November 1969 NOTES 1101

Anticholinergic Esters of

2,6-Bis(methoxymethyl)piperid-4-01

D. G. HILL AND A. B. A. JANSEN

J o h n Wyeth and Brother Ltd., Institute of Medical Research, Taplow, Buckingharnshire, England

Rereived J l a y 2, 1969

Some of the pharmacological properties of atropine are shared by relatively simple piperidol esters, e.g., eucatropine, and we considered whether suit- able oxygenation of such bases would lead to changes in their pattern of activity comparable for example with the well-known differences in the actions of atropine arid scopolamine.

Esters of carbinol 8a met some of the criteria me envisaged and we have devised a synthesis of i t by the route depicted (1 + 8). S-3Iethylchelidamic acid (l), which is readily prepared' from chelidonic acid, promised to be a convenient starting material. Con- version to its ethyl ester 2 by conventional Fischer- Speier or azeotropic techniques proceeded in only rela- tively poor yield because of the ease with which de- carboxylation took place. The yield was much en- hanced when the bisethoxyformic anhydride (3) was allowed to decompose in the presence of Et& or, better, when a salt of the acid was treated with triethyloxoniuni tetrafluoroborate.

0 II

HC/'YH II II xc, ,CX

I N

I

CH, CH, 1, X = COOH

3. X = COOCOOC,H 4, X = CH-OH 5, X = CH,CI

7 . X = Y = H

b, X=CH,, Y =COXHCH, C , X =CH,; Y = COCH(C,H,)? d, X=CH,; Y = COCHOHC,Hj

2, X = COOC2Hj 8a, X = CH,; Y = H

6, X = CH,OMe e, X = CH,, Y = COCH04cC,H,

Suitable conditions could not be found for the selec- tive reduction of 2 to 4 with IAiAlH4 but with LiBH, in T H F this w a ~ readily accomplished in good yield. SaBH4 in NeOH also appeared effective but we have riot given :It tention to the isolation procedure which is complicated by the ch:inge of c' 'I t ' 1011.

Treatment of diol 4 with SOClz converted it to the corresponding dichloro derivative 5 which in turn reacted with methanolic S a O l l e to give the bis- (methoxymethyl) derivative 6.

There remairied the task of reducing the pyrid-4-one system to a piperid-4-01. A preliminary experiment had shown that diol 4 could be hydrogenated in high yield to give 7 which was characterized as its tri-X-methyl- carbamic ester. The bimethoxy derivative 6 was simi- larly hydrogenated to 8a, from which the crystalline hydrochloride and K-methylcarbamate 8b were ob- tained. The OCH3 protons of the free base gave rise to a single peak a t T 6.7 in the nmr spectrum and the

OCHz protons 5~ doublet a t 6.55 which indicated that the CH30CH2 groups were symmetrically disposed and therefore cis.

Carbinol 8a was converted to its dipheriylacetate 8c, its mandelate 8d (via the phenyl glyoxylate), and its acetylmandelate 8e. These esters had only a very weak anticholinergic action (Table I).

Preliminary general observation in mice (dose 400 mg/kg) Compound

Xa Inactive 8b Weak depressant (ip) 8 C Weak depressant (PO)

Convulsant, respiratory depressant (ip)

8d \Veak depresbant (ip) 8e Weak depressant (ip)

Atropine sulfate Scopolamine

hydrobromide

Dose (Ng) causing 25% reduction of acetylcholine

spasm in up ileum

1 > 10

)

> 10 5

50% reduction

0,0025

0.0001

Experimental Section3

Diethyl N-Methylchelidamate. (a) S-llethylchelidamic acid (18.5 g) was heated under reflux for 20 hr in dry EtOH (500 ml) sat,urated with HCI. The solution was concentrated and basified with Sa2C03 and extracted wit,h CHCl3. Evaporation of the dried (MgS04) extract left an oil (10.7 g, 45%) which soon crys- tallized. For analysis, a portion was recrystallized from benzene (charcoal) to give needles, mp 46-47'. Anal . (Cl2HljNOe) C , H, S.

(b) A solution of triethyloxonium tetrafluoroborate (225 g) in CHaC12 (500 ml) was added slowly with stirring over 1.5 hr to a sohition of S-methylchelidamic acid (95 g) and EtsN (72.5 ml) in CH2Cln (950 ml). Next morning the solvent was removed under reduced pressure and H90 (1 1.) was added, follon-ed by K2C03 to render t,he mixture alkaline. The ester (80.5 g, 6 6 5 ) \vas isolated as before.

EtOCOCl (47.5 ml) was added to an ice-cold solution of S-methylchelidamic acid (50 g ) and Et3S (70 ml) in CHCI, (500 ml). After 15 min, more EtJ ('25 nil) was added and the mixture was kept a t room temperature for 48 hr. The solution was washed with HIO and evaporated leaving the ester as ail oil (35 g, 5 5 % ) which soon crystallized. 2,6-Bis(hydroxymethyI)-l-methylpyrid-4-one. ~--LiBH4 (11.2 g )

\vas added in small portions over 1.5 hr to a stirred ice-cooled solution of diethyl N-methylchelidamate (95 g) in dry T H F (950 ml). AAfter 16 hr a t room kmperature, H20 (200 ml) was added sloivly to decompose the excess borohydride, and the solu- tioii after iieiilralization with HCl was evaporated to dryness Iinder rediiced pressure. A solutioii of the residue taken up in EtOH slowly deposited the crystalline diol (63 g) which was sufficiently pure for t.he next stage. Recrystallization from aqueous EtOH afforded the pure product (io';, yield) as prisms, mp 242-243', A,,,, 213 and 267 mp ( e 16,900 and 18,145). And.

2,6-Bis(hydroxymethyl)-l-rnethylpiperid-4-ol Tris-N-methyl- carbamic Ester.--L',G-Bi~(h?.dloxymeth?-l)-l-niethylpiperid--l-oiie ( 3 g ) in EtOH (800 ml) was hydrogenated uver Raiiey S i \Vi a t 70 kg/cm2 and 150' for 5 hr. The gummy residue from the evaporation of the filtered solution was redissolved in C5HS (30 ml) and methyl isocyanate (4 ml) was added. After 3 hr a t SO", excess reagents were evaporated under reduced pressure and the residue was recrystallized from hIe2CO-isopropyl ether to give prisms (3.2 g, 367,), mp 146'. Anal . (ClrH*sN,Os) C , H, X.

(c)

(C8HiiXO8) C, H, N.

( 1 ) I,. Haitinger and .Id. Lieben, Mortutsh. Chem., 6, 293 (1885). ( 2 ) 11. Jleerwein. E. Battenberg, H. Gold, E. Pfeil, and G . l\-illfang,

.I. Prak t . Chem., 154, 111 (1939) .

(3 ) \VIiere analyses are indicated only h y ~ y m l m l of the eleinentb or func- tions, analytical results obtained for those elements or functions were nithin i O . 4 % of the theoretical values.