1166
e. D. T,UNSFORD,
R. P.
I\TAPS,
J. A. RICHMAN, JR.,AND R.s. MURPHEY
passed through the reaction mixture and then through 3% hydrochloric acid for 15 hours. The acid solution was evaporated to dryness in DQCUO and the white, crystalline residue identified as a mixture of methylamine hydrochloride, m.p. 225O, and ammonium chloride, no m.p. t o 300°, by recrystallization from methanol-ether and b y vapor phase chromatography. For the latter a Perkin-Elmer model 154 Vapor Fractometer with a 1-m. triethanolamine impregnated Celite column wasused a t 79". The mixture of amines was introduced in methanol solution after liberation from their hydrochlorides by addition of methanolic potassium hydroxide. Four sharp maxima were obtained corresponding t o control peaks obtained for ammonia, methylamine, methanol and water. The area under the ammonia peak was smaller than that from methylamine.
[CONTRIBUTION FROM
THE
Vol. 81'
Control Experiments.-(a) The above procedure was repeated with 1 g. (0.0032 mole) of 4-ami110-6-cliloro-N,X'dimethyl-nt-benzenedisulfonainide ( Y h ) . Onlv a sm,lll amount of ammonium chloride W A S isolated in this case. S o trace of methylamine could be detected by vapor phase chromatography. ( b ) A suspension of 0.50 g. (0.0016 mole' of X wds refluxed for 2 hours in 60 ml. of 10ychydrochloric acid, cooled and made strongly basic with saturated sodium hydroxide solution. A stream of nitrogen T V ~ Tpassed through the solution and through a trap of 3y0 hydrochloric acid for 15 hours Evaporation of the acid to tiryneqs did not le tve any residue. SUMMIT,N. J.
CHEMICAL RESEARCHLABORATORY, A. H. ROBISSCo., INC.]
5-Aryloxymethyl-2-oxazolidinones BY CARLD. LUNSFORD, RICHARDP. MAYS,JOHNA. RICHMAN, JR.,
AND
ROBERTS. X~URPHEY
RECEIVED JUNE 22, 1959 When (a) 3-(o-methoxyphenoxy)-1,2-propanediol (11) is fused at 180-200O with two molar equivalents of urea or when
(b) 2-hydroxy-3-(o-methoxyphenoxy)-propylcarbamate ( I ) and one molar equivalent of urea are similarly fused, the major
(IIIa). A sequence of reactions b y which the oxazolidinone product is 5-(o-methoxyphenoxymethyl)-2-oxazolidinone ring is formed under these conditions has been investigated and these reactions are discussed. Following method (a) twentyfive 5-aryloxymethyl-2-oxazolidinones, in which the substitution in the aryl nucleus is alkyl, alkyloxy and/or halogen, have been prepared for pharmacological testing. A total of nineteen corresponding N-substituted-5-aryloxymethyl-2-oxazolidinones, prepared by condensation of l-amin0-3-aryloxy-2-prop~1101~ with ethyl carbonate or phosgene, are also reported.
I n an effort to develop other processes of pre- been extended to other a-aryl ethers of glycerol and paring the skeletal muscle relaxant 2-hydroxy-3- found to be a general one. The resulting 5 (o-methoxyphenoxy)-propyl carbamate (I) the aryloxymethyl-2-oxazolidinones possess several inreaction between 3- (0-methoxyphenoxy) - 1,2-pro- teresting pharmacological activities. They are panediol (11) and urea was studied. Instead of generally antagonists of strychnine convulsions in yielding the desired carbamate, the fusion of these rats and have consequently been investigated for use as skeletal muscle relaxants and for related 0 pharmacological indications. I1 These compounds have also been prepared by the i OCHi CHCH?OCKH, \= I fusion of l-chloro-3-aryloxy-2-propanol or 3-arylI or1 oxy-1,2-epoxypropane with urea, and by the rematerials a t 180-200° gave 5-(o-methoxyphenoxy- action of 3-aryloxy-l,2-epoxypropanewith uremethyl)-2-oxazolidinone (IIIa) as the major isol- than or acidiiied sodium cyanate.8 A recent patent4 reported the preparation of able product as well as minor amounts of the cyclic carbonate of I1 (IV) which has been reported IIIa by the reaction of urethan and 3-(o-methoxyphenoxy)-1,2-propanediol (11), but the structure previously.2 was reported with the o-methoxyphenoxymethyl 0 11 group located at position 4 of the oxazolidinone AiOCH,CHCHrOII + I4vSCNHZ ring. Repetition of this work has shown that the product is identical to IIIa prepared by the glycolOH I1 urea fusion. c In order to locate unequivocally the aryloxy.'hOCH,CH--CH, -- ArOCH,CH-CH, I I I I1 methyl group of the compound I I I a a t position 5 (rather than 4) of the oxazolidinone ring, i t was O \ subjected to basic hydrolysis which gave the expected l-amino-3-(o-methoxyphenoxy)-2-propanol (V). Lithium aluminum hydride reduction of ,OCH, I I I a produced the corresponding N-methylamino alcohol VI. The identical amino alcohols were .. synthesized by condensation of l-chloro-3-(0While the present investigation was in progress, methoxyphenoxy)-2-propanol(VII) with ammonia the same reaction was reported to have occurred or methylamine, respectively. The corresponding between mephenesin and urea.a The reaction has oxazolidinones IIIa and IIIb were obtained again when V and VI were treated with phosgene or (1) R. S. Murphey, U. S. Patent 2,770,649 (1956); generic name, diethyl carbonate. methocarbamol. (2) M . M . Baizer, J. R. Clark and J. Swidinsky, THIS JOURNAL, The mechanism by which the 5-aryloxymethyl-279, 1696 (1957). oxazolidinones are formed in the fusion of an a(3) Y.M. Beasley, V. Petrow, 0. Stephenson and A. S. Thomas, J .
J-FHd
!
" c,
Pharm. and Pharmacol., 9, 10 (1967).
(4) Belgian Patent 670,147 (1968).
March 5. 1960
5-ARYL.OXYMETHYL-2-OXAZOLIDINONES
1167
of the cyclic carbonate I V , which is the major reaction a t temperatures below 175’; or (c) by losing carbon dioxide to form the l-amino-3aryloxy-2-propanol (V) according to equation 3. The amine V cannot be isolated under the con”., ArOCH2CHCH, ditions, but immediately reacts with more isoI I cyanic acid from the decomposing urea forming the substituted urea VI11 (equation 4) which then cyclizes by loss of ammonia and forms the oxazolidinone IIIa (equation 5). In order to support this reaction sequence, the feasibility of each reaction and the behavior of each proposed intermediate under the reaction ArOCH2CH-CH, OCH, I I conditions have been investigated. /4 OH ”CHI It may be noted that the over-all reaction (equa*I.= VI tion 6) requires two molar equivalents of urea for each mole of glycol 11, and i t was found experiaryl ether of glycerol and urea appears to follow mentally that maximum yield of the oxazolidinone the reaction sequence outlined: IIIa was realized when this ratio was used. Although a larger ratio of urea to glycol had no effect 2HzNCOPu”s 2HNCO 2NH3 on the yields, they were appreciably lowered when ArOCHzCH-CH20H HNCO the amount of urea was decreased. I OH I1 0 A rigorous proof has already been reported that /I I is the carbamate ester of the primary alcohol of ArOCHzCHCHPOCXHz the glycol I1 as opposed to the carbamate ester I of the secondary alcohol.2 Since i t is assumed that OH I the first molar equivalent of urea is consumed in I --+ ArOCH~CHCHzNHz COz the formation of this carbamate I, it was fused I OH v with a single molar equivalent of urea (equations 3, 4 and 5) and, as expected, the oxazolidinone 0 IIIa was obtained. Although the crude yields I/ V f HNCO ArOCHzCHCHzSHCXH2 using this process were generally of the same order I as for the over-all glycol-urea process, the material OH VI11 was always of higher purity and consequently gave 1.111 ArOCHzC;II-CH* + NHa higher yields of purified compound. d, ,NHI An unsuccessful attempt was made to isolate the amino alcohol V by subjecting the carbamate I C I/ to the reaction conditions; however, the isolated 0 IIIa products were 3-(o-methoxyphenoxy)-1,2-propaneOver-all reaction 0 diol (II), together with a small amount of the oxazoI/ lidinone I I I a indicating that any Va formed I1 2HzNCNHz --+ 2SH3 COP + IIIa reacted with isocyanic acid furnished by the reSide reaction versal of equation 2. I --f NHa f ArOCHzCH---C€Iz To further investigate the formation of the I I amino alcohol by loss of carbon dioxide from the OCH, O/O \, carbamate (equation 3), 2-hydroxy-3-(o-methoxyII phenoxy) -propyl N,N-dimethylcarbamate (IX) was 0 I\’ heated under the reaction conditions and this reIVheii urea is heated a t 1S0-2OO0 thc chief prod- action yielded a minor amount of glycol I1 and as ucts are isocyanic acid and ammonia. Normally, the major product, 1-dimethylamino-3-(o-methoxythe reaction between urea and primary alcohols phenoxy)-2-propanol (X). i5n analogy to this under these conditions, which were those used in reaction is found in the pyrolysis of N-methoxythis study, results in the formation of urethansj (equations 1 and 2). It has been assumed then CH3 that this is the initial reaction between the 3-aryl- & 2 H 2 y H c H L o c N / oxy-1,2-propanediol (11) and urea and that the ‘CH, originally desired carbamate I is formed a s an IX OH k-200’ OCH, intermediate. However, under the reaction cond o c H 2 C H C H 2 N ;C H , ditions, the carbamate is unstable and can logically decompose in three ways which are: (a) by losing I1’\ / I isocyanic acid according to the reverse of equation CH: x OH 2, which is usually the predominate reaction in the pyrolysis of carbamates; (b) by losing ammonia carbonylcarbazole which results in the formation of according to equation 7 with consequent formation N-methylcarbazole and carbon dioxide.6 Compound X was synthesized independently from ( 5 ) T. L. Davis and S. C. Lane, “Organic Syntheses,” Coll. Vol. I,
\
211 8.5
82 1,5
o
,-I
52
! .;o
7.(is
1).
.,-
$7, 23
r
r -
i ,/ % I
A . 15 6.80 3.69 4.89 7.74 7.81
0.28 6.2s 6.28 5.28 3.28
6.15 6.15 6.15 r, . 1li
6.70 6.3 ii. 33
3 . 3
4.05
.?.-I8 -1. fi7
5.62 r, 62
tis
7.68
19 ti:; 56.2fi
.-,94
t .->2
1,lil
1 . x:i
-57. 8ti
5.98
G.41 3.93
5 IO 6. In
57.78 154-155' 14 ,58,80 The reported yields are generally the results of a single r u n . Recrystallized from ethanol, e isopropyl ether, f isooctane-ethyl ether, 0 isooctane. ii
)%-
61.87
( i 3 1% 6.5.86 A; 69. 08
f
-Hydrogen, c , c - Calcd. Found
Found
5.19 *5.97 5.32 8.59 ethyl acetate, methanol, 5.98
8.01
b
95%
to the amino alcohol obtained by pyrolysis of - chloro - 3 - (0 - methoxyphenoxy) - 2 - propanol (VII)and dimethylamine and proved to be identical IX. 1
March 5, 1960
1169
5-ARYLOXYMETHYL-2-OXAZOLIDINONES
TABLE I1 1-AMINO-3-ARYLOXY-2-PROPANOLS R
D o c H 2 c H c H s . ' /R' 1
OH -N/ R
R' \R
f
M.P.,
C.
Yield,a
%
2-CH3 CzH6NH 85-87d 41 70.c5-71.5" 52 3-CH3 CzHjNH 4-CH3 CzHjNH 75-76d 30 NHz 107-108.5* 28 2-CH3O 2-CH30 CHBNH 77.5-78" 39 2-CH3O GCDH~NH 81-82d 72 35 C>T-C6Hiih7H G 1 . 5-62d 2-CH3O 59 (CH3)ZN 59-59. jc 2-CH30 39 CzHjNH 93-93.5" 4-C1 4G C2HjNH 98-99' 1-Br 64 CzHjXH 95.5-96" 3,5-(CH~)z 95 C2HsA-H 130- 131' 2,4-c12 21 C2HjSH 98-98, 3-Cl-2-CH3 28 CzHjSH 93.5-96' 4-Cl-3-CHa 27 CzHjSH 114. c5-l15c t5-Cl-2-CHa 33 CzHsSH 121-122d 2,3,5-(CH3)3 Recrystallized from 5 The yields are generally the result of a single run. isooctane. Calcd.: C, 63.98; H, 8.50. Found: C, 63.71; H , 8.28.
'R'
Elementary formula
--Nitrogen, Calcd.
%-
Found
ClzH19h'Oz 6.69 6.80 CizHi9NOz 6.69 6.56 CIZHI~NOZ 6.69 6.70 C10H15N03 7.10 6.82 CiiHnN03 6.63 6.73 C13H21h'03 5.85 5.91 C16Hd03 5.01 4.83 ClZH19~03 6.22 6.02 CiiH1eClN02 6.10 6.18 Cl1H1~BrK02 5.11 4.98 C13H21h'OZ 6.27 6.06 CiiHijClZSOz 5.30 5.10 ClrHisClNOz 5.75 5.68 CizH18ClNOz 5.75 5.31 CizHiaClNOz 5.75 5.92 C14H23h'Oz 5.90 5.95 methanol-isopropyl ether, isopropyl ether,
When heated alone a t 180-200°, l-amino-3- in Table I. These compounds were all prepared (o-methoxyphenoxy)-2-propacol (V) was stable; from the corresponding amino alcohol by condensahowever, when a single molar equivalent of urea tion with ethyl carbonates under basic catalysis or was added, the oxazolidinone IIIa was isolated in with phosgene While most of the amino alcohols excellent yield. This reaction is depicted by equa- have been previously reported, the properties of those which are new are given in Table 11. tions 4 and 5. Finally, to further support equation 5, 1-[2Many of the oxazolidinones reported here have hydroxy - 3 - (o - methoxyphenoxy) - propyl]- shown pharmacological activity as skeletal muscle urea (VIII) (prepared from V and acidified potas- relaxants, psychotherapeutic agents, etc. A resium carbonate) was subjected to the reaction port of these findings will appear elsewhere. conditions and I I I a was again formed in good yield. Experimentalg Ethylene glycol itself reacts with urea a t 180All of the phenols used in this study were either obtained 200' to form 2-imidazolidinone rather than an commercially or prepared by known methods except 3,4,5oxa~olidinone.~The courses of these two reactions trimethoxyphenoll0 which was prepared by diazotization of are quite compatible since ethylene glycol, having 3,4,5-trimethoxyaniline which, in turn, was prepared from by the Hofmann hypobromite two primary hydroxyl groups, might be expected 3,4,5-trirnethoxybenzamide method. The 3-aryloxy-1,2-propanediols (11) were preto form the dicarbamate as an intermediate and the pared by the condensation of the sodium salt of the phenol reaction then proceed analogously to that outlined with a-glyceryl-monochlorohydrin according to known methods.l1 for the formation of the oxazolidinone. In the preparation of the oxazolidinones by fusion of the 3Following the procedures indicated above, a series aryloxy-l,2-propanediols(11) with urea it was found to be of 5-aryloxymethyl-2-oxazolidinones, in which the advantageous to bring the urea-glycol mixture rapidly to aryl substitution has been varied among alkyl, the reaction temperature of 180-200° to minimize the formaalkyloxy and halo substituents, have been pre- tion of the cyclic carbonate ester IV. In runs smaller than n.25 molar, this was convenientlp done by placing the flask pared. These compounds are listed in Table I. containing the mixture in a preheated metal-bath. In I t was desirable to label one of the more pharnia- larger runs the glycol was heated to the reaction temperature cologically interesting of these compounds, 5- and molten urea was added with stirring. Reaction times (0-methoxyphenoxymethy1)-%oxazolidinone, with of 3-5 hours were required. The 5-aryloxymethyl-2-oxaC14for use in tissue distribution studies. This was zolidinones (111) which have been prepared by this method listed in Table I. The following (method -4) is a typical accomplished by condensing l-amino-3-(o-meth- are example: oxyphenoxy)-2-propanol (V) with p h 0 ~ g e n e - C ~ ~ . 5-(o-Methoxyphenoxymethy1)-2-oxazolidinone (IIIa). I t mas of interest to examine the changes in (Method A).--A mixture of 39.6 g. (0.2 mole) of 3-(o-methpharmacological activity resulting when the nitro- oxyphenoxy'kl,2-propanediol (11) and 21 g. (0.4 mole) of gen of the oxazolidinone ring was substituted with urea was heated in a flask equipped with a thermometer and (8) A. H. Homeyer, U. S . Patent 2,399,118 (1942). an alkyl group. The ethyl radical was arbitrarily (9) All melting points are corrected. Carbon a n d hydrogen analychosen except in the case of the N-substituted-5by Schwarzkopf hlicroanalytical Laboratory, 56-19 37th Ave.. (o-methoxyphenoxymethyl)-2-oxazolidinones(111) sis Woodside 77, N. Y. Kitrogen analysis b y Mrs. R u b y Higgins of the where the substituent was more extensively varied. A. H. Robins Co , Inc., Control Laboratory. The N-substituted-5-aryloxymethyl-2-oxazolidi- (10) S. Hattori, Acta Phytochim., 6 , 219 (1931); a n d P. L. Pauson nones which have been prepared are also included and B. C. Smith, J . O r g . Chem., 18, 1403 (1953). (7) H R. D i t t m a r , U S P a t e n t 2,416,046 (1947), J Org Chenz , 15, 471 (1950).
(11) For some typical procedures, see R. I. Meltzer a n d J. Doczi, THISJOURNAL, 72, 4986 (1950); and H. L. Yale, E. J. Pribyl, W. Baker, F. H. Bergeim and W. A. L o t t , ibid., 72, 3710 (1950).
1170
1-01. s2
air condcnser. T h e misture w:is 11r~ted rapidly to thr range of 180-200" by immersing the flask in a \Vood's metal-bath
mixed with an authentic sample of melting point 78-70" t h e mixture melted 73.5-78". .Use obtained was 1.1 g. of 5-(0which had previously been heated to 190". Heating in this methoxyphenoxymethyl)-2-oxazolidinone( I I I a ) , m .p. 140temperature range was continued for 5 hours and then the 142.5'. The product was identified by the method of mixreaction mixture was poured into 200 ml. of water and ex- ture melting point with an authentic sample prepared actracted with chloroform. The chloroform extract was dried cording to method A . The infrared spectra of the two over sodium sulfate, filtered and concentrated. The res- samples were identical. idue was fractionated a t reduced pressure and gave a small Hydrolysis of 5-( o-Methoxyphenoxymethyl)-2-oxazolidmamount of low boiling material and 30 g. (6iYo) of IIIa, one (IIIa).-A mixture of 101.0 g. (0.45 mole) of I I I a and b.p. 220-225' (0.1 mm.). After crystallization from 95% 45.2 g. (1.13 moles) of sodium hydroxide (in 300 ml. of ethanol, the compound melted 143-145'. water) and 600 ml. of 95% ethanol was refluxed for 24 hours, filtered and concentrated in vacuo to approximately Alternatively, the residue from the Chloroform extract was crystallized from 95% ethanol, acetone or ethyl acetate 200 inl. The residue which solidified was dissolved in without distillation. When this method of isolation was methyl alcohol and the solution was acidified with ethereal hydrogen chloride. The hydrochloride salt of l-amino-3-( oused, the yields were of the order of 40%. The lower boiling fraction proved to be 3-(o-methoxy- methoxyphenoxy)-2-propanol (V) was precipitated by displacing some of the methanol with boiling butanone and plienoxy)-1,2-propanediol cyclic carbonate which, after crystallization from 95y0 ethanol, melted 60.5-61'. A cooling the resulting solution, yield 87.2 g. (83%), m.p. 172-173.5' (lit.12 173-175'). mixture of this material and a sample prepared from phosgene and 3-( o-methoxyphenoxy)-l,2-propanediol as deAnal. Calcd. for CloHl&Os.HC1: C1-, 15.17. Found: C1-, 14.98. scribed below melted 62-63'. When the reaction was run at 150-175' no oxazolidinone could be isolated and the. The base was precipitated from an aqueous solution of the cyclic carbonate was the major product. salt with aqueous sodium carbonate and recrystallized from a The Fusion of 2-Hydroxy-3-(o-methoxyphenoxy)-propyl methanol-isopropyl ether mixture; m.p. 107-108.5'. This Carbamate (I) and Urea. (Method B).-A mixture of 24.1. compound proved to be identical by methods of mixture g. (0.10 mole) of I and 6.0 g. (0.10 mole) of urea was heated melting point and infrared spectra t o a sample prepared from rapidly to the temperature of 180-200' and maintained l-chloro-3-( o-methoxyphenoxy)-2-propanol and ammonia.12 there for 5 hours. The reaction melt was crystallized from Anal. Calcd. for CIOH&O~: C, 60.89; H, 7.67. Found: 50% ethanol: yield 18.3 g. (82%), m.p. 131.5-137'. Crys- C, 61.08; H , 7.52. tallization from water and 95% ethanol gave 9.0 g. (40%), Lithium Aluminum Hydride Reduction of 5-(o-Methoxym.p. 141-143'. This melting point was not depressed when phenoxymethy1)-2-oxazolidinone(IIIa).-A suspension of the material was mixed with an authentic sample prepared according to method A . The infrared spectra of the two 37.9 g. (1.O mole) of lithium aluminum hydride in 200 ml. of dry ether and 800 ml. of dry tetrahydrofuran was stirred samples were identical. The Fusion of l-Amino-3-(o-methoxyphenoxy)-2-propanol and refluxed under anhydrous conditions for 1.5 hours. ( V ) and Urea. (Method C).-Under the conditions of re- There was added to this mixture, 112 g. (0.5 mole) of I I I a action and isolation outlined in method B, 4.93 g. (0.025 portionwise so that gentle refluxing was maintained. After mole) of V and 1.50 g. (0.025 mole) of urea gave 3.8 g. complete addition, the mixture was stirred and refluxed for %hours and cooled; the excess hydride was decomposed with (fi8l70) of pure I I I a . Identification was again by methods of water. About 1 liter of chloroform was then added and the mixture melting point and infrared spectra. mixture was filtered. The filtrate was concentrated until F'yrolysis of 1- [2-Hydroxy-3-( o-methoxyphenoxy)-propyl] most of the chloroform was removed and diluted with 8!)0 urea (VIII). (Method D).-The pyrolysis of 1.2 g. (0.005 mole) of 1'111 a t 186-200' for 4.5 hours followed by crystal- ml. of dry ether. On standing, the product precipitated The lization of the reaction melt from %yoethanol gave 0.8 g. as white needles; yield 56 g. (5Syo), m.p. 77.5-78'. ( 7 2 % ) of I I l a , m.p. 141-1445'. When the material w a s melting point was not elevated by recrystallization from isopropyl ether and proved t o be identical to that of a sample riiixed with an authentic sample of oxazolidinone prepared of 3-( n-methoxyphenox)-)-l-methylaniit~o-2-propanol(1'1) iiccording to method A, this melting point wils not depressed. from l-chloro-~-(~-rnetlioxyphenoxy)-2-propanol Pyrolysis of 2-Hydroxy-3-( n-methoxyphenoxy )-propyl N, prepared outN-Dimethylcarbamate (IX).-Compound I X (31.9 g., 0.118 (VII) and monomethylamine according to the method iiide) was heated rapidly t o the reaction temperature of 190- lined below, An admixture of the two exhibited no melting point depression and the infrared spectra were identical. 2iIirIo and maintained there for 5 hours. The mixture was The hydrochloride salt was prepared by treating a solu~iartitionedbetween 50 ml. of benzene and 50 ml. of water. the base in butnnone with ethereal hydrogen chloTlie benzene layer (extract A ) was washed with ten 2 5 m l . tion of The resulting precipitate was recrystallized from a ride. portions of water and then extracted with 6 ilr hydrochloric :Icid. The acid extract was basified with dilute sodium hy- butanone-methanol mixture; m.p. 115-116'. Anal. Calcd. for CIIITl~r\;03.HC1:C, 53.33; H, i . 3 3 ; droxide and extracted with benzene (extract B). The original benzene extract ( A ) mts concentrated and the C1-. 14.31. Found: C, 53.08: H , 7.13; C1-, 14.46. idue was distilled and 8.05 g. was collccted a t 16.ili'O" Although many of the l-amino-3-aryloxy-2-propanols used 07 mm.). This was crystallized from carbon tetracllloin this study have not previously been described in the ri( e and melted 78-i8.5". When mixed with a n authentic literature, they werc all prepared by a known method; sample of 3-(o-methoxyphenoxy)-l,2-propanediol (11) of namely, the condensation of l-chloro-3-aryloxy-2-propanol or melting point 78-79' the melting point was not depressed. 3-aryloxy-l,2-epoxypropane with amines.I3 Those comThe infrared spectra of this compound and of the known pounds which have not been described in the literature preglycol were identical. The benzene extract ( E ) from the viously are listed in Table 11. The following is a typical basic layer was washed with water aud concentrated and the example: residue was distilled and 7.9 g. was collected a t 120-125' 3-( o-Methoxyphenoxy)-l-methylamino-2-propanol(VI) (0.08 mm.). The material solidified and after recrystallizaA solution of 56 g. (0.39 mole) of l-chloro-3-(o-methoxytion from isopropyl ether melted 58-59'; when mixed with phenoxy)-2-propanol and 34 g. (1.1 moles) of methylamine an authentic sample of l-dimethylamino-3-( o-methoxyphenin 500 ml. of absolute ethanol was heated in a sealed bottle oxy)-2-propanol (X), prepared from 1-chloro-3-(n-methoxyon the steam-bath for 22 hours. The excess amine and phenoxy)-Ppropanol (VII) and dimethylamine, the melting alcohol were removed by distillation and the product was point was not depressed. The infrared spectra of the two distilled a t 164" (0.6 mm.) and crysttllized from isopropyl compounds were identical. ether: yield 23 g. (29%), m.p. 78-79 . 3-( o-Methoxyphenoxy)-1 ,z-propanediol Cyclic Carbonate .4naZ. Calcd. for C12H1~NOs: C, 63.08; 13, 8.50; K, (IV).2-A mixture of 54.5 g. (0.275 mole) of 3-(o-rnethoxy6.22. Found: C,63.71: H,8.28; N,6.02. phenoxy)-12-propanediol (11) and 27.2 g. (0.275 mole) of Pyrolysis of 2-Hydroxy-3-~o-methoxyphenoxy)-propyl phosgene in ca. 500 ml. of dry benzene was stirred a t 5-10" Carbamate (I).-When 12.0 g. (0.05 mole) of I was sub- for 2 hours. Pyridine (43.6 g., 0.55 mole) was then added jFcted t o the conditions of reaction and isolation outlined (12) V. Petrow a n d 0 . Bteplicrison, .I. I'bnrnt. a i d Pharmacal., 5 , 359 f
