-p-toluoyl-(-)-tartaric acid is replaced by 0, 0-dibenzoyl- (H-)-tartaric acid. Thus, solu- tions of 5,3 g. (0.02 mole) of ( )-3-chloro-4-(3-tert-but - . ( amino-2-hydroxypropoxy) -1,2, 5-thiadiazole in 20 ml. of an-. hydrous ethanol and 7.5 g. (0.02 mole) of 0, 0-dibenzoyl-(-1-)- ' tartaric acid in 4 ml, of anhydrous ethanol are mixed and left two days at room temperature to give 1.7 g. of product, m. . 177-8° C. a 0° -42. c = 1. in CH 0H . Recr s- 1.35 g. of di-[ (-)-3-chloro-4- j-tert-butyla lno-2-hydro:x,y-prcpcxy) 1,2, 5- t ia≤ia.:cle)-C,0-diucuzoyl--(-r)-tarl.i-ale, m.p. 177.7-178.2°C. (dec). ([a]p0° -44.6°, c = 1.24 in CH3OH).

Step B: The salt is partitioned between 50 ml. of diethyl ether and 50 ml. of water containing 1 g. of sodium carbon-ate, the layers are separated after vigorous shaking and the aqueous phase extracted four times with diethyl ether. The combined ethereal extracts are washed with water and evapo-rated to give the free base. This product is recrystallized from "Skellysolve B" to give 600 mg. of (-)-3-chloro-4-(3-tert-butylamlno-2-hydroxypropoxy ) -1,2, 5-thladiazole, m.p. n 0 59.5-60.5°C. ([aj^ -7.16°, c = 3.5 in CH3OH) . Work-up ■ of the mother liquors from the dibenzoyl tartrate by the procedure of Section 3 affords' (+ ) -3-chloro-4- ( 3-tert-butyl-amino-2-hydroxypropoxy)-l,2, -thiadiazole, m.p. 59-60°C.

Section 10 Isolation of (-) and (+) -3-chloro-4- ( 3-tert- butylamino-2-hydroxypropoxy)-l ,2, -thiadiazole via 0,0-dibenzoyl- (·<-) -tartaric acid Similarly, following the procedure set forth in Section 1 with the exception that the 0,0-di-p-toluoyl-(-)- tartaric acid is replaced with 0,0-dibenzoyl-(+)-tartaric ' acid there is obtained specimens of (-)- and (+ ) -3-chloro- 4-(3-_tert-butylamino-2-hydroxypropoxy)-l, 2, 5-thiadiazole.

Example 1A 3-Morpholino-4- ( 3-tert-but,ylamino-2-hydroxypropox ) -1, , 5- thladiazole hydrogen malea'te" ': ■'" T '.·■-. ■ .. ■ .. , A solution of 5.0 g. of 3-hydroxy-4-morphpll.no- · 1,2, 5-thiadiazole (2o.7 mmole) in 18.95 ml. of 1,41 N . methanolic sodium methoxide is treated with 10. ml. o chloroh d n 1 m o . filtered and viashed with methanol. The filtrate is evapor-ated in vacuo to an oil residue. The residue is refluxed ·· for 12 hours in 15 ml. t-butylamine and the excess amine evaporated in vacuo. The residue of crude 3-morpholino-4-( 3-tert-butylamino-2-hydroxypropoxy ) -1 , , 5-thiadiazole free base (6.1 g. ) is converted to: the maleate salt and recrys-tallized from ethanol, m.p. 2l4-215°C.

Example IB 3- orpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-l ,2, 5- . thiadiazole, hydrogen maleate A mixture of 0.22 mole of 3-morpholino-4-hydroxy-1,2, 5-thiadiazole, 71 g. (0.77 mole) of epichlorohydrin, and 0.6 ml. of piperidine is maintained at 65-70 °C. for 2. hours. Excess epichlorohydrin is removed at about 95°C. jLn vacuo. The residual gum is dissolved in diethyl ether and refrigerated. The supernatant ethereal liquor is sepa-rated and evaporated to a viscous oil. An excess of t-butylamine is added and the mixture is heated at 100°C. for 10 hours in a sealed vessel. The product is isolated by the method described- in Example 1A to 3-morph61ino-4- (3-tert-butylamino-2-hydroxypropoxy)-l, 2, 5-thiadiazole, hydro-gen maleate.

By following substantially the same procedure described in Example 1, 1A or IB but replacing the 3-chloro-4-hydroxy-l, 2, -thiadiazole in Example 1', Step A, and the amine employed in Example 1, Step B .by the :reactants "A" and "Έ" Identified in the following table there are obtain-ed thiadiazoles I-b which also are Identified in Table I. The groups identified for the variable radicals R, Rs and' R6 in the reagents "A" and "E" remain unchanged during the ' Ex. Empirical M. P.." No. R R5 R6 Formula in °C 2 H H -C(CH3) 2CH2OH C9H17N303S . 94· -6 C: 43 F: 43 3 H ·--(CH2) 2-0- (CH2) 2—! C9Hi5N303S. HC1 150· -2 C: 38 F: 38 4 CI H -CII(CH3)2 C8H ltlClN302S. HCl 153 -5 ; C: 32 F: 33 TABLE I (Cont'.d.) Ex. Empirical M. P.

No.' R R5 RG Formula in °C C . C2K5 H -CH(CH3)2 C10H19N3O2S. HC1 144.5-145.5 C: 42.6 6 . c2n5 H -C(CH3) 3 d !H21N302S. HC1 137-8 F: 44.6 7 C2H5 H -C (CH3) 2CH2OH Ci iH21N303S.. HC1 · 125-7 C: 42.3 F: 42.8 8 C2H50 H -CH(CH3)2 C10H19N3O3S. HC1 167-70 C: 40.3 F : 40.4 9 C2H50 H -C(.CH3) 3 Ci iH21N303S. HCl 147-9 C: 42.3 F: 42.8 . C2H50 H -CH2C(CH3)3 Cl2H23N3°3S. HC1 168-9 C: 44.2 F: 43.9 11 c2u5o H -C (.CH3) 2C≡CH C12H19N303S. HCl 130-1 C: 44.7 F: 44.7 12 C2K,50 -(CH2) 2-0-(CH2) 2—' 1 C11H19N3O S. HCl 124-6 C: 40.5 F: 41.1 13 H -CH(CH3)2 ClttH19N302S. HCl 165-7 C: 50.9 F: 51.0 4 C6H5 II -C(CH3)3 C15H21N302S. HCl 168-170.5 C: 52.3 F: 52.1 1 EXAMPLE 16 2 3-Morpholino-4- (3-tert-butylamino-2-hydroxypropoxy)-- 2 ; 1, 2 , 5-thiadiazole ■ ■ , A mixture of 11.8 g. (39 milli oles) of 3-chloro- 5 4- (3-tert-butylamino-2-hydroxypropoxy) -1 , 2 , 5-thiadiazole 6 hydrochloride from Example 1, Step B, and 65.5 ml. (752 7 millimoles) of morpholine is heated and stirred at 125-135°C. 8 for four hours. This mixture is refrigerated overnight and 9 the precipitated morpholine hydrochloride is collected and dried; yielding 8.55 g. (88.5%) m.p. 175-180°C. . The excess 11 morpholine is removed by distillation in vacuo to. give 16.8 . 12 g. of residual oil. The residue is shaken with 10 ml. of 13 water containing 1.6 g. of sodium hydroxide and extracted 14 with diethyl ether. The combined ethereal extracts are washed sparingly with water and evaporated to dryness to give 11.7 16 g. of residue. The product is dissolved in anhydrous diethyl 17 ether and treated with excess hydrogen chloride in diethyl 18 ether to give 10.3 g. of crystalline product, ' m.p. 151-161°C. 19 Recrystallization of this material from anhydrous acetone- 20 diethyl ether gives 3-morpholino-4- (3-tert-butyiamino-2- 21 hydroxypropoxy) -1 , 2 , 5-thiadiazole hydrochloride, m.p. 161- 22 163°C. , (ED50 = 0.013 mg/kg) . . .

Racemic 3-morpholino-4- (3-tert-butylamino~2- . hydroxypropoxy) -1,2, 5-thiadiazole from Example 16, (11.7 g., 0.038 mole), and 2.8 g. (0.0187 mole) of (+) -tartaric acid ([o]^8° +12.9°, c=20 in.H20) are dissolved in 200 ml . of hot acetone containing 20 ml. of water and aged with stirring at room temperature over a weekend. Filtration of the crystalline precipitate gives 9.6 g. of di- [3-morpiolino-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole] - (+) -tartrate , m.p. 181-183°C. ([α) 8° +12.9°, c=1.82 in CH3OH) . Recrystal-lization of 9.2 g. of this tartrate from 125 ml. of hot acetone containing 12.5 ml. of water gives 6.4 g. of solid material, m.p. 179.5-181°C. ([ot]^8° +13.5°, c=2.32 in CH3OH) . A 6.3 g. sample of this solid is shaken in a. separatory funnel with 45 ml. N ammonium hydroxide and 100 ml. of ether for 10 minutes. The. aqueous layer is extracted with 2 x 100 ml. portions of ether. The combined ethereal' extracts are washed with 2 x 20 ml. aliquots of water, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5 g. of non-crystalline 3-morpholino-4- (3-tert~butylaroino-2-hydroxypropoxy) -1,2, 5- · 28° thiadiazole, ([o]D -1.82°, c=2.45 in CH3OH) . A mixture of this base and 1.84 g. of aleic acid is dissolved in 240 ml. of hot ethyl alcohol and allowed to age at room temperature [ with stirring for 18 hours. Filtration of the crystalline solid yields 4.96 g. of 3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole hydroge . maleate , m.p. 211-214°C. ( [a]^8° +0.45°, c=2.8 in CH30H) . The mother liquors are refluxed with 100 rng. of "Darco" decolorizing charcoal for 5 minutes, filtered hot, and concentrated to 30 ml. This solution is aged at room temperature with stirrin 1 in CH3OH) . The mother liquors are diluted with.100 ml. of 2 ether, from which is collected by filtration an additional 3 350 mg. of product, m.p. 203-204°C. A 321 mg. sample is 4 recrystalliz.ed from 3 ml. of ethyl alcohol to give 270 mg. of (-) -3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) - 28° 6 1,2, 5-thiadiazole hydrogen maleate, m:p. 202-203°C. ([u.^ 7 +5.0°, c=3.02 in CH3OH) . The infrared 'spectrum of this 8 sample is identical to that of the racemic hydrogen maleate. 9 Analysis calculated for C 7H2 QN4O7S : 0 C, 47.21; H, 6.53; N, 12.95; S, 7.41; 1 Found: C, 47.57; H, 6.56; N, 12.86; S, 7.48 2 ' Section 12 3 Preparation of optically active (-) -3-morpholino-4-4 (3- ert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole from its' dextrorotatory hydro-gen maleate salt ' ' 6 _ (-) -3-Morpholino-4- (3-tert-butylamino-2- , hydroxypropoxy) - (.a3D 280 7 1, 2 , 5-thiadiazole hydrogen maleate, 8 +5.0°, c=3.02 in CH30H) , (100 mg. from Section 11), 100 ml. 9 of ether and 20 ml. of N airimonium hydroxide is shaken in a 0 separatory funnel for 5. minutes. The aqueous laye ' is 1 extracted with an additional 50 ml. of ether, and the combined 2 ethereal extracts are washed with 2 x 20 ml. of water, dried 3 over magnesium sulfate, filtered, and concentrated in vacuo 4 to give 70 mg. of oily (-) -3-morpholino-4- (3-tert-butylamino-5 2-hydroxypropoxy) -1,2, 5-thiadiazole, ([a]^8° -4.32°, c=5.13 6 in CH3OH) . 7 "· Section 13 ■ 8 ' Resolution v;ith (-) -tartaric acid 9 By following the resolution procedure described 0 in Section 11 above, but substituting an equal' quantity of . 1 - -tartaric acid for the + -tartaric em lo ed in Section 1 4- ( 3-tert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole oo 2 hydrogen maleate, ([α]^" -4.4°, c=2.56 in CH3OH) . Further ' 28° 3 fractional recrystallization gives rise to [α]β -5.0° 4 for the hydrogen maleate salt.

' Sectio 14 6 Preparation of (+) -3-morpholino-4~ (tert-butylamino-2 7 hydroxypropoxy) -1 , 2 , 5-thiadiazole from its 8 ' ' levorotatory hydrogen' maleate salt By replacing the (-) -3-morpholino-4- (3-tert- 0 butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole hydrogen 11 maleate employed in Section 12, with the (+) -3-morpholino- 12 4- ( 3-tert-butylamino-2-hydroxypropoxy) -1, 2 , 5-thiadiazole 13 hydrogen maleate prepared as described in Section 13 above, 14 and following the same procedure described in Section 12, 15 there is obtained the (+) -3-morpholino-4- (3-tert- 28° 16 butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole, ([a_D 17 +4.32°, c=5.13 in CH3OH) . 18 ALTERNATIVE PREPARATION OF OPTICALLY ACTIVE 19 ISOMERS OF EXAMPLE 16' PRODUCT . Conversion of (■)■) -3-chloro-4- (3-tert-butylamino-2 21 hydroxypropoxy) -1 , 2 , 5-thiadiazole to (+) -3- 22 morpholino-4- (3-rtert-butylamino-2-hydroxypropoxy) 23 1, 2 , 5-'thi'adi'azole 24 ' Section' 15 ' Preparation of (+) -3-morpholino-4- (3-tert- 26 ' b'u't'ylamino-2-hyd oxypropoxy) -1,2,5-thiadi ?ole 27 A mixture of 5.3 g. (20 millimoles of m.p. 58.5 28 62.5°C.) of (4·) -3-chloro-4- (3-tert-butylamino-2-hydroxy- 29 propoxy) -1,2, 5-thiadiazole and 26.5 ml. of freshly distilled orpholine are heated for four hours at 135^40°C. The 31 cooled mixture is refrigerated overnight and the precipitated 32 solids collected, washed with anhydrous diethyl ether, and 33 dried to give 2.18 g. (88.3%) of morpholine hydrochloride. 1 diethyl ether, washed several times with water, and evaporated 2 to dryness to give 5.7 g. of (+) -3-morpholino-4- (3-tcrt- 3 butylamino-2-hydroxypropoxy) -1, 2 , 5-thiadiazole as a slightly 4 yellow oil. . ·' . ' ;'' Section 16 6 Preparation of (+) -3-morpholin6-4- (3-tert- 7 butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole 8 ' ' ' hydrogen maleate' ' '* ■ ■ ■ ■ ■ 9 A warm solution of 5.7 g. (18 millimoles) of {+) -3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) - 11 1,2, 5-thiadiazole in 10 ml. of isopropanol is" treated with 12 a warm solution of 2.09 g. (18 millimoles) of maleic acid 13 in 10 ml. of isopropanol. The solution is allowed to cool, 1 left 2 hours at 5°C, and the solids collected to give 6.7 g. (86%) of (+) -3-morpholino-4- (3-tert-butylamino-2- . 16 hydroxypropoxy) -1,2, 5-thiadiazole hydrogen maleate, m.p. 17 192-4°C. (dec.) -4.3°, c=3.3 in CH3OH) . Crystallization 18 of this product from anhydrous ethanol affords 3.85 g. of 19 (+) -3-morpholino-4- (3-te_rt-butylamino-2-hydroxypropoxy) - 20° 1,2,5-thiadiazole hydrogen maleate, m.p. 201-2°C. , ([a]D 21 -5.57°, c-3.35 in CH30H), (ED50 = 0.0066 mg/kg) . . 22 Conversion of (-) -3-chloro-4- (3-tert- 23 butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole 24 to (-) -3-morpholino-4- (3-tert-butylamino-2- 25 ■■·; hydroxypropoxy) -1, 2 , 5-thiadiazole ■ · · ■ 26 Section 17 27 ■ Preparation of (-) -3-morpholino-4- (3-tert- 28 butylamino-2-hydroxypropox ) -1 , 2 , 5-thiadiazole 29 Following the procedure described in Section 15, a mixture of 6.9 g, (26 millimoles of material of m.p. 31 57-60°) of (-) -3-chloro-4- (3-tert-butylamino-2-hydr'oxy- 32 propoxy) -1 , , 5-thiadiazole and 34,5 ml. of freshly distilled ° a slightly yellow oil.

Section 18 Preparation of (-) -3-morpholino-4- (3-tert- butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole ' ' hydrogen' maleate ' * The oily (-) -3-morpholino-4- (3-tert-butylamino- 2-hydroxypropoxy) -1,2, 5-thiadiazole (7.2 g.) in 13 ml. of : isopropanol is treated with a solution'of 2.65 g. (22.8 millimoles) of aleic acid in 13 ml. of isopropanol to afford .9.04 g. (80%) of crude (-) -3-morpholino-4- (3- tert-butylamino-2-hydroxypropoxy) -1 , 2 , 5-thiadiazole hydrogen maleate, .p. 190-3.5°C. Careful fractional crystallization of this material from ethanol affords 5.0 g. of (-)-3-. morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2,5- thiadiazole hydrogen maleate, m.p. 201.5-2.5°C. (dec), ' 22° +5.30 c=3.3 in CH30H) .. A further recrystallization from the same solvent affords material, m.p. 201-2°C. (dec), (.α] 2° +5.56°, c=3.2 in CH30H) , (ED50 = 0.088 mg/kg) .

Additional products of this invention that advantageously are prepared by the procedure described in Example 16 are identified in Table II, below. These products are synthesized by following the procedure identified in Example 16 but replacing, the 3-chloro-4- (3-tert-butylamino- 2-hydroxypropoxy) -1,2 , 5-thiadiazole hydrochloride by the . reactant I-d having the R6 substituent identified in the Table and replacing the morpholine · employed in Example 16 by the amine reactant "F" having the spbstituents identified for this reactant in the following Table under the headings R7 and R8. The R6, R7 and R8 groups identified for the startin materials "F" and I-d are retained in the end roduct Ex. Empirical M. P.

No. R 6 Formula L -J (CH3) 2CH- C12H22N4°3S-. KCl 168.5-170.5 C: 42 .54 F: 42 .36 , -J (CH3) 3C- Cii)H27 502S. 2HC1. H20 205 C: 40 .00 CH3 F: 39 .92 19 (cir2) 5 (CH3) 2CH- C13H2i, il02S. HC1 169-170.5 C: 46 .35 F: 46 .71 -(CH2) 5 (CH3) 3c- Ci-,H26 ..02S. HC1 171-2 C: 47 .92 F: 48 .06 J (CH3) 3c- C1L,H26Nit03S. CL,H¾OL, 171-3 . C: 48 .42 I OH F: 48 .33 C = Calculated values F = Found values The preparation by Route 3 of products having a carbamyl substituent in the 3-position of the thiadiazole is illustrated by the following two Examples: ■ EXAMPLE 2.2 3-N-tert-butylcarbamoyl-4- (3-tert-butylamino- . ' 2-hydroxypropoxy) -1, 2 , 5-thiadiazole ' Step' A: 4-Allyloxy-l , 2 , 5-thiadiazole-3- ' carboxylie 'acid · ■ ■ ·.· ■ A mixture of 1 mole of 4-allyloxy-3-cyano-l,2, 5-thiadiazole in 10 parts (volume/grams) of 80% ethanol containing 4 equivalents of sodium hydroxide per equivalent of the thiadiazole is refluxed for- 2 hours. The ethanol is removed in' vacuo and the remaining residue dissolved in a minimum amount of water and made acidic (pK 2) with hydrochloric acid. The precipitated 4-allyloxy-l , 2 , 5-thiadiazole-3-carboxylic acid, is removed by filtration and washed with water to give a 90% yield of product, m.p. 138-139°C.

' Step' B; 4- (3-Bromo-2-hydroxypropoxy) -1 , 2 , 5-. ' ' ' ' th'iadia?,ole-3-carboxylic acid ' , .

A mixture of 9.3 g. (50 millimoles) of 4-allyloxy-1, 2 , 5-thiadiazole-3-carboxylic acid and 8.9 g. (50 milli-moles) of N-bromo-succinimide is suspended in 50 ml. of water. The mixture initially turns brown and evolves heat but after one minute a colorless solution results. The white crystals that deposit upon cooling are collected, washed with. ater, and dried giving 8.0 g. (56.5%) of 4- (3-bromo-2-hydr xyp cp^xy) -1,2, 5-thiadiazole-3-carboxylic acid. Recrystallization' of the product from ethyl acetate affords the purified bromohydrin, m.p. .175.0-177.5°C .

Analysis calculated for C6H73r 20itS : Ste C; 3-Carbomethoxy-4~ (3-bromo-2-hydroxypropo>:y) - ' ." Ί' .'2 f'S'-'tb'i¾rl?'^ ο'Ι'© To a solution of 5 ml. (excess) of acetyl chloride in 40 ml. of anhydrous methanol is added 5.66 g. (20 millimoles) of 4- (3-bromo-2-hydroxypropoxy) -1 , 2 , 5-thiadiazole~3-carboxylic acid and the suspension is stirred for eighteen hours at room temperature. The resulting solution is evaporated to dryness to afford a colorless oil whose infrared spectrum is consistent with the proposed structure of 3-carbomethoxy-4- (3-bromo-2-hydroxypropoxy) -1, 2 , 5-thiadiazole which is used without further purification in the following step.

' Step' D; 3-N-tert-butylcarbamoy1-4- (3-tert-butylamino- ■ ■ ■ ■ ■ ■ 2-hydroxypropoxy) -1,2 , 5-thiadiazOle ' · . A mixture of 1.49 g. (5 millimoles) of 3-carbb-methoxy-4- (3-bromo-2-hydroxypropoxy)-l, 2, 5-thiadiazole in 6 ml. (excess) of tert-butyla ine is refluxed for ninety hours. Considerable tertiary butylamine hydrobromide is precipitated by the addition of 100 ml. of diethyl ether. " The salt is collected and the filtrate concentrated to remove diethyl ether and excess tert-butyl mine . The resulting oil is dissolved in chloroform and washed sparingly with water. The chloroform layer is evaporated to give an oil that is dissolved in a mixture of methanol-diethyl ether and treated with a stream of hydrogen chloride until precipitation is complete. The solvent and excess hydrogen chloride ar.e : removed, in vacuo . The residual oil is dissolved in hot ethyl acetate and cooled to give 1.2 g. of crystals. Further recrystallization of the product from ethyl acetate-diethyl ether and then methanol-diethyl ether affords pure 3- -tert-but lcarbamoy1-4- (3-tert-butylamino-2- Analysis calculated for Ci L,H27C1NI(03S: CI, 9.66; N, 15.27; S, 8.74 .

Found: CI, 9.69; N, 15.61; S, 8.75 : EXAMPLE 2.3 " 3-N-isopropylcarbamoyl-4- (3-isopropylamino-2- hydroxypropoxy) -1, 2, 5-thiadiazole ' A mixture of 1.49 g. (5 millimoles) of 3-carbo- methoxy-4- (3-bromo-2-hydroxypropoxy) -1,2, 5-thiadiazole (prepared as described in Example 22, Step B) and 10 ml. of isopropylamine is refluxed and stirred for seven days. The excess isopropylamine is removed in vacuo , and the residue is. dissolved in diethyl ether. The ethereal solution is washed with wate , dried, and evaporated to give 0.4 g. of oil. The oil is dissolved in methanol-diethyl ether and treated with excess hydrogen chloride. Evaporation of the solvent and treatment of the residue with ethyl acetate-methanol-diethyl ether gives 0.4 g. of crystalline product. Recrystallization of the product from. ethyl ' acetate-methanol-diethyl ether gives 3-N-isopropylcarbamoyl- 4- (3-isopropylamino-2-hydroxypropoxy) -1 , 2 , 5-thiadiazole hydrochloride, m.p. 96-99°C.

Analysis calculated for Ci ζΚ2 : ' . ci, 10.46;: N, 16.53; S, 9.46; Found: CI, 10.46; N, 16.11; S, 9.25 The following Examples ;Qlustrate methods for the preparation of products of this invention illustrated by structure I above, wherein R1, R2, R3 and/or R1* are other. than hydrogen: ■ EXAMPLE- 2 A " ' ■ Ste A: Preparation of 3-chloro-4- (3-chloro~2- ' · hydroxybutoxy) _"T, 2 , 5-thiadiazole ' ' _ 3-Chloro-4-hydroxy-l, 2 , 5-thiadiazole is treated with 2-chloroacetic acid in the presence of ethanolic sodium hydroxide to give 3-chloro-4-carboxymethoxy-l,2,5-thiadia-zole. Treatment of this acid with thionyl chloride or oxalyl chloride affords the acid chloride. The acid chloride (1 part) in 20 parts of diethyl ether is treated dropwise at -10° to -15°C. with a slight excess of diazoethane in 30 parts of diethyl ether and the mixture stirred one hour longer at -10°C. The solution is left at room temperature. overnight, cooled to -10° to -15°C. and treated with anhydrous hydrogen chloride until evolution of nitrogen is complete. The solution is successively washed with water, a 5% sodium carbonate solution, and water. The dried solution is . evaporated to a residue to give- 3-chloro-4- (3-chloro-2-oxobutoxy) -1,2, 5-thiadiazole. The crude 3-chloro-4- (3-chloro-2-oxobutoxy) -1,2, 5-thiadiazole (1 part) in 5 parts of isopropanol is treated at 0-5°C. with a solution containing an excess of sodium borohydride in 5 parts of isopropanol. The mixture is left for 3 to 5 hours at room temperature, then poured onto a mixture of ice and acetic acid, the mixture is extracted with ether, and worked up to give 3-chloro-4- '' (3-chloro-2-hydroxybutoxy) -1,2, 5-thiadiazole.

' Step B; Preparation of 3-chloro-4- (3-butylamino-2- ' hydroxybutoxy) -1,2 , 5-thiadiazole hydrochloride A mixture of 1 part of 3-chloro-4- (3-chlpro-2-hydroxybutoxy) -1,2, 5-thiadiazole and 7.5 parts of butylamine. is heated for 10 hours at 100°C. in a .sealed vessel . The product is isolated by the method described in Example 1, Ste B to ive 3-chloro-4- 3-but lamino-2-h drox butox - to give 3-chloro-4- (3-butylamino~2-hydroxybutoxy) -1, 2 , 5-thiadiazole hydrochloride.

Ste C: Preparation of 3-morpholino-4- (3- butylamino-2-hydroxybutoxy) - 1,2 , 5-thiadiazole A mixture of 1 part of 3-chloro-4- (3-butylamino-2-hydroxybutoxy) -1,2,5-thiadiazole hydrochloride in 5 parts of freshly distilled morpholine is heated for four hours . at 135-40°C. The product is isolated by the method described in Example 16 to give 3-morpholino-4- (3-butylamino-2-hydroxybutoxy) -1, 2 , 5-thiadiazole which is converted to its hydrochloride salt.

EXAMPLE 25 3-Morpholino-4- (3-butylamino-2-hydroxy-l- ' ' ' methylpropoxy)-!, 2 5-thiadiazole ■ Step A: Preparation of 3-chloro-4-(3-chloro-2- hydroxy-l-methylpropoxy) - ' 1 ,'2','5-thi'adia'zoTe -Chloro-4- (3-chloro-2-hydroxy-l-methylpropoxy) 1,2,5-thiadiazole is prepared by a sequence of reactions similar to those described in Example 24, Step A. Thus . 3-chloro-4-hydroxy-l , 2 , 5-thiadiazole is condensed with 2-bromopropionic acid to give 3-chloro-4- (1-methylcarboxy-methoxy) -1,2, 5-thiadiazole. The acid is converted by conventional methods to the acid chloride and the acid chloride* treated with diazomethane in diethyl ether at -10° to -15°C. The dried ethereal solution is treated with . anhydrous hydrogen chloride and the resulting chloroketone reduced with sodium borohydride to give 3-chloro-4- (3·^· chloro-2-hydroxy-l-methylpropoxy) -1 , 2 , 5-thiadiazole .

' Step B: Preparation of 3-morpholino-4- (3- butylamino-2-hydro>:y-l- methylpropoxy) -1,2, 5-thiadiazole ' 1 hydroxybutoxy) -1,2, 5-thiadiazole is replaced by ,3-chloro-4- 2 (3-chloro-2-hydroxy-l-methylpropoxy) -1,2, 5-thiadiazolc . Thus 3 3-chloro-4- (3-butylamino-2-hydroxy-l-methylpropoxy) -1,2, 5-. ' 4 thiadiazole is obtained and isolated as the hydrochloride salt. Treatment of either 3-chloro-4- (3-butylamino-2- 6 hydroxy-l-methylpropoxy) -1, 2 , 5-thiadiazole or its hydro- 7 chloride salt with morpholine as described in Example 16 8 gives 3-morpholino-4- (3-butylamino-2-hydroxy-l-methylpropoxy) 9 1, 2 , 5-thiadiazole that is isolated as its hydrochloride 10 salt. 11 .. ' EXAMPLE' 26 12 3-Morpholino-4- (3-butylamino-2-acetoxypropoxy) - 13 ' '■ 1 ,2 , 5-thiadiazole hydrochloride ■ 14 A mixture of 1 part of 3-morpholino-4- (3- 15 butylamino-2-hydroxypropoxy) -1 , 2 , 5-thiadiazole, 5 parts 16 of acetic acid, and 1 part of acetic anhydride is left 17 24 hours at room temperature. The solution is poured on 18 ice, made alkaline with ammonium hydroxide, extracted with 19 ethyl ether, and the ethereal solution dried over anhydrous magnesium sulfate. The ethereal solution is treated with 21 anhydrous hydrogen chloride and the precipitated product 22 is recrystallized from ethanol-diethyl ether to give 23 3-morpholino-4- (3-butylamino-2-acetoxypropoxy) -1,2,5- 24 thiadiazole hydrochloride.

■ EXAMPLE 2 Ί ' 26 3-Morpholino-4- (3-butylaraino-2-benzoyloxypropoxy) - 27 " 1', 2 , 5-thiadiazole 'hydrochloride' ' ' ' ' ' 28 A mixture of 1 part of 3-morpholino-4- (3- 29 butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole hydrochloride and 2.5 parts of benzoyl chloride is heated for 4-6 hours ° the mixture is filtered. The collected product is washed several times with further amounts of diethyl ether. The solid is recrystallized from ethanol-diethyl ether to give 3-niorpholino-4-(3-butylamino-2-benzoyloxypropoxy)-lj , 5- thiadiazole hydrochloride.

The compounds represented by those prepared in Examples 26 and 27, i.e., those in which the 2-hydroxy group of the side chain are esterified are readily converted back saponification to the starting 2-hydroxy compounds by either with dilute alkali or acid, using standard experi- mental conditions.

Example 28 3-Morpholino-4-(3-butylamino-2-hydroxypropoxy)- 1,2, -thiadiazole benzoate A solution of 1 part of 3-morpholino-4- ( 3-butyl- amino-2-hydroxypropoxy)-l,2, 5-thiadiazole in 50 parts of ' ethyl acetate is added to a solution of 1 part of benzoic acid in 40 parts of diethyl ether. The resulting solid is collected on a filter plate and washed several times with diethyl ether. The product is crystallized from · ethanol-diethyl ether to give 3-morpholino-4- (3-butylamino-' 2-hydroxypropoxy)-l,2, 5-thiadiazole benzoate.

Preparation of 3-R-4-hydroxy-l, 2, -thiadiazoles The hovel 3-R-4-hydroxy-l, 2, -thiadiazole start- ing materials in Route I synthesis are made by esterifica- tion of the α-amlnoa.cid, R-CH(NH2)C02H, by reaction with a suitable lower alkanol to produce the ester, R-CH(NH2)C02- Alkyl, which when treated with ammonia is converted to the amide, R-CH(NH2)C0NH2. Reaction of the amide with sulfur monochloride provides the desired 3-R-4-hydroxy-l , 2, - starting materials that are and can be prepared by the procedure described above, employing the α-aminoacid,· R-CH (NH2)C02H, . . · ' ... . ... , . ... * *· ' having the R-group identified in the following Table, which are esterified with methanol (although other lower alkanols can be employed, as ethanol, . propanol, isopropanol and the like) to provide the methyl or other lower alkyl ester, which then is converted by · treatment with ammonia to give the amide. Reaction of the amide with sulfur monochloride provides the 3-R-4-hydroxy-l, 2, 5-thiadiazole (product "A") having the group R attached to the carbon present, at position.3 identified in the Table.

By substituting the thiadiazole products thus obtained in Route I, for example, by replacing the 3-chloro-4-hydroxy-l, 2, 5-thiadiazole of Example 1 by an equivalent quantity of the 3-R-4-hydroxy-l, 2 ,'5-thiadiazole identified in the following Table and using an excess of an amine of the structure HNR5R6 (also identified in the . Table) for the tert-butylamine. used in Step B -of Example 1, but otherwise following substantially the same procedure there described, the thiadiazole products I-b are obtained having the R, R5 and R6 substituents identified in Table III. 1 i Additional products of this inventipn that are pre- ■i1 2 pared by the procedures described in Routes I and II and more 3 particularly illustrated by Examples 1 and 16 are identified 4 in the following table.. The compounds identified in Table IV wherein R is a group having the structure R7R8N- are advan- 6 tageously prepared from the compound * 8 synthesized by the process substantially as described in 9 Example I and then replacing the 3-chloro by the R7RaN- group by reaction with the selected amine by substantially the same 11 procedure" described in Example Ιβ.' The following products 12 are prepared according to Examples 1 and 16 procedures ex- 13 cept that the 3-R- -hydroxy-l, 2 , 5-thiadiazole ■ starting sub-l^ stances, where necessar , can be prepared by the procedure .15· described above for the products disclosed in Table III. 32239/2 - 63 'TABLE IV (Cont'd.) R Rs R& H -CH(C2HB)-CH2-OH 0 II N- H -CH EXAMPLE 9 3-Chloro-ll- ( 3-isopropylamino-2-hydroxy- propoxy)-l, , 5-thiadiazole The acid chloride, 3-chloro-Jl-chlorocarbonylmethoxy 1,2 , 5-thiadiazole, from Example 2 , Step A, is treated with potassium cyanide by the usual. method to give the cyanoketone 3-chloro-4-cyanocarbonylmethoxy-l,2 , 5-thiadiazole. This pro-duct then is hydrogenated in the presence of a catalyst such as palladium on charcoal or reduced with lithium aluminum . hydride to give 3-chloro- - (3-amino-2-hydroxypropoxy)-l,2 , 5- ' thiadiazole. This amine, when reductively alkylated with acetone affords 3-chloro-4- (3-isopropylamino-2-hydroxypro-poxy) -1,2 , 5-thiadiazole.

By replacing the cyanoketone and the acetone re-" actants employed in Example 29 by the 'products identified in the following table, other 3-R-4- {3- [ (CHYZ)NH]-2-hydroxy-propoxyj-l,2 , 5-thiadiazole compounds are obtained wherein the groupings R, X, Y and Z are those given.

R 1 Example 30 2 -3-~( 3-Amlno-2-hydroxypropoxy)- -morphollno-l,2, 5-thiadiazole 3 Ά solution of 5.0 g'. of ' 3-hydroxy-4-morpholino- · 4 1,2,5-thiadlazole (26.7 mmole) In 18.95 ml: of 1.41 N methanolic sodium methoxide is treated with 10.5 ml. of epi- 5 chlorohydrin (134 mmole) and the mixture is stirred at 25°C. γ for 16 hours. The precipitated .sodium chloride is filtered 8 and washed with methanol. The filtrate is evaporated in' 9 vacuo to an oil residue. The- oil is taken up in 0 mis. of methanol and .treated with 5 ml- o concentrated ammonium 11 hydroxide solution. After ' standing for 48 hours , the .solu- 12 . tion was concentrated to dryness. · 13 ' Example 31 1 3- ( 3-t-Butylamino-2-hydroxypropox ) -4-morpholino-l ; 2 , 5-thla- 15 dia?,ole * 16 A solution of 260 g. (1 mole) of 3-(3-amino-2- ' 17 hydroxypropoxy) -4-morpholino-l , 2 , 5-thiadiazole from Example 18 30 in dioxane is treated, slowly with (0.4- mole) .Of t-butyl 19 chloride at 50-60°C. under vigorous stirring-.- A. solution -.of 23 g. (0.4 mole) of potassium hydroxide in 20-25 ml. water 21 is then added, and the precipitated salt 'is removed · by fil- 22 tratlon. The filtrate is concentrated to dryness and the 23 product is 24 butylamino '25 ■ ■26 ing for th 27 . (1) 28 (2) 29 (3) there is p whereupon it is made basic by the addition of sodium hydroxide. The reaction mixture then is extracted with, ether,' the excess amine is removed from the ethereal solution under reduced pressure and the ether then removed by evaporation to give 3-tert-butylamino-2-oxopropanol .

By replacing the tert-butylamine employed in Step A by an equivalent quantity of isopropylamine , 2 , 2-dimethylprop-ylamine and 1 , l-dimethyl-2-hydroxyethylamine there is obtained, respectively, 3-isopropylamino-2-oxopropanol , . 3- (2 , 2-dimethylpropylamino) -2-oxopr.opanol , and 3- (1 , l-dimethyl-2-hydroxyethylamino) -2-oxopropanol .

Step B: A solution of the 3-tert-butylamino-2-oxopropanol in a mixture of pyridine hydrochloride and pyridine is treated with p-toluenesulfonylchloride. The mixture is stirred for one-half hour at 25-30° C. and then poured into cold water. The solution is treated with potassium carbonate and the pyridine evaporated in vacuo at a temperature between 55-60° C. The aqueous residue is treated with potassium carbonate and the mixture extracted with methylene chloride. Evaporation of the dried extract provides l-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane .

By replacing the 3-terjt-butylamino-2-oxopropanol and the p-toluenesulfonyl chloride employed in the preceeding step by the following reaction pairs: 1) 3-isopropylamino-2-oxopropanoi and benzene^lfonyl chloride, '■■<: .2) 3- (2, 2-dimethylpropylamino) -2r:ox0propanpl and methylsulfonyl chloride or other lower alkylsulfonyl chloride, and 3) 3- (1, l-dimethyl-2-hydroxyethylamino) -2-oxopropanol nd -ch ) 1) . i-benzenesulfonyloxy-2-oxo-3-isopropylaminopropane ,· 2) l-methylsulfonyloxy-2-oxo-3- (2 ,2-dimethylprjylamino) propane or other lower alkylsulfonyloxy derivatives, and 3) 1- (p-chlorophenylsulfonyloxy) -2-OXO-3- (1,1-dimethyl- ' 2-hydroxyethylamino) propane .

Any other sulfonyl halide, particularly (though not necessarily) any of the commercially available sulfonyl halides identified hereinabove can be employed with equal success if substituted in the process illustrated in Step Β· of this ex.r-ample for reaction with any desired 3-amino (or substituted amino) -2-oxopropanol to provide the sulfonyloxy derivative . thereof which upon reaction with the appropriate 3-R-4-hydroxyl-1 , 2 , 5-thiadiazole according to Step D of this example provides the desired 3-R-4- (3-amino or substituted amino-2-oxopropoxy) -1 , 2 5-thiadiazole . These compounds , in turn , , are reduced by the methods of Example 1-3 to the corresponding 2-hydroxypropoxy products.

Step C: Preparation of 3-morpholino-4-hydroxyl-l , 2 , 5-thia-— diazole ' ' 3 , 4-Dichloro-l , 2 , 5-thiadiazoie (0.6 mole) is added dropwise over a 30-minute period at 105-110° C. to morpholine (2.6 ole). After the addition, the mixture is stirred two hours at 105-110° C. , then cooled to 15° ,C. and quenched with . water (250 ml.) . This mixture then is made acidic with concentrated hydrochloric apid (250 ml.) whereupon an insoluble oil soon crystallizes to a heavy solid mass. After crystallization is complete the solid is filtered and washed with water and then dried at 35° C. in vacuo giving a 95% yield ! By replacing morpholine in the above reaction with 2 an equivalent quantity of N-methylpiperazine , piperidine and 3 4-hydroxypiperidine , and then following substantially the 4 same method there is obtained, respectively, 1) 3- (4-methylpiperaziny 1) -4-chloro-l , 2 , 5-thiadiazole , 6 2) 3-piperidyl-4-chlorb-l, 2, 5-thiadiazole, and 7 3) 3- (4-hydroxypiperid^?-4-chloro-l , 2 , 5-thiadiazble .· 8 The 3-morpholino-4-chloro-l , 2 , 5-thiadiazole (125 g.) 9 is added to 2.5N sodium hydroxide (1 liter) in dimethyl sulfoxide (100 ml.). The mixture is refluxed with stirring. 11 for about 3 hours and the solution then is cooled to .15° C. 12 and made acidic with concentrated hydrochloric acid (250 ml.). 13 The precipitated material is removed by filtration at 15° C. 14 and slurried well with water. The solid material then : is : ' dried to constant weight thus providing 108 g. of 3-morpholino- 16 4-hydroxy-l, 2, 5-thiadiazole, m. p. 198-200° C. (dec.).. 17 By replacing the 3-morpholino-4-chloro-l , 2 , 5- 18 thiadiazole employed in the above reaction by ,19 1) 3- (4-methylpiperazinyl) -4-chloro-l, 2, 5-thiadiazole, 2) 3-piperidyl-4-chloro-l ,2 , 5-thiadiazole, and ino 21 3) 3- (4-hydroxypiperid ^H-chloro-l, 2 , 5-thiadiazole 22 and following substantially the same procedure described above 23 there is obtained the corresponding refluxed for 16 hours. The solvent is evaporated in vacuo and the residue is treated with excess potassium carbonate to provide 3-morpholino-4- (3-tert-butylamino-2-oxopropoxy) - 1 , 2 , 5-thiadiazole .

EXAMPLE 32 CHEMICAL REDUCTION Preparation of 3-morpholino-4- (3-tert-butylamino- 2-hydroxypropoxy) -1,2 , 5-thiadiazole The 3-morpholino-4- (3-tert-butylamino-2-oxopropoxy) - 1 , 2 , 5-thiadiazole (0.01 mole) is dissolved in isopropanol (10 ml.). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to cyrstallization. The solid material is removed by filtration and dried thus. providing 3-morpholino-4- (3-te_r_t-butylamino-2-hydroxyproppxy) - 1,2 , 5-thiadiazole, m.p. 161-163° C. (as hydrochloride) .' EXAMPLE 33 3-Morpholino-4- ( 3-tert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole Hydrochloride Equimolecular quantities of aluminum isopropoxide · ' and 3-morpholino-4- (3-tert-butylamino-2-oxopropoxy) -1,2,5- thiadiazole in dry isopropyl alcohol are refluxed'on a steam bath for about one hour with simultaneous removal of acetone. when the distillate gives a negative test for acetone, the reaction mixture is cooled and hydrolyzed with dilute hydro- chloric acid and the reci itated 3-mor holino-4- 3-tert- 1 The isopropanol solvent employed in the above ex- 2 amples can be replaced by other alkanols or other polar organi .3 solvents of the type hereinbefore described. ; · 4 Similarly the product of Example 33 can be' prepared by replacing the aluminum isopropoxide by other aluminum al- 6 koxides. . 7 By replacing the l-toluenesulfonyloxy-2-oxo-3-tert- 8 butylaminpropane and the 3-morpholino-4-hydroxy-l ,2 , 5-thia- ·' 9 diazole employed i Preparation 1, Step D, by equivalent quantities of the following reaction pairs: 11 , 1) l-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane 12 and 3-chloro-4-hydroxy-l , 2 , 5-thiadiazole , 13 2) 1-benzenesulfonyloxy-2-oxo-3-isopropylaminopropane 14 and 3-chloro-4-hydroxy-l , 2 , 5-thiadiazole , 3) 1-benzenesulfonyloxy-2-oxo-3-isopropylaminopropane 16 . and 3-ethyl-4-hydroxy-l , 2 , 5-thiadiazole , 17'/;. 4) 1-toluenesulfonyloxy-2-oxo- 3-tert-butylaittinopropane 18 and 3-ethyl-4-hydroxy-l ,2 , 5-thiadiazole , 19 5) 1- (p-chlorophenylsulfonyloxy) -2-ΟΧΟ-3- (1 , 1-dimethyl- 20 2-hydroxyethylamino) propane and 3-ethyl-4-hydroxy- 21 1 , 2 , 5-thiadiazole , 22 6) l-benzenesulfonyloxy-2-oxo-3-isopropylaminopropane 23 ■ and 3-ethoxy-4-hydroxy-l , 2 , 5-thiadiazole , 24 7) 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropahe , , and 3-ethoxy-4-hydroxy-l , 2 , 5-thiadiazole , 26 8) l-methylsuifonyloxy-2-oxo-3- (2 , 2-dimethylp'ropylamino) 27 propane or other lower alkylsulfonyloxy derivatives 28 ' and 3-ethoxy-4-hydroxy-l , 2 , 5-thiadiazole , 29 9)-. 1-benzenesulfonyloxy-2-oxo-3-isopropylaminopropane and 3-phenyl-4-hydroxy-l , 2 , 5-thiadiazole , '31'.' 10) l-toluenesulfonyloxy-2-oxo-3-tert-butylaminopr pane · 32 and 3-phenyl-4-hydroxy-l , 2 , 5-thiadiazole , . and 33 11) 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane 34 and 3-benzyl-4-hydroxy-l , 2 , 5-thiadiazole , and following substantially the same procedures described in 36 Step D of Preparation 1, followed by the process described in . l) 3-chloro-4- ( 3-tert-butylamino-2-hydroxypr0p6xy) - . 1,2, 5-thiadiazole, m.p. 78-79°. C. , 2) 3-chloro-4- (3-isopropylamino-2-hydroxypropoxy) - ■ 1,2, 5-thiadiazole, m.p. 153-5° C. (as HC1) , , . 3) 3-ethyl-4- (3-isopropylamino-2-hydroxypropoxy) -1 , 2', 5- thiadiazole, m.p. 144.5-145.5 (as HC1) , . 4) 3-ethyl-4- ( 3-tert-butylamino-2-hydroxypropoxy) -1,2,5- thiadiazole, m.p. 137-138° C. (as HC1) , . . 5) 3-ethyl-4-[3-(l,l-dimethyl-2-hydroxyethylamino)-'2- hydroxypropoxy] -1 , 2 , 5-thiadiazole ,m.p. 127-5 (as HC1) , 6). 3-ethoxy-4- (3-isopropylamino-2-hydroxypropoxy) - 1,2, 5-thiadiazole, m.p. 167-70 (as HC1) , ' ' 7) 3-ethoxy-4- ( 3-tejrt-butylamino-2-hydroxypropoxy) - 1,2, 5-thiadiazole, m.p. 147-9 (as HC1) , 8) 3-ethoxy-4- [3- (2 ,2-dimethylpropylamino) -2-hydroxy- . propoxy] -1,2, 5-thiadiazole, m.p. 168-9 (as HCl) , . 9) 3-phenyl-4- (3-isopropylamino-2-hydroxypropoxy) -' ·, 1,2, 5-thiadiazole, m.p. 165-7 (as HC1) , ) 3-phenyl-4- (3-tert-butylamino-2-hydroxypropoxy) - ' 1,2, 5-thiadiazole, m.p. 168-170.5° c. (as HCl) , and ' 11) 3-benzyl-4- (3-tert-butylamino-2-hydroxypropoxy) - 1,2, 5-thiadiazole, m.p. 122-3° C. (as HCl) :.

EXAMPLE 3 '..;',..···,.', Reduction with a reductase '..:·· Sucrose (1 kg.) is dissolved in water (9 liters) in · a 20-liter bottle equipped with a gas trap. Baker's yeast (Saccharomyces Cerevisiae , 1kg.) is made into a paste with water ( 1 liter) and . added to the sucrose solution with stirring. After lively evolution of gas begins (within one to three hours),. 3-morpholino-4- (3-tert-butylamino-2-ox0-propoxy) -1,2, 5-thiadiazole hydrogen maleate [1.35 mole> pre- ■ pared by reaction of the 3-morpholino-4- (3-tert-butylamino-2-oxopropoxy) -1 ,2 , 5-thiadiazole with an equimolecular quantity of maleic acid in tetrahydrofuran] . ■ The mixture is. allowed. (in approximately 1-3 days) . The yeast is filtered off with : addition of diatomaceous earth, and the filtrate is evaporated: to dryness to give S-3-morpholino- -0-tert-butylamino-2-hydroxy- propoxy) -1 , 2 , 5-thiadiazole , m.p. 195-198° C. (as hydrogen maleate) .

The addition of 3-morpholino-4- ( 3-tert-butylamino- 2-oxopropoxy) -1 ,2 , 5-thiadiazole hydrogen maleate or other' salt to the growth medium containing any one of the bacterial'; '"■ actinomycetales or fungal reductase identified above produces the same optically active product obtained in Example 34.

By replacing the thiadiazole employed in Example 34 ·... by ' an equivalent quantit of a salt, conveniently the hydrogen 'maleate salt of : 1) 3-chloro-4- ( 3-_tert-butylamino-2-oxopropoxy) -1 , 2 , 5- · - .thiadiazole, 2) 3-chloro-4- (3-isopropylamino) -2-oxopropoxy) -1,2,5-. thiadiazole, 3) .3-ethyl-4- (3-isopropylamino-2-oxopropoxy) -1 , 2 , 5- thiadiazole, ' 4)' 3-ethyl-4- (3-tert-butylamino-2-oxopropoxy) -1,2,5- . . thiadiazole, . 5) 3-ethyl-4- [3- (1 , l-dimethyl-2-hydroxyethylamino) -2-.;' . oxopropoxy] -1,2, 5-thiadiazole, 6) 3-ethoxy-4- (3-isopropylamino-2-ox0propoxy) -1 ,2 , 5- · thiadiazole, 7) 3-ethoxy-4- (3-tert-butylamino-2-oxopropoxy) -1,2 , 5- thiadiazole, 8) 3-ethoxy-4- [3- (2 , 2-dimethylpropylamino) -2-oxopro- poxy] -1 ,2 , 5-thiadiazole , . . 9) 3-phenyl-4- (3-isopropylamino-2-oxopropoxy ) -1 , 2 , 5- thiadiazole, - · -. .. . :. . ' ) 3-phenyi-4- ( 3-tert-butylamino-2-oxopropoxy) -1,2,5- thiadiazole , ·"■ .<·. '■■> ' 11) 3-benzyl-4- (3-tert-butylamino-2-oxopropoxy-l , 2 , 5- thiadiazole, · . . . and following substantially the same procedure described in addition "of the 2-oxo 'compounds 1. to 11 above after. good ' growth is: observed and 'the continuation of the · incubation .. .,■· at about 28° C. for an additional 1-3 days ;' there is obtained .. the corresponding 2-hydroxypropoxy derivatives of compounds 1 through 11 above in the sinister configuration., '■. ^ . Preparation of S-3-R-4- [3- (B^-amino) -2-hydroxypro- t ,! poxy] -1 ,2 , 5-thiadiazole via 3-R-4-chloro-l , 2 , 5- . thiadiazole ■ ■ . ' . ■ ·' ■' - <·...

EXAMPLE 55, , - Step A; Preparation of S (-) -glycolamine ..

- ■, . A mixture of tert-butylamine (37.44 g. ;"0.513 mole) , methanol (150 fml . )·' arid 5%' palladium-on-carboh (1.0 g. ) is ' shaken in a hydrogenatibn bomb under three atmospheres ■ hydrogen pressure. A solution of D-glyceraldehyde (15 g.) in methanol (60 ml.) is added over a one hour period during hydrogenation. After the addition, the mixture is .shaken fbr an additional 15 hours. The catalyst is removed by filtration and the solvent evaporated in vacuo yielding S (-) -1 , 2-dihydroxy-3-tert-butylaminopropane [S.(-) -glyco.lamine] in the form of an oil which is crystallized by trituration, with ether to give 11.0 g. (45%) yield of product, m.p. 80-82° C.■ .[o] -30.1 (IN aqueous HCl) .

By replacing the tert-butylamine employed. in Step A by an equivalent quantity of isopropylamine , 2 , 2-dimethyl--, propylamine, and 1 , l-dimethyl-2-hydroxyethylamine arid following substantially the same procedure described i Step A, there is obtained, respectively, ;·· S-l , 2-dihydroxy-3-isopropylaminopropane , S-l,2-dihydroxy-3- (2 , 2-dimethylpropylamino) propane, and S-l,2-dihydroxy-3- (i,l-dimethyl-2-hydroxyethyl-. ;/· .... . amino ro ane . ··.. - \ S (-) -glycolamine also can be 'prepared by the following method: ' ' · ·. ·· . - ··', ·"' ' ·*'·*··'.

Preparation of S(-) -glycolamine from iso- propylidene-D-glyceraldehyde Isopropylidene-D-glyceraldehyde (0.276' mole) in 35 ml. of cold tetrahydrofuran is added, with ice bath cpol- ing over a one-hour' period during hydrogenatioh to a mix- ture of tert-butylamine (103 ml.), methanol (103 ml.) and', 5%. palladium-on-carbon (7.2 g.) in an hydrogenation apparatus under 3 atmospheres hydrogen pressure.. The mixture is hy- drogenated at ambient temperature until the absorption of hydrogen ceases. The catalyst then is removed by filtration ' and washed with methanol (52 "ml.) and the combined filtrates' treated with 6N hydrochloric acid (350 ml.) with cooling.' The mixture then is distilled until a vapor temperature of. 98° ± 1° C. is reached and then refluxed one hour. The ' · solution then is cooled to 0° C. and treated with sodium hyr droxide pellets (140 g.) keeping the temperature under 35 °C, Thereafter the mixture : is treated, with water (140. ml.) and . extracted with four 175 ml. portions of methylene chloride. The combined extracts are dried over magnesium sulfate and evaporated to a thick crystalline slurry which is flushed twice with ether^ (50 ml.) and filtered at 0-5°. C. After drying at 35° C. in vacuo there is obtained 28.5 g. ' (70%) ■ of S (-).-glycolamine.

· Another method by which S (-) -glycolamine can be prepared will be described in Example 0. "" .';;·.'; -:' -M- · Step_jB:' Preparation of 3-morphoiino-4-chloro-l ,2■ 5-" thiadiazole ..-·"' ' The procedure described under "Preparation 1" Step C on pages 76 and 77 is followed. ..' Step C: Preparation of S (-) -3-morpholino-4- (3-tert-butyl- ' amino-2-hydroxypropoxy ) -1 , 2 , 5-thiadiazole and its hydrogen maleate salt . * A mixture of 3-morpholino-4-chloro-l , 2 , 5-thiadiazole (20.57 g. ) . and S (-) -glycolamine (14.72 g.) in anhydrous tert-butanol (50 ml.) is heated to reflux under a nitrogen atmosphere. A solution of potassium tert-butoxide in tert-butanol (100 ml. of lM solution or equivalent) is added in 10. ml. portions and the mixture refluxed 10 minutes between additions After the last addition the mixture is refluxed an additional 10 minutes, then cooled to 60° C. , and treated with 6N hydrochloric acid (50 ml.) in a. thin stream while maintaining good cooling. An additional 50 ml. of water is added and the tert-butanol is evaporated in vacuo leaving an' oil-water residue. This \residue is extracted with one.50 ml . portion and one 20 ml. portion of methylene chloride and the combined organic layers are backwashed with two 50 ml. portions of 4 hydrochloric acid. The combined acid layers are made .alkaline with excess potassium carbonate (approximately 80 g.) and extracted with two 50 ml. portions of. ether. The combined. ether layers are washed with two 20 ml. portions of water, dried over magnesium sulfate and evaporated in vacuo to give' 13.7 g. of S (-) -3-morpholino-4- (3-tert-butylamino-2-hydroxy-· propoxy)-l,2,5-thiadiazole in the form of an oil. ." ·' . This oil . is dissolved, in 50 ml . of tetrahydrofuran, treated with charcoal (1.5 g.), filtered, and the cake washed with 20 ml. of tetrahydrofuran. To this solution is added maleic acid [5.0 g. ; 1 mole' equivalent per mole of S(-)-3- morpholino-4- ( 3-tert-butylamino-2-hydroxypropoxy)-l , 2 , 5-thia- diazole] dissolved in tetrahydrofuran (25 ml .) .. ' The mixture ' then is seeded and aged one hour at 25° C. The crystallized hydrogen maleate salt is separated by filtration, washed with tetrahydrofuran and dried at 50° C. in vacuo to give 7.3 g.' of S (-) -3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy ) - 1,2,5-thiadiazole hydrogen maleate, m.p. 195-198° C, (sample inserted at 190° C. and heated at rate of 3°/min.). [ct] i+05 -12° [C =» 4, IN HC1] , equivalent weight 429-431 (titrated with base), calculated 432. ' . - By replacing the maleic acid employed in the above. procedure by hydrochloric acid, sulfuric acid, tartaric' acid or any other desired acid the corresponding acid salt is formed. When sulfuric acid is employed in the ratio of 1 mole of acid to 2 moles of thiadiazole the sulfate salt of S (-) -3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) - — Step B: Preparation of S (-) -3-morpholino-4- (3-tert-butyl- . amino-2-hydroxypropoxy)-i, 2, 5-thiadiazole and its hydrogen maleate salt ■ A mixture of 3-morpholino-4-chloro-l, 2, 5-thiadiazole (2.05 g.; 10 mmole) , S-3-tert-butyl-5-hydroxymethyloxazolidine (10 mmole) and potassium tert-butoxide in tert-butariol . (11.7 ml. of 0.885 N, lO mmple) is stirred at 25° C. for 16 hours. The solvent then is evaporated in vacuo and the resi- due treated with 20 ml. of IN hydrochloric acid.. The mixture is heated at 65° C. for one-half hour, cooled to 25° C. and extracted with ether. The aqueous layer is made alkaline "·■* with potassium carbonate and extracted with ether.' The ex-' tracts are washed with water, dried and evaporated to. an oily residue of S (-) -3-morpholino-4- (3-tert-butylamino-2- hydroxyprqpoxy) 1,2, 5-thiadiazole. This oil in 10 ml. of tetrahydrofuran is converted to the crystalline hydrogen , maleate salt by treatment with an equivalent amount of maleic acid by the procedure described in Example35- / · Step By to . ' i provide a 30% yield of S (-) -3-morpholino-4- (3-tert-butylamino- 2-hydroxypropoxy)-l, 2, 5-thiadiazole hydrogen maleate.

EXAMPLE 37 ' . ' ·.,· .' :'ν..·:, ,..■· ' Step A; .. Preparation of S-2-isopropyl-3-tert-butyl-5- ■. hydroxymethyloxazolidine . ■ ' .

· A mixture S (-) -glycolamine (10 g.; 68 mmole): in . freshly distilled isobutyraldehyde (50 ml.) is heated under ' reflux with continuous removal of water for 2 hours . The solvent then is removed in vacuo and the oily .residue dis- tilled. A forerun of 0.85 g. of material with b.p. 70-75°C.. . (0;1 mm. pressure) is obtained which is 98% pure S-2-isbpropyl- 3-tert-butyl-5-hydroxymethyloxazolidine when analyzed by vapor pressure chromotography (vpc) . 0.031 mole) in anhydrous methanol (75 ml . ) is prepared and cooled to 0-5° C. This solution is stirred while adding lead tetraacetate (13.7 g. 0,031 mole) and while maintaining the temperature at about 10° C. After the oxidant has been added, the mixture is aged 1 hour at 10° C. whereupon it was found by testing with starch-iodide paper that the oxidant had been completely consumed. The reaction mixture then' is cooled to 0° C. and tetramethylammonium chloride (7.2 g. ; 0.066 mole) is added. The reaction mixture is aged an addi- tional hour at 0-5° C. and then filtered cold. The filter cake is washed with two 10 ml. portions of precooled anhydrous methanol, the filtrates combined and added dropwise to a mixture of tert-butylamine (11.3 g.; 0.155 mole), in anhydrous ., methanol (12. ml.) while hydrogenating at an initial pressure of 40 p.s.i. over palladiup-onTcarbon (1.2 g. of 5%). The addition rate is such that about 1 hour is required for the addition. The reduction is continued until 1 hour after hydrogen uptake ceases (generally 6-10 hours in all) . The r (72.5% yield) of S (-) -3-morpholino-4- (3-tert-butylamino) -2- ,, , hydroxypropoxy)-l,2,5-thiadiazole. This is converted, to its: hydrogen maleate salt by treatment with maleic acid . (0.85 g.; 0.0073 mole) in tetrahydrofur n (3 ml.) by substantially the same procedure described in Example 36, Step B, to give 2.14 g. (49.5%) of S (-) -3-morpholino-4- (3-tert-butylamino) -2- ' hydroxypropoxy)-!, 2, 5-thiadiazole hydrogen maleate;.

EXAMPLE 40.

. A solution of 2.5 g., (0.0059 mole) . S-bisamine maleate (or the free base thereof), prepared as described in Example 39, Step A, in 15 ml. 4. ON hydrochloric acid is. re- ' . . . fluxed for 1-1/2 hours. The clear solution is cooled to 0° C. and made basic with concentrated ammonia water, followed by 8 g. sodium hydroxide. This solution is then' extracted with five 25 ml. portions of methylene chloride and the ex- . tracts dried over magnesium sulfate and concentrated in vacuo to a residue of 1.47 g. (85%) of colorless S (-) -glycolamine , ■ m.p. 81.5-83° C.

EXAMPLE 41. - · Step A: Preparation of S (-) -glycolamine-l-toluenesulfonate , Λ solution of S(-) -glycolamine (4.0 g.), prepared as described in Example 3:5, . Step . A, and pyridine hydrochloride (3.14 g.) in pyridine (8 ml.) is treated with p-toluenesUl- fonyl chloride (5.31 g.) . The mixture is stirred for .one- half hour at 25-30° C. and then poured into 50 ml. of cold · water. The solution is treated with potassium carbonate potassium carbonate ( 4. 5 g.) .and the mixture extracted with methylene chloride (50 ml.). Evaporation of .the dried ex- '■·'.· tract provides 6.2 g. ( 75% yield) of S (-) -glycolamine*-!-toluenesulfonate [S (-) -l-tbluenesulfonyloxy-2-hydroxy-3;-tert-butylaminopropahe] , m.p. 91-93° C.

By replacing the S (-) -glycolamine and the p-tolu- ' enesulfonyl chloride by equivalent quantities of-the following reaction pairs : - 1 ) S-1 , 2-dihydroxy-3-isopropylaminopropane and ■ benzenesulfonyl chloride, 2 ) S-1 , 2-dihydroxy-3- (2 , 2-dimethylpropylaminp).- . ' ".' propane and methylsulfonyl chloride and/or . ' ·, other lower alkylsulfonyl chloride, . ' 3 ) S-i , 2-dihydroxy- 3- ( 1 , l dimethyl-2-hydroxyethyl- ·■■' amino) propane and p-chlorophenylsulfonyl chloride, ■ there is obtained respectively, .,, S-l-benzenesulfonyioxy-2-hydroxy-r3-isopropylamino- . propane, ■ . ·. . 2 ) S-l-:methylsulfonyloxy-2-hydroxy-3- (2 , 2-dimethyl- propylamino) propane or other lower alkylsulfonyl- . oxy derivative, and 3 ) S-1- (p-chlorophenylsulfonyloxy) -2-hydroxy-3- (1 , l-dimethyl-2-hydroxyethylamino) propane. · ; Any other sulfonyl halide, particularly (though not necessarily) any of the commercially available sulfonyl halides identified hereinabove can be employed with equal' success if substituted in the process illustrated in Step A of this Example for reaction with any desired S-1 , 2-dihydroxy' 3-amino(or substituted amino) propane, or S-5-hydroxymethyl-oxazolidirie to provide the sulfonyloxy deriyatiyes thereo which upon reaction with the. appropriate 1,2, S-tliiadiazple according to Step C of this Example. or Step B of Example 5 v gives product S-III..

Step -B: Preparation of 3-morpholino-4-hydroxy-l , 2 , 5-thiadiazole · '■ .. „ '■' ■ . ., · "' ·' ■·■·.

The procedure , of "Preparation 1" Step C on page 77 s followed . · f Step C; Preparation of S (-) -3-morpholino-4- (3-^tert-butyl- amino-2-hydroxypropoxy)-l , 2 , 5-thiadiazole S (-) -glycolamine-l-tolu.enesulfonate (3.45 g.; 11.45 mmole) is added to 0.805N methanolic sodium methoxide (15 ml. at 0° C. The mixture is stirred for 15 minutes, at 0-5° . C. , treated with 3-morpholinp-4-hydroxy-l , 2, 5-thiadia'zoie! (4.29 g and then refluxed for 16; hours. The solvent is evaporated in vacuo and the residue treated with excess potassium carbonate. The insoluble oil is extracted with ether, the. ether extracts dried and evaporated to provide S (-) -3-morpholino- 4- (3-tert-butylamino-2-hydroxyprop xy>-l, 2, 5-thiadiazole in ■'· % yield.

By replacing the S (-) -glycolamine-l-toluenesulfori-ate and. the 3-morpholino-4-hydroxy-l, 2 , 5-thiadiazole employed in Step C by equivalent quantities of the following reaction pairs: · ' ' .. ' ·' ■'' '.'·''.'··■ ■'' ; 1) S (-) -glycolamine-l-toluenesulfonate and 3-chloro- 4-hydroxy-l, 2, 5-thiadiazole or its. alkali metal 'salt, · I .. . 2) S-l-benzenesul roxy-3-isopr0pylamino- propane and 3- xy-l, 2, 5-thiadiazole or its alkali met 3) S-l-benzenesulfonyloxy-2-hydroxy-3-isopropylamino- . propane and 3-ethyl-4-hydroxy-l , 2 , 5-thiadiazole or. its alkali metal salt, 4) S(-) -glycolamine-l-toluenesulfonate and 3-ethyl-4- hydroxy-1 , 2 , 5-thiadiazole or its alkali metal salt, . · 5) S-l- (p-chlorophenylsulfonyloxy) -2-hydrpxy-3- (1 ,1- dimethyl-2-hydroxyethylamino) ropane and 3-ethyl-4- hydroxy-1 , 2, 5-thiadiazole or its alkali metal salt, . 6) S-l-benzenesulfonyloxy-2-hydroxy-3-isopropylamino- propane and 3-ethoxy-4-hydroxy-l , 2 , 5-thiadiazole or its alkali metal salt, 7) S(-) -glycolamine-l-toluenesulfonate and 3-ethoxy-4- hydroxy-1, 2, 5-^thiadiazole or its alkali metal salt , . 8)· S-l-methylsulfonyloxy-2-hydroxy-3- (2 ,2-dimethylpropyl amino) propane or other lower alkylsulfonyloxy deriva- " tive and 3-ethoxy-4-hydroxy-l , 2 , 5-thiadiazole .or its alkali metal salt, 9) S-l-benzenesulfonyloxy-2-hydroxy-3-isopropylamino- ' propane and 3-phenyl-4-hydroxy-l , 2 , 5-thiadiazole or "· its alkali metal salt, '"' .10) S (-) -glycolamine-l-toluenesulfonate and 3-phenyl-4- ' ' hydroxy-1, 2, 5-thiadiazole or its alkali metal salt, 11) S (-) -glycolamine-l-toluenesulfonate and ,3-berizyl-4- hydrpxy-1, 2, 5-thiadiazole or its alkali metal salt, and following substantially the same procedure described in. Step C of Example 41, there is obtained respectively,. 1) S-3-chloro-4- (3-tert-butylamino-2-hydroxypropoxy) 1,2, 5-thiadiazole, '■ "^ - - '. S ':; - 2) S-3-chloro-4- (3-isoprppylamino-2-hydroxypropoxy) - 1 , 2 , 5-thiadiazole , 3) S-3-ethyl-4- (3-isopropylamino-2-hydroxypropoxy ) - . 1 , 2 , 5-thiadiazole , 4). S-3-ethyl-4- (3-tert-butylamino-2-hydroxypropbxy) - 1,2, 5-thiadiazole , ) . S-3-ethyl-4- [3- (1 , l-dimethyl-2-hydroxyethylamiho) 2-hydrpxypropox ] -1 , 2 , 5-thiadiazole , 6) S-3-ethoxy-4- ( 3-isopropylamino-2-hydroxypropoxy) - 1 , 2 , 5-thiadiazole , 7) S-3-ethoxy-4- ( 3-tert-butylamino-2-hydroxy ropoxy) 1 , 2 , 5-thiadiazole , - - S-2, 3-epoxy-l- (2, 2-dimethylpropylamino) ropane D-10-camphorsulfonate salt, and S-2 , 3-epoxy-1- (1 , 1-dimethy1-2-hydroxyethylamino) - propane D-10-camphorsulfonate salt.

Other inorganic or organic salts of these epoxide can be prepared by replacing the D-10-camphor sulfonic acid by any desired acid such as hydrochloric, sulfuric, maleic, tartaric or other selected acid,- and those as well as other salts can be employed in the following step to prepare the . S (-)-3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy) - 1,2, 4-thiadiazole.

Ste B; Preparation of S (-) -3-morpholino.-4- (3-tert-butylamino- 2-hydroxypropoxy) -1,2, 5-thiadiazole and its hydrogen . maleate salt To a mixture of the sodium salt of 3-morpholinp-4- hydroxy-1, 2 , 5-thiadiazole (0.52 g.; 0.0025 mole), prepared , by treating 3-morpholino-4-hydroxy-l, 2 , 5-thiadiazole with methanolic sodium hydroxide) and 3-morpholino-4-hydroxy- 1, 2, 5-thiadiazole (0.47 g..; 0.0025 mole) in anhydrous di- ; methyl sulfoxide (2 ml. ) there is added S (-) -2 , 3-epoxy-l- tert-butylaminopropane D-10-camphor sulfonate (0.92 g.; ■ 0.0025 mole). The mixture is stirred at room temperature for about 4 days and then quenched on 35 ml.- of ice 'water.: The solution then is brought to ca. pH 9 with sodium carbonate and extracted with three 40 ml. portions of methylene chloride. The methylene chloride extracts then are back- extracted with distilled water (20 ml.). After magnesium . sulfate drying and evaporation in vacuo there is obtained , 0.47 g. (60% yield) of S (-) -3-morpholiho-4- ( -tert-but l- amino-2-hydroxypropoxy ) 1, 2 , 5-thiadiazo].e . This product is taken up in tetranydrofuran (8 ml.) and added to a solution of maleic acid (0.28 g.; 0.0025 mole) in tetrahydrofuran 0.63 g. (58.5%) of S (-) -3-morpholino-4- (3-tert-butylamino-2- hydroxypropoxy) -1,2, 5-thiadiazole hydrogen maleate.

By replacing the S (-) -2 , 3-epoxy-l -tert-butylamino-. propane D-10-camphorsulfonate salt employed in Step iB. by the same molecular amount of S (-) -2 , 3-epoxy^l -tert-buty lamino propane and following the same procedure there described, there is obtained an equivalent yield of S (- ) -3-morpholino-- 4- (3-tert-butylamino-2-hydroxypropoxy ) -1, 2 , 5-thiadiazole . , · Other S-3-morpholino-4- (3-substituted amino-2- hydroxypropoxy ) -1, 2 , 5-thiadiazoles and their hydrogen maleate salt are obtained when the S (-) -2 , 3-epoxy-l -tert- butylaminopropane D-10-camphorsulfonate salt is replaced ,. in the above procedure by an equivalent quantity of one or '. another of the following reactants: 1) S-2, 3-epoxy-l -isopropylaminopropane D-10-camphor- sulfonate salt 2). S-2, 3-epoxy-l- (2, 2-dimethylpropylamino)propane D-10-camphor , and 3) S-2, 3-epoxy-l- (1, l-dimethyl-2-hydroxyethylamino) - . propane D-10-camphorsulfonate salt, whereupon there is obtained, respectively 1) S-3-morpholino-4- (3-isopropylamino-2-hydroxypropoxy ) 1,2,5-thiadiazole 2) S-3-morpholino-4- [3- (2 , 2-dimethylpropylamino) -2- hydroxypropoxy] -1,2 , 5-thiadiazole 3) S-3-morpholino-4- [3- (1 , l-dimethyl-2-hydroxyethyl- . . amino) -2-hydroxypropoxy] -1, 2 , 5-thiadiazole EXAMPLE A Step A: Preparation of S-3-terti-butyl-5- (benzenesulfonyloxy- methyl) oxazolidine ; ' , .

To a solution of S- 3-tert-buty1-5-hydroxymethy1- ; oxazolidine (1.59 g. ; 10 mmole) , prepared as described in Example 56, Step A, in pyridine (3 ml.) there is added benzene about 1 hour at 25° C. Ether (20 ml.) is added whereupon S-3-tert-but l-5- (benzenesulfonyloxymethyj) -oxazolidine hydrochloride is precipitated, removed by filtration and washed well with ether and dried i_n vacuo at 40° C.

The same oxazolidine product is obtained.by replacing the S (-) -glycolamine employed in Example 3'6, ' Step A", by equivalent quantity of S-l-benzenesulfonyloxy-2- hydroxy-3-tert-butylaminopropane and than following sub- stantially the same procedure described in Step A of Example 2.

By replacing the benzenesulfonyl chloride employed , in Step A by 10 mmole of p-tolylsulfonyl chloride, p-nitro-,' . benzenesulfonyl chloride, and p-bromobenzenesulfonyl chloride there is obtained respectively: S- 3-tert-buty1-5- (p-toluenesulfony loxymethyl) - oxazolidine, m.p. 143.5-145° C, yield 83.5% . S- 3-tert-buty1-5- (p-nitrobenzenesulfonyloxymethyl ) - oxazolidine, yield 98% S-3-tert-buty1-5- (p-bromobenzenesul onyloxymethyl) - ' oxazolidine, m.p. 118-120°C, yield 95% '. Step B: S-3-tert-buty1-5- (benzenesulfonyloxymethyl) oxazoli- dine (10 mmole) are dissolved in benzene (12 ml.) and tetrahydrofuran (0.9 ml.). The sodium salt of 3-morpholino- 4-hydroxy-l, 2 ,5—hiadiazole (10 mmole) is added and the mixture refluxed for 16 hours. ; The reaction mixture then is extracted with three 10 ml. portions of IN hydrochloric acid and the aqueous layer then made alkaline with ammonia . and extracted with three 10 ml,- portions of benzene. The combined benzene extracts are dried and evaporated to give . S (-) -3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy ) - 1, 2 , 5-thiadiazole. This product is converted to the By replacing the S-3-tert-butyl-5- (benzenesulfonyl- oxymethyl) -oxazolidine employed in Step B by an equiruolecular quantity of S-3-tert-buty.l-5- (p-toluenesulfonyloxymethyl) oxazolidine, S-3-tert-butyl-5- (p-nitrobenzenesulfonyloxy- . methyl) oxazolidine , and S-3-tert-butyl-5- (p-bromobenzenesulfonyloxy*- methyl) oxazolidine EXAMPLE 45 A solution of 5.2 g. of cyanogen (0.1 mole) in 60 ml. of DMF is treated with 8.7 g. of morpholine (0.1 mole).

The solution is stirred one hour at 25° C. and 23.5 g. of S- 2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine ■ (0.1 mole) is added. Dry hydrogen chloride is passed into the solution at 25° C. until 4.0 g. (0.11. mole) is absorbed. After stirring 2 hours, 24 ml. of sulfur monochloride (0.3 mole) is added over a 10-minute period at 20-25° C. The mixture is stirred 4 hours at 25° C, poured into .600 ml., of water, the precipi- tated sulfur removed by filtration and the filtrate is heated. at 60° C. for one-half hour. The mixture is extracted with. two 50 ml. portions of ether and the aqueous layer then made · strongly "alkaline with excess sodium carbonate.

The mixture is extracted again with two 100 ml. portions of ether and the ether extracts backwashed with two 25 ml. portions of water. The ether is removed by evaporation. in vacuo and the- oil residue obtained, S-3-morpholino-4- (3-tert-butylamino- 2-hydroxypropoxyH-» 2, 5-thiadiazole is dissolved in 50 ml. of tetrahydrofuran. This solution is treated with a solution of 11.6 g. of maleic acid and 40 ml. of tetrahydrofuran and the mixture aged 3 hours at 20° C. The precipitated maleate salt is filtered, washed with tetrahydrofuran and dried in

Claims (1)

1. C A S having the structure in which R is optionally substituted with one or more lower alkyl or 7 8 hydroxy or alternatively and can be joined through an or sulfur atom to form with the nitrogen atom to which they are attached a or saturated heterocyclic optionally substituted with R additionally is a carbamoyl group of the structure R group wherein R is lower alkyl R ie hydrogen or alkyl i is an aliphatic hydrocarbon radical optionally or R and R joined directly gether to form with the nitrogen to which they are attached saturated heterocyclic g a to or alternatively R and can be joined through an oxygen atom to form with the nitrogen to saturated heterocyclic which they are attached a to ring the pharmacologically acceptable salts thereof or in the form of optically active isomer or mixtures having the structure wherein R igned to them in Claim 1 having the structure wherein ie or and R is a branched chain lower chain lower or a branched chain lower alkynyl Compounds claimed in Claim 3 wherein is isopropyl or having the structure or and R has the same meaning as in Claim Compounds as claimed in Claim 5 wherein R is isopropyl or of formula in Claim 6 wherein R is hydrogen and R has the meaning assigned to it in of formula in Claim wherein R is hydrogen and is a branched chain lower of formula in Claim 2 wherein R is hydrogen and R chain lower compounds of formula I in 5 6 Claim wherein R is hydrogen R is of formula in Claim wherein R is chloro and branched chain lower alkyl compounds of formula Claim wherein R is chloro and is The the of formula in Claim wherein R is chloro and is ter The of the of formula in Claim wherein R is chloro and is compounds of formula in Claim wherein R is chloro and is of formula Claim wherein is and R is a branched lower of formula in Claim wherein R is ethyl and R is of formula in Claim wherein R is ethyl and is of formula in Claim wherein R is and R is branched chain lower of formula in Claim wherei R is ethoxy and R is of formula in Claim g wherein R is ethoxy and R is of formula in Claim wherein R is lower alkoxy and is branched chain lower of in Claim 6 wherein R is ethoxy and R of formula in Claim 6 wherein R is raorphoiino and is a branched chain of formula in Claim wherein R is and R is The of the as claimed in Claim wherein R is morpholino and R The of a as in Claim wherein R is morpholino and is 28 Pharmacologically acceptable salts of hydrogen of formula in Claim wherein is morpholino and is rmula in Claim wherein R is and is a branched chain lower of formula in ino wherein R is and R is er of formula in Claim wherein R is R is of formula in Claim wherein R is and R a branched chain lower of formula in Claim wherein R is and is butyl of formula in Claim R is phenyl and is branched chain lower alkyl of formula in Claim 6 wherein R is phenyl and R is of Claim 6 wherein is phenyl and R is A pharmaceutical composition comprising a pharmaceutically acceptable carrier and about 1 to 20 per unit dosage of a compound as claimed in any of Claims 3 and A pharmaceutical composition comprising a pharmaceutically acceptable carrier and from about 1 to 20 per unit dosage of a pound as claimed in any of Claims 13 and A pharmaceutical composition comprising a pharmaceutically acceptable carrier and from about 1 to 20 per unit dosage of a compound as claimed in an one of Claims 24 to A process for the preparation of thiadiazole compounds of formula I in Claim wherein an epoxide having the structure is reacted with an amine of the structure R R and R have the same meaning as in Claim A process the preparation of a zole of formula in Claim 1 having the etructuret OH N comprising the reduction of a follow ed by reductive alkylabion of the product thus with a ketone of the structure wherein X one of the groups 0 0 0 OH 1 OH and Y is a saturated or lower radioal optionally Z is lower and has the same meaning as in Claim A process claimed in Claims prising the as starting of a compound 5 6 in which is is hydrogen and is isopropyl or A process as claimed in Claims 43 or prising the as a starting of a compound 5 6 in which R is is hydrogen and R ie isopropyl or A process for the preparation of compounds according to Claim 1 having the structure I in Claim wherein a compound of structural is reacted with an amine of structural formula 5 6 5 6 E H where and R have the same meaning as in Claim 1 and halo represen or 106 A according to Claim for the preparation of an optically active compound of which comprises reacting an optically active compound of the H with A process the preparation of a compound of structural formula which comprises reacting a compound of structural formula N and is lower alkyl or wherein the ketonie funotion of a is reduced by means of sodium borohydrlde or an aluminum or biologically by the reductase action of organisms such as Clostridium Escherichia Aerobacter Mycobacterium Bacillus ascendens and Lactobacillus lavendulae f lcata and process as claimed in wherein is employed as the starting prooess as claimed Claim starting ketone reduced by aluminum isopropoxide Optically active in sinister configuration of formula in Claim wherein and R have the same meaning as Claim A process for the preparation of the opticall in the sinister configuration claimed in Claim comprising the reaction of a with the sinister modification of a o a or of a en or q the reaction of a with the sinister modification of a ro where and R have the same meaning in Claim 11 R is hydrogen or an alkali metal and R is a leaving process as claimed in Claim wherei the reaction is carried out in the presence of a strong base at a ture between and re temperature the reaction process as claimed in Claims 55 or wherein is reacted w ith or with an or with A process as claimed in Claims 54 or wherein reacted with or with an ί or with or a A process as claimed in Claim wherein a is reacted with an or an alkali metal salt thereof and the oxazolidine thus formed is hydrolyzed under acid conditions to yield wherein in each of the foregoing compounds and R have the same meaning as in Claim 51 and is the residue of any aldehyde having the structure A process as claimed in Claim wherein the diazole reactant is thus yielding thiadlazole wherein R has the same meaning as in Claim A process as claimed in Claim wherein the reactants are and methyl or an alkali metal salt thereof thus yielding wherei has the same meaning as in Claim A process as claimed in Claim wherein the reactants are and or an alkali metal salt thereof thus yielding A process as claimed in Claim wherein a reacted with an and the oxazolidine thus formed is hydrolyzed under acid conditions to yield wherein in each of the foregoing compounds and R have the same meaning as in is the 3 residue of any aldehyde having the structure and R is an or A process as claimed in Claim wherein an amine 6 of the structure R where R the same as in Claim is reacted with and hydrogen in the presence of a palladium or Raney nickel and the optically active ropane thus obtained is further reacted wi th a where is the as in Claim A process as claimed in Claim 55 for the production of compounds according to Claim wherein the product of the structure in Claim 51 where is is reacted and the thus formed is further reacted with a and then with a base to provide where R is the same as in Claim A process for the production of compounds according to Claim 1 of the formula in Claim where hydroxypiperidino or the same as Claim comprising the reaction of an oxazolidine in the sinister configuration of insufficientOCRQuality