P I P E R I D O L D E R I V A T I V E S OF S O M E A R O M A T I C

I . L . K o t l y a r e v s k i i , M. I . B a r d a m o v a a n d T . G. S h i s h m a k o v a

ACETYLENES

UDC 542.91:547.823.547.362

The physiological act iv i ty of acetylenic amines is quite dependent not only on the s t r u c t u r e of the acetylenic f r agmen t of the molecule , but also on the s t ruc tu re of the amine moie ty enter ing into it [1]. P rev ious ly we had synthes ized some mono- and diacetylenic amines , into the acetylenic f r agment of which were inser ted hydroxyl and alkoxyl groups [2, 3]. In the p r e sen t paper we synthesized a number of pi - per idol de r iva t ives of some mono- and d ie thynylarenes in o rde r to es tabl i sh the effect of inser t ing a hy- droxyl group in the amine f r agmen t on the i r physiological activity, all the more so s ince the propyl e ther of 2, 4-b is [3 ' - N - (2", 5 "-d i m e t h y l - 4 " - p i p e r i d o l o ) - i ' - p r o p y n - l ' - y l I-phenol, p rev ious ly desc r ibed by us [4], d isc losed a high act ivi ty as a vasod i l a to r agent (the tes ts we re run in the Depar tment of Pharmaco logy of the Novos ib i r sk State Medical Institute).

HO__O_COCH3 BrCHzCH=CHz CH~=CHCHo0_O_COCHa I-I~ KzCO~ ~ -- Pd/CaCOa

(I)

. CaH, O _ O _ C O C H 3 pcl, . CaHTO_ O_C~_=C H NaNHt, NH3 - -

(II) (III) CH3 \

\ dioxane (IV) CHa

CHa >-.,

--, R--Q--C--C--CH~--N~__../--OH \

CH3 R = 0CsH, (V), H (VI), OH (VII)

CuCl HC=_~C--< ~--C--=CH + (IV) + (CH~O)n dioxane "

CH3 CHa / \

-~HO x/-'-'~/NCH2C--C - ~ C--=CCH. N ~ - - 0 H / \

CH~ (V I I I) CH~ CHa

\ C~H~NHz, CuCl

(Ill) + BrC=CCH2N< >--OH \

(IX) CH3 CH3 \

--~ C,,H~O--~--C_~CC_~CCH2N~--OH \

(X) CH3 CHa \

+ HC~CCH~N@__0COC2H a Cu, I~.CO~, I'y 11o--115%45 h

i / ~ 7 \ i (XVI) "\ CHa

Institute of Chemical Kinetics and Combustion, Siberian Branch of the Academy of Sciences of the USSR. Trans la ted f r o m Izves t iya Akademii Nauk SSSR, Ser iya Khtmieheskaya , No. 10, pp. 2254-2257, October, 1972. Original a r t i c l e submit ted May 5, 1971.

�9 1975 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced [or any purpose whatsoever without permission of the publisher. A copy o[ this article is available from the publisher for $15.00.

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TABLE 1

u 85 ,t

a

106--107 6,05

t29--t3t[ 5,48 from l

acetone) 2t8--220 6,79

Empirical formula

C~H~NO

C~H~O~,N

C~Ha~N~0~

~. ~ Hydrochlorides

- "o~ ,.z

~ empirical formula

5,76 Very hy t2,69 C~6H~NOCI

I 5,40 170 f2,13 C~H2~NO~C1

6,86 270--275 14,76 C_~6 H~sN~O~CI~

(..) s

12,67

ii,99

i4,73

TABLE 2

XI 84,95

XIII 79,7

XIV 84,5 XVI 56,16

P

Liquid

t45--i47

77--78 n D i ,4738

]~ ~ Empirical formula

3,92 C2iH31NO8

5 ,t9 [ C3~H44N204 !

3,95 ] C~4HalNO a 6,33 l ClaH~IN02

Hydrochlorides

lemp ical Imula 3,92/ 165

~decornp/ 5 38| 250--255

' i(decomp.: 3,67| 185 6,27|

9,07 C22H3~N0aCl 9,00

ii,94 ! C3~H~6N20~C12 ii,95

I 8,50 C~4H82N03C1 8,48

CH3 C Ha / \

-~C2HsCOO--~NCH~C=C ~"h C-~C--CH~--N~/-~/-OQOC2H5

CH8 (XV) CH3'

Ally[ ether (I) was obtained by heating a mixture of p-aeetylpheno[, allyl bromide, and K2CO 3 in re- fluxing acetone, which when hydrogenated over Pd/CaCO 3 is smoothly converted to the propyl ether (If). The latter was converted in conventional manner to the acetylene (Ill). The aminomethylation of acetylene (Ill) with 2, 5-dimethyl-4-ptperidol (IV) leads to aminoacetylene (V). Amines (Vl), (VII), and (VIII) were obtained in a similar manner. The yield is substantially lower in the case of the synthesis of amine (VII). The condensation of acetylene (KI) with bromoaminopropyne (IX) by the Chodkiewicz method gave the cor- responding diacetylenic amine (X) in good yield. The proplonates (Xl)-(XIV) of all of the amines (attached to the hydroxyl in the piperidol ring) [respectively (V), (VI), (VII), and (X)] were obtained by refluxing a benzene solution of the appropriate amine and propionyl chloride in the presence of magnesium for 4 h.

In a similar manner the dipropionate (XV), a derivative of m-diethynylbenzene, was obtained by the condensation of m-diidobenzenewith am[nopropyne propionate (XVI) in pyridine solution in the presence of Cu powder and K2CO 3 [5]. Propionate (XVI) was obtained in the same manner as (XI)-(XIV) from N-pro- pynyl-2, 5-dimethyl-4-piperidol (XVII), which was synthesized by heating (IV) with propargyl bromi.de in absolute alcohol. The IR spectra of all of the compounds correspond to their structure. The results of the biological tests will be published later.

E X P E R I M E N T A L

Allyl E t h e r of p - A c e t y l p h e n o l (I). A m i x t u r e of 20 g of p - a c e t y l p h e n o l , 150 ml of ace tone , 30.6 g of K2CO3, and 38 g of a l ly l b r o m i d e was re f luxed fo r 9 h, cooled , pou red into w a t e r , e x t r a c t e d with e the r , w a s h e d with w a t e r , d r i ed o v e r K2CO3, and the e t h e r was r e m o v e d . We obta ined 24.84 g (96%) of c o l o r l e s s l iquid with bp 115-119 ~ (1 mm); n~ 1.5545. Found: C 74.47; H 7.01%. CilH1202. Ca lcu la t ed : C '74.97; H 6.86%.

P r o p y l E t h e r of p -Ace ty lpheno l (II). The hyd rogena t ion of (I) in a lcohol o v e r P d / C a C O 3 gave (II) in quan t i t a t i ve y ie ld as a c o l o r l e s s l iquid with bp 109-111 ~ (1 ram); n~ 1.5386. Found: C 73.51; H 7 .86~. CIiH1402. Ca lcu la ted : C 74.13; H 7 .92~.

P ropy l E t h e r of p -E thyny lpheno l (III). A m i x t u r e of 6.1 g of (K), 50 ml of abso lu t e benzene , and 8.56 g of PCI 5 was hea ted up to 65 ~ and then cooled g radua l ly , a f t e r which it was di luted in half with e the r and

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added in drops to a suspension of NaNH 2 in liquid NH 3 (from 9 g of Na and 500 ml of NH3) , followed by the addition of 300 ml of absolute ether, af ter which the mixture was s t i r red for 7 h, the ammonia was evap- orated, and water was added to the residue. The organic layer was washed with water, dried over K2CO3, dissolved in ether, and the solution was passed through A1203. Removal of the ether gave 4.86 g (86.8%) of (III) as a color less liquid with bp 98-98.5 ~ (1 mm); n~ 1.5400. Found: C 82.49; H 7.652. Cl1H1202. Calculated: C 82.46; H 7.55%.

p-Ethynylphenol (XVIII) was obtained in a s imi lar manner f rom p-acetylphenol in 55 % yield.

p - P r o p o x y - [ 3 ' - N - ( 2 " , 5 t ' - d i m e t h y i - 4 " - p i p e r i d o l o ) - l ' - p r o p y n - l ' - y l ] - b e n z e n e (V). A mixture of 0.6 g of paraform, 2.42 g of (IV), and 30 ml of absolute dioxane was s t i r red for 4 h. In a nitrogen s t r eam were added 2 g of (III) and 0.05 g of CuC1, and the mixture was s t i r red for 3 h. The reaction mixture was diluted with 150 ml of ether, washed with water, and the ether extracts were dried over K2CO 3. The pas- sage of a s t r eam of dry HCI through the ether solution gave a white precipitate of the (V) hydrochloride, with mp 170 ~ (from alcohol). Found: CI 10.47%. C19H28NO2Cl. Calculated: CI 10.49%. To convert it to the amine a saturated solution of Na2CO 3 in water was added to a suspension of the (V) hydrochloride in ether. (V) was isolated f rom the e ther extract as a white powder with mp 122-123 ~ (yield 55% when based on the (III) taken for reaction). Found: N 4.78%. C19H2~NO 2. Calculated: N 4.65%.

Amines (VI), (VII), and (VIII), and the (VI) and (VII) hydrochlorides, were obtained in the same man- ner as (V). The hydrochlor ide of (VII1) was obtained by passing dry HCI through an acetone solution of the free base (Table 1).

(2', 5 ' -D ime thy l -4 ' ) -p ipe r ido lo - l -p ropyne (XVII). To a mixture of 10 g of (IV), 100 ml of absolute alcohol, and 12.3 g of powdery calcined K2CO 3 was gradually added a solution of 11.13 g of propargyl b r o - mide in 50 ml of absolute alcohol, after which the mixture was heated up to 60 ~ and s t i r red for 6 h. The mixture was allowed to stand overnight. The inorganic precipi tate was fil tered, the alcohol was evaporated f rom the fil trate, and the residue was rec rys ta l l i zed f rom benzene. We obtained 7.75 g (60.5%) of a white c rys ta l l ine substance with mp 112-113 ~ Found: N 8.52%. C10H17NO. Calculated: N 8.38%.

1 - Bromo-3 -N- (2 ' , 5 ' - d ime thy l -4 ' - p ipe r ido lo ) - l -p ropyne (IX). To a s t i r red solution of 10.94 g of NaOH in 75.4 ml of water , cooled to - 8 ~ was gradually added 21.7 g of Br2, and after 15 rain a solution of 7.6 g of propyne (XVII) in ether was added, the mixture was s t i r red for 20 min, the temperature was g rad- ually raised up to room temperature , and the s t i r r ing was continued for another 3 h. The ether solution was passed through A1203 in ether. We isolated 6.76 g (60.5~) of (IX) as white c rys ta ls with mp 134-135 ~ (from benzene). Found: N5.95; Br 32.77%. C10H16NOBr. Calculated: N5.69; Br 32.47}.

p - P r o p o x y - [ 5 ' - N - { 2 " , 5 ' - d i m e t h y l - 4 " - p i p e r i d o l o ) - l , 3 ' - p e n t a d i y n - l - y l ] - b e n z e n e (X). To a cooled to - 5 ~ mixture of 4.62 g of (III), 100 ml of methanol, 15 ml of ethylamine, and 2 g of NH2OH. HC1 in a ni- trogen a tmosphere were added 0.1 g of CuCI and 7.8 g of (IX) in methanol, after which the mixture was s i t r red at - 3 ~ for 2.5 h, diluted with ether, washed with water , and the ether solution was dried over K2CO 3. The product obtained after removal of the solvents was recrys ta l l tzed f rom benzene, converted to the hy- drochloride, and then back to the amine. We isolated 6.37 g (67.9%) of (X) with mp 135-136 ~ Found: N 4.60%. C21H27NO2, Calculated: N4 .30~ . Hydrochloride, mp 165 ~ Found: CI 9.72%. C21H28NO2C1. Cal- culated: C1 9.80%.

Propionate of (2', 5 ' -D im e thy l -4 ' - hyd roxyp ipe r i d ino ) - l - p ropyn - l -y l -benzene (XII). To a mixture of 1.6 g of amine (VI), 40 ml of absolute benzene, and 3-4 Mg turnings was gradually added a solution of 3 ml of propionyl chloride in 5 ml of absolute benzene, after which the mixture was s t i r red at 20 ~ for 5 h, and then at 80 ~ for 4 h. The cooled mixture was netural ized with NaHCO3, followed by the addition of 10 ml of water and 2 granules of KOH. The organic layer was separated, washed with water, and passed through A1203 in benzene. F r o m the benzene solution was isolated 1.74 g (88.8~) of (XII) as a viscous liquid. Found: N 4.83%. C19H25NO 2. Calculated: N 4.68%. Hydrochloride, mp 215-220 ~ (decompn.). Found: CI 10.51~. Ci9H26NO2C1. Calculated: C1 10.56%.

In a s imi la r manner, f rom amines (V), (VIII), (X), and (XVII) were respect ively obtained propionates (XI), (XIII), (XIV), and (XV1).

The hydrochlor ides of (XI), (XIII), and (XIV) (Table 2) are readi ly soluble in alcohol and slowly so l - uble in hot water.

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D[propionate of 1 ,3-bis -[(2 ", 5"-Dim e thy l -4" -hydroxypiper id ino) - i ' -propyn-1 '-yl] -benzene (XV). A mixture of 5 g of m-diiodobenzene, 7.5 g of (XVI), 50 ml of d ry pyridine, 5 g of ground calc ined K2CO3, and 0.3 g of activated Cu powder was s t i r r ed in a nitrogen a tmosphere at 110-115" for 45 h. Copper was added twice to the mixture in 0.1 g port ions. After the usual workup we obtained 1.43 g (17.1%) of (XV), mp 127-128 ~ (from acetone). Found: N 5.39%. C]2H44N204. Calculated: N 5.38%. Hydrochloride, mp 250 ~ (decompn.). Found: CI 12.08~c. C32H2~N20~Cl 2. Calculated: CI 11.95%.

C O N C L U S I O N S

A number of acetylenic amines, represen t ing piperidol der iva t ives , was synthesized, which are po- tential vasodt la tor agents.

L I T E R A T U R E CITED

1.

2.

3.

4.

5.

G. N. Pershin , S. I. Milovanova, A. L. Mtkerina, T. G. Shishmakova, M. I. Bardamova, and I. L. Kotlyarevski i , Izv. Akad. Nauk SSSR, Ser. Khim. , 1904 (1970). M. I. Bardamova, R. N. Myasnikova, and I. L. Kotlyarevski i , Izv. Akad. Nauk SSSR, Ser. Khim., 443 (1967). I. L. Kot lyarevski i , R. N. Myasnikova, and M. I. Bardamova, Izv. Akad. Nauk SSSR, Ser. Khim. , 1906 (1970). M. I. Bardamova, [. L. Kotlyarevski i , V. A. Lyubushkin, and R. N. Myasnikova, Izv. Akad. Nauk SSSR, Ser. Khim. , 634 (1971). M. S. Shvar tsberg, A. A. Moroz, and I. L. Kot lyarevski i , Izv. Akad. Nauk SSSR, Ser. Khim. , 1306 (1971).

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