CA1075701A - Production of n-substituted oxazolidines - Google Patents
Production of n-substituted oxazolidinesInfo
- Publication number
- CA1075701A CA1075701A CA258,154A CA258154A CA1075701A CA 1075701 A CA1075701 A CA 1075701A CA 258154 A CA258154 A CA 258154A CA 1075701 A CA1075701 A CA 1075701A
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- Canada
- Prior art keywords
- hydrogen
- phenyl
- lower alkyl
- alkyl
- oxazolidine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
PRODUCTION OF N-SUBSTITUTED OXAZOLIDINES
Abstract of the Disclosure N-substituted oxazolidines having the formula in which:
a) R is C1-C10 haloalkyl, C1-C10 alkyl or lower alkyl-thio; R1 and R2 are independently hydrogen, C1-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are indepen-dently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, or in which:
b) R is haloalkyl or chloroalkenyl, R1 is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy or hy-droxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower akyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloroacetoxymethyl;
R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl and R6 is hydrogen; provided that at least one of R1 or R5 is phe-nyl, substituted phenyl or naphthyl, are prepared by reacting an oxazolidine with an acid chloride or analogous compound in the presence of a hydrogen chloride acceptor and water. The process is characterized by minimization of by-product formation.
Abstract of the Disclosure N-substituted oxazolidines having the formula in which:
a) R is C1-C10 haloalkyl, C1-C10 alkyl or lower alkyl-thio; R1 and R2 are independently hydrogen, C1-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are indepen-dently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, or in which:
b) R is haloalkyl or chloroalkenyl, R1 is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy or hy-droxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower akyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloroacetoxymethyl;
R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl and R6 is hydrogen; provided that at least one of R1 or R5 is phe-nyl, substituted phenyl or naphthyl, are prepared by reacting an oxazolidine with an acid chloride or analogous compound in the presence of a hydrogen chloride acceptor and water. The process is characterized by minimization of by-product formation.
Description
~07570~
Background and ~rior Art This application relat~s to the production of oxazolidines having the formul~
R3 ~ R6 - R ---C - N o ~ R
Rl 2 in which: -a) R is Cl-C10 haloalkyl, Cl-C10 alkyl or lower alkylthio; Rl and R2 are independently hydrogen, Cl-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkoxyalkyl or lower - alkylol; or in which:
b) R is haloalkyl or chloroalkenyl, Rl is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloro-acetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of Rl or R5 is phenyl, substituted phenyl or naphthyl.
,In describing the above group of compounds, in the compounds in group (a) above, the terms "alkyl" and "haloalkyl"
include members which contain from 1 to 10, or 12 carbon atoms inclusive, as indicated, in both straight and branched chain configurations, the term "halo" including chloro and bromo with `~ubstitution being either of the mono, di, tri, tetra and/or . 2 . .. .
- :
-~ ~ 7 57 U 1 per. For in~tance, the alkyl portion may be a group such aR me-thyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, l,l-dime-thylbutyl, amyl, isoamyl, 2,4,4-trimethylpentyl, n-hexyl, iso-hexyl, n-heptyl, n-octyl, isooctyl, nonyl, decyl, dimethylheptyl, and the like. The terms "lower allcyl", "lower alkylthio", "lower ~lkoxy~lkyl" and "lower alkylol" preferably include such groups which contain from 1 to 6, most preferably ~rom 1 to 4 carbon atoms, inclusive, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl and : 10 the like; methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and the like; methoxymethyl, ethoxyethyl, hydroxy-methyl, hydroxy-n-propyl, snd the like. For purposes of clarity, these compounds will be referred to below as the "alphatic-substituted oxazolidines" (which term ~ncludes hydrogen as a substituent, as in compound 1 herein).
In the compounds of group (b) above, the following em-bodiments are intended for the various substituent groups: For R, "haloal~yl" prefer*bly includes those members which contain from 1 to 6 c~rbon atoms, inclusive, in both straight chain and branched chain configurations and the term halo includes chloro and bromo as mono, di, tri and tetra substitut~ons. As examplsry of the alkyl portion within the preferred embodiment are the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, l,l-dimethylbutyl, amyl, isoamyl, n-hexyl and isohexyl.
For R, "chloroalkenyl" preferably includes those members which contain from 2 to 4 carbon atoms and at ~east one olefinic double bond and the chloro substitu@n~s are present as mono-,di-, tri-, or tetra- substitutions, such as tri-chlorovinyl. For Rl, R2, R3, R4 and R5, "lower ~lkyl" in each lnstance preferPbly lncludes -.
those members which contain from 1 to 4 carbon atoms, inclusive, in both straight chain and branched chain configurations, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl tert.-butyl and the like. For purposes of clarity, those com-pounds will be hereafter referred to as the "aromatic-substituted oxazolidines". A preferred type of aromatic-substituted oxazoli-dine is that in which Rl and R2 are both lower alkyl (Rl and Rz may be the same or different) and R5 iS phenyl.
Compounds of these types have been found to possess activity as herbicidal antidotes and, in some cases, as herbi-cides, and are disclosed in several publications including, for instance, Belgian Patents 782,120; 806,038 and 806,040, German Offenlegungsschrift 2,341,810. Aromatic-substituted oxazolidines are further shown in Canadian patent application 245,696 of Eugene G. Teach, filed February 13, 1976.
Representative examples of compounds of these types are included in Table I, hereinbelow. --TABLE I
~ j5 R C N ¦
~0 Rl R2 Compound Number R 1 2 3 4 5 6 Aliphatic-Substituted Oxazolidines . 2 CH3 CH3 H H H H
3 CHCl CH3 CH3 H H CH3 H
~ :
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._. - - : .
. : - . - .
:. , . - j ~.
- .... , . , . . .. ` . . ..
~075701 TABLE I (cont.) Number R Rl R2 R3 4 R5 R6 CH2Cl CH3 CH3 H H H H
6 CBr3 CH3 CH3 H H H H
7 CH2Br CH3 CH3 CH3 CH3 H H
12 CHC12 CH3 t C4Hg H H H H
; 14 CBr3 H H C2H5 H H H
CHC12 CH3 i C3H7 H H H H
16 CBr3 CH3 C2H5 H H H H
17 CBr3 C2H5 H H H H H
18 CH3cHBr CH3 CH3 H H CH3 H
, CH3CHBr C2H5 H H H CH3 H
2020 CH2Br CH3 CH3 C2H5 H H H
21 CH2Br CH3 H H H H H
22 CH3(CHBr)4 CH3 CH3 H H H H
. 23 2CH2 CH3 CH3 H H H H
~ 24 CH2BrCHBr CH3 4 9 H H H
s 25 CHBr2 C2H5 H H H H H
s 26 (CH ) CB C2H5 H H H CH3 H
~ 27 CC13 CH3 H H H H H
.i1 28 CH2BrC(CH3)Br CH3 H H H CH3 H
; 29 CH2BrCH2 CH3 CH3 H H H H
; 3030 Cl(CH2)3 CH3 CH3 H H H H
., ' :~ _5_ :--' .
TABLE I (cont.) 107~701 .
Number R Rl R2 R3 4 5 6_ 31 CH3CHClCH2 CH3 CH3 H H H H
32 C2H5CHBr CH3 CH3 H H CH3 H
33 C3H7CHBr CH3 CH3 H H H H
34 CH2ClCH2CH2 CH3 CH3 H H CH3 H
CH2Br(CH2)4 CH3 CH3 H H CH3 H
: 38 C3H7S CH3 CH3 C2H5 H H H
39 i-C3H S CH3 CH3 C2H5 H H H
41 4HgS CH3 H C2H5 H H H
CH2Cl CH3 CH3 H H 3 7 H
48 CH2C1 2,6-dimethyl- H CH3 3 H H .-heptyl 49 CH2Cl n-C3H7 CH3 CH3 3 H
51 2Cl n-C3H7 n~C3H7 CH3 3 H H
Aromatic-Substituted Oxazolidines ., :
:. 52 CHC12 m NO2 C6H4 H CH3 3 H H
54 CHBrCH3 C6H5 H H H H H
56 CHBr2 C6H5 H H H H H
57 CCl~CC12 C6H5 H H H H H
.. . .
~ . . . . . . . .
~07~701 TABLE I (cont.) Compound R R R R R R
Number R 1 2 3 4 5 6 _ _ _ _ _ _ 58 CH2Cl m-ClC6H4 H H H H H
59 CH2Br m-ClC6H4 H H H H H
64 CH2Cl CH3 3 6 5 H
CHBrCH2Br p-CH3-C6H4 H H H H H
67 CHC12 m-CH3O-C6H4 H H H H H
68 2CH3 m-CH3O-C6H4 H H H H H
69 CH2Cl ~ H H H H H
CC12CH3 ~ H H H H H
72 2Cl C6H5 H CH3 CH3 CH3 H
CH2Cl , 2 C6H3 H H H H H
76 CHC12 , 2 6H3 H H H H H
77 2CH3 , 2 C6H3 H H H H H
78 CH2Cl H H H H C6H5 H
79 CH2-CH2Br H H H 6 5 H
CHC12 m-OH-C6H H H H H H
~i .
107S70~
TABLE I (cont.) Compound R - R2 R3 4 R5 6_ _ _ 84 CHC12 o-Cl-C H H H H H H
CH2Cl p-Cl-C H H H H H H
86 CHC12 p-Cl-C6H H H H H H
87 CCl=CC12 p-Cl-C H H H H H H
In one preferred embodiment of the alkyl-substituted oxazolidines, Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy-alkyl or lower alkylol.
According to the prior art, oxazolidines were generally prepared by the condensation of alkanolamines wi$h a suitable aldehyde or ketone in a solvent such as benzene, with water being removed from the reaction product. Such a method is describea, for instance, in the article by Bergmann et al., JACS 75 358 - -(1953). In order to produce N-substituted oxazolidines of the types mentioned herein, the product of this reaction was further --treated with an acia chloride in the presence of a hydrogen chloriae acceptor, such as triethylamine. This reaction was conducted in the anhydrous state, the water having been removed . ' .
after the condensation of the alkanolamine with the carbonyl compound. Processes of this type, for example, are described in the above-mentioned Belgian patents and U.S. patent 3,707,541.
~, , 30 .
~ .
.
;. . ~ - ~ . ~ - -, : .. .
- . . : . - . - . ~ . :
iO75~701 Substituted ox~zolidines produced in this m~nner ~re fre~uently cont~minPted with by-products, gener~lly resulting from the re~ction of the ~cid chloride w~th by-products or resc-tion intermedi~tes formed during the condens~tion step. These by-products h~ve often proved difficult to seper~te either because of their quantity or their che~icel beh~vior, or both. In the production of substituted ox~zo~ idines on P sm~ll sc~le, such PS
for l~bor~tory or testing purposes~ the desired product c~n be obt~ined in the subst~nti~lly pure st~te with sufficient purifi-c~tion. Such purificPtion steps, however, m~y result in suffi-cient product loss es to be detriment~l if the desired product is to be produced on ~ l~rger scPle, for inst~nce, commerci~lly.
Furthermore, the elimin~tion or reduction of such purific~tion steps would be ~dv~ntPgeous in a co~erciPl f~cility since the inst~lled ~nd/or oper~ting cost could be reduced by the cost of - eauipment and/or solvent not reauired.
It is ~n ob3ect of the present invention to provide ~n improved process for the production of N-substituted oxazolidines.
Another object of the present invention is to provide ~ process for the production of N-substituted ox~zolidines of ~deau~te purity.
Yet ~ further object of the present invention is to provide ~ process for the production of N-substituted ox~zoli-dines re~uiring fewer purific~tion steps thPn previously.
Still ~nother ob3ect of the present invention is to provide P process for the production of N-substituted ox~zolidines in which the production of undesir~ble by-products c~n be mini-mized.
~ -9-.... . . . .
. .
Summary of the Invention The present invention comprises a process for the pro-duction of N-substituted oxazolidines having the formula 3 ~ R6 R C N
~0 R
in which:
a) R is Cl-C10 haloalkyl, Cl-C10 alkyl or lower alkyl-thio; Rl and R2 are independently hydrogen, Cl-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are indepen-dently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, j or in which:
b) R is haloalkyl or chloroalkenyl, Rl is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy - or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloro-` acetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of Rl or R5 is phenyl, substituted phenyl or naphthyl, com-~ prising reacting an oxazolidine having the formula :, ' R3 R4 5 >~ R6 HN
.''' ~ ~
. 30 Rl R2 ''. O
with a compound having the formula R C - X, in which X is a --10-- -' , - ' halogen, in ~he presence of a hydrogen chloride acceptor and water.
In a preferred embodiment, the invention herein com-prises a process for production of N-su~stituted oxazolidines having the above formula comprising the steps of:
a) Reacting an alXanolamine having the formula IR5 l3 with a carbonyl compound having the rormula il Rl C R2 to produce a reaction product com-- prising an oxazolidine and water; and b) reacting the oxazolidine in the presence of water and a hydrogen chloride acceptor, with a compound having the formula q in which X is a halogen.
t R X
In another aspect, the invention comprises a process - for the production of N-substituted oxazolidines having the aforesaid formula comprising:
a) Reacting an alkanolamine having the formula l3 - H N - C - O~
. 2 R6 R4 with a carbonyl compound having the formula n Rl - ~ R2 to produce a reaction product comprising an oxazolidine ~: and water, .~
. ~ , . . .
~075701 b) removing w~ter from the re~ction product of (~);
~nd c) re~cting the ox~zolldine from step (b) with ~ com-pound hPving the formul~ R- ~ - X , in which X is ~ h~logen, in the presence of ~ hydrogen chloride ~cceptor Pnd w~ter.
This v~riPtion of the process is the method by which the ~rom~tic-substituted ox~zolidines ~re prepared ~nd i8 ~180 suit~ble for the production of the filiphPtic-substituted ox~zoli-dines.
Det~iled Description of the Invention As is known in the prior ~rt, when an ~lk~nolamine is -~ condensed with ~n ~ldehyde or ketone, the resulting product is anoxazolidine. However, the ox~zolidine is gener~lly believed to be in t~utomeric eauilibrium wth ~ Schiff b~se. For exsmple, the rePction of eth~nolamine with scetone in the presence of ~ solvent such PS benzene produces a mixture of 2,2-dimethylox~zolidine Pnd a Schiff bPse h~ving the formul~
CH20H CH~N=C \ , plus water.
C~l~
Longer ch~in ~lk~nolAmines, in which the hydroxyl group is ~tt~ched I to the cPrbon ~tom ~dj~cent to the ~mino group, rePct in ~ simil~r; 20 f~shion~ resulting in ox~zolidines cont~ining v~rious substituentson the ring. Gener~lly both the desired ox~zol~dine ~nd the - undesired Schiff b~se ~re present in the re~ction mixture. In : the prior ~rt, w~ter is removed from the re~ction mixture by strippng or distill~tion ~nd the rem~ining products re~cted in ~n , ~ . - .
.
- -: `' ' : - .
1075'701 Pnhydrous system with ~n ~cid chloride to produce ~n N-substituted ox~zolidine, plus hydrogen chloride.
However, the Schiff b~se will Plso re~ct with the ~cid chloride, producing undesir~ble by-products of v~rious types, believed to be prim~rily esters. These must be sep~r~ted from the desired N-substituted ox~zolidine in order for the l~tter to be used either commerciPlly or otherwise. In ~ number of c~ses, good sep~r~tion is difficult to schieve: in others, it c~n be ~chieved, but m~y reauire sever~l purific~tion steps.
It h~s now been found, however, if, contrPry to the prior ~rt pr~ctice, the rePction of the 02~zolidine ~nd acid chloride is conducted in the presence of wPter, the purity of the substituted ox~zolidine obtPined is substPnti~l~y gre~ter, per-- mitting purific~tion with ~ewer steps. Addition~lly, the yield of the desired oxazolidine mey ~lso be incre~sed.
In general, the process is conducted by re~cting the ox~zolidine with the ~cid chloride in the presence of water ~nd ~ hydrogen chloride ~cceptor, such as sodium hydroxide. The hydrogen chloride ~cceptor is generally present in ~ concentr~tion of between ~bout 5 ~nd ~bout 5~/0.
In one embodiment, the w~ter produced during condens~-tion of the ~ nol~mine with the ~ldehyde or ketone is ret~ned in the re~ction system ~nd the totPl rePction products (including the ox~olidine ~nd w~ter) ~re cont~cted with ~n ~cid chloride in the presence of ~ hydrogen chloride ~cceptor.
In ~nother embodiment, w~ter is removed from the con-dens~tion re~ction products, but is re-introduced into the system in the form of ~n ~aueous solution of ~ hydrogen chloride ~cceptor ~ such ~s sodium hydroxide.
:.
In ~nother preferred embodiment, ~n ~aueous solution of c~ustic contPining ~bout 5 - 5~/0 NPOH i~ ~dded to the system prior to ~ddition of the ~cid chloride, The strong b~se serves to function PS the hydrogen chloride ~cceptor in the following step ~nd is ~lso believed to be effective in lowering the water v~por pressure over the re~ction system, promoting the form~tion of the ox~olidine from the diol intermediAte, r~ther th~n the Schiff b~se. If the concentr~tion of the N~OH is greater thPn 20qo~ sodium chloride will be precipit~ted from the system. re-~uiring dilution of the mixture before purific~tion or remov~l by filtr~tion or simil~r me~ns.
Another Pdv~nt~ge of the present process is th~t since the rePction of the ox~zolidine ~nd the ~cid chloride ~re con-ducted in ~ueous solution, it is not necess~ry to utili~e com-p~r~tively expensive hydrogen chloride Pcceptors such ~s triethyl~-mlne, although these c~n be used ~s they will serve to effectu~te ` this reaction. The hydrogen chloride acceptor utilized m~y be - less expensive subst~nce, for example, ~ we~k CPUStiC solution, or ~nother ~lk~li met~l hydroxide such ~s pot~ssium hydroxide (in ~aueous solution). Most common hydrogen chloride ~cceptors are miscible with or soluble in w~ter under the conditions employed;
however, w~ter-immiscible hydrogen chloride ~cceptors such as dimethyl~niline m~y be used. As mentioned above, if ~n squeous c~ust~c solution is added to the re~ction product prior to the ~ddition of the ~cid chloride, this c~ustic will ~lso serve to function ~s the hydrogen chloride ~cceptor.
i . Prefer~bly, the re~ction is run ~t low temper~tures, such ~s -5 to ~5C. However, the re~ction c~n be run ~t somewh~t higher temPer~tures, for ex~mple, up to ~bout 25C, though ~t ~ 10 75~70 ~
these temper~tures the product yield m~y be somewhat less, The ~lk~nolPmine used c~n be ~ny lower Plk~nolsmine, thPt is one hsv-ing from ~bout 2 to ~bout 6 c~rbon ~toms, provided th~t the hydroxyl group ~nd ~mino group Pre ~tt~ched to sd~cent c~rbon ~toms. The c~rbonyl compound can be ~ny suit~ble ~ldehyde or ketone of the formuls RlCOR2 in which Rl ~nd R2 sre as previously defined.
The following ex~mples ~re illustr~tive of the u~e of the process of the present invention.
PrepsrAtion of 2,2-dimethyl-3-dichloro~cetyl ox~zolidine (Compound 2 ~n the T~ble) Ex~mple 1 (Prior Art) 5.1 grPms of 2,2-dimethyl oxszolidine dissolved in 50 - ml of benzene ~5 tre~ted with 5.5 g. of triethyl~mine ~nd 7.4 g.
of dichloro~cetyl chloride w~s ~dded dropwise with stirring ~nd cooling in an ice b2th. The mixture w~s poured into w~ter, the ben~ene solution sepPr~ted, dried over anhydrous m~gnesium sulf~te ~nd the solvent stripped under v~cuum. The product w~s a wPxy .
solid which h~d ~ melting point of 113-115C on recryst~ zation from diethyl ether.
Ex~mple 2 122 ml (122 g.) eth~nolamine, 150 ml scetone ~nd 600 ml benzene were introduced into ~ 2-liter re~ctor. The mixture w~s he~ted to reflux~ water w~s stripped off, the resction mixture was ~llowed to cool, and 200 ml of 37~/0 N~OH And 175 ml of w~ter were ~dded. The mixture wss m~intPined Pt sbout 5C while 100 ml of dichloro~cetyl chlor~de w~s ~dded. The ~ixture w~s let st~nd for 1 hour, then ~n ~dditionsl 93 ~1 of dichloro~cetyl chloride w~s added. The pH of the mixture dropped to below 13 ~nd 25 ml of 2~b N~OH w~s ~dded, bringing the pH up to 13.8. The .. . .
- . . . . .
107570~
re~ction product w~s neutr~lized with concentrated hydrochloric ~cid: benæene was stripped off ~nd the product filtered ~nd dr-ed.
There w~s obt~ined 282 g. (66.~/~ of theoretic~l) of ~ solid, m.p. 117.5-119.5C.
Ex~ple 3 122 ml (122 g) eth~nol~mine, 150 ml (116 g) ~cetone ~nd 600 ml benzene were in~roduced into ~ 2-liter reactor. The re~ction proceeded ~t ~ temper~ture of ~bout 33-34C. The re~ction mixture was stirred for 1 hour, 200 ml of 3~/O N~OH were added, the temper~ture lowered to ~bout 5C with ~n ~cetone-ice b~th ~nd the m~xture stirred for 3 more hours. 110 ml (168.5 g) of dichlo-ro~cetyl chloride w~s Pdded over ~ period of 1 hour, followed by 25 ml of 33% N~OH Pnd ~ second portion of 110 ml of dichloro~cetyl chloride (slowly ~dded). The re~ction product w~s neutr~lized with concentr~ted hydrochloric ~cid. Water (190 ml) w~s added to dissolve the sodium chloride formed, benzene w~s stripped off ~nd the product filtered ~nd drled. There w~s obt~ined 347 g (8270 of theoretic~l) m.p. 117.5-119C.
Prepar~tion of 2,2,5-trimethyl-3-dichloro~cet~l oxazo~idine (Compound 3 in the T~ble) Ex~mple 4 (Prior Art) 18 ml of P benzene solution containing 4.6 g of 2,2,5-trimethyl oxazolidine w~s ~dded to 25 ml of benzene ~nd 4.5 g of triethylamine. Five ~nd nine-tenths (5.9) gr~ms of dichloro-- ~cetyl chloride w~s ~dded dropwise with stirring ~nd cooling in ~n ice b~th. When re~ction w~s complete the mixture w~s poured into w~ter ~nd the benzene l~yer sep~r~ted, dried over ~nhydrous m~gnesium sulf~te Pnd the benzene removed under v~cuum. Yield w~s 7.7 g of ~n oil, n30 ~ 1.4950.
, - , - ~
- ' ' - . . -, . . -Ex~mple 5 150 g (162 ml) of isoprop~nol~mine, density 0.961, wPs mixed with 150 ml (116 g) ~cetone and 600 ml benzene. W~ter w~s stripped off~ the re~ction mixture cooled down ~nd 200 ml of 20qo of N~OH ~nd 175 ml of w~ter were mixed with the products Subseauently, 202 ~1 (310 g) of 96% pure dichloroPcetyl chloride w~s ~dded. Te~perPture w~s m~intained ~t 5C. The re~ction product w~s neutr~lized with concentr~ted hydrochloric ~cid, tr~nsferred to P separ~tory funnel ~nd w~shed once with distilled w~ter. Benzene w~s stripped off. 343 g of 2,2,5-trimethyl-3-dichloro~cetyl ox~zolidine were recovered (76% of theoretic~l), melting point 77-84C.
Ex~mple 6 150 g (162 ml) of isoprop~nol~mine, 150 ml (116 g) of ~cetone ~nd 600 ml of benzene were introduced into a 2-liter re~ctor. The products were ~eated to 40 ~nd stirred for ~n hour.
200 ml of 3370 sodium hydroxide w~s added and the resulting mix-ture ætirred for two more hours. The resulting mixture w~s chilled ~t 5C with an ice b~th using acetone and 110 ml of dichloro~cetyl chloride w~s slowly ~dded over ~ period of one hour. The mlxture w~s allowed to st~nd for one Pnd ~ half hours more,then 110 Pdd~tion~l ml of dichloro~cetyl chloride were ~dded over ~nother hour's time, together with ~n addition~l 10 ml of 3370 N~OH. The pH of the re~ction product wPs 11.1. The re~ction products were neutrPlized with hydrochloric ~cid until the pH w~s about 3. Water (185 ml) was added to dissolve the 25~ sodium chloride formed. Benzene w~s stripped o f under v~cuum.
The product w~s filtered, stripped ~nd dried without further cryst~llizPt~on. 346.2 g were recovered (7770 of theoretic~l), melting point 87-88C.
:~ . ' :' ' , , ' Preparation of 2,2-dimethyl-3-dichloroacetyl-5-phenyl oxazolidine (Compound 63 of the table).
Example 7 (Prior Art~
100 grams of 1-phenyl-2-amino ethanol was dissolvet in 250 ml of benzene and 45 g of acetone was added. The mixture was heated at reflux for several hours while about 15 ml of water was remo~ed with a modified Dean-Stark apparatus. The mlxture was cooled and 75 ml of triethylamine was added, followed by 108 g of dichloroacetyl chloride added dropwise with stirring and cooling in a room temperature water bath. The solution was allowed to stand over anhydrous magnesium sulfate, and the sol-vent stripped under vacuum. The thick o~l, wt. 170 g., crystal-~Q lized on standing and was triturated with dry ether to give 132 g (6370 of theoretical) of the desired compound, a-white solid, m.p.
99.5-100.5C.
` Example 8 One liter of benzene containing 531.6 g of l-phenyl-
Background and ~rior Art This application relat~s to the production of oxazolidines having the formul~
R3 ~ R6 - R ---C - N o ~ R
Rl 2 in which: -a) R is Cl-C10 haloalkyl, Cl-C10 alkyl or lower alkylthio; Rl and R2 are independently hydrogen, Cl-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkoxyalkyl or lower - alkylol; or in which:
b) R is haloalkyl or chloroalkenyl, Rl is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloro-acetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of Rl or R5 is phenyl, substituted phenyl or naphthyl.
,In describing the above group of compounds, in the compounds in group (a) above, the terms "alkyl" and "haloalkyl"
include members which contain from 1 to 10, or 12 carbon atoms inclusive, as indicated, in both straight and branched chain configurations, the term "halo" including chloro and bromo with `~ubstitution being either of the mono, di, tri, tetra and/or . 2 . .. .
- :
-~ ~ 7 57 U 1 per. For in~tance, the alkyl portion may be a group such aR me-thyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, l,l-dime-thylbutyl, amyl, isoamyl, 2,4,4-trimethylpentyl, n-hexyl, iso-hexyl, n-heptyl, n-octyl, isooctyl, nonyl, decyl, dimethylheptyl, and the like. The terms "lower allcyl", "lower alkylthio", "lower ~lkoxy~lkyl" and "lower alkylol" preferably include such groups which contain from 1 to 6, most preferably ~rom 1 to 4 carbon atoms, inclusive, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl and : 10 the like; methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and the like; methoxymethyl, ethoxyethyl, hydroxy-methyl, hydroxy-n-propyl, snd the like. For purposes of clarity, these compounds will be referred to below as the "alphatic-substituted oxazolidines" (which term ~ncludes hydrogen as a substituent, as in compound 1 herein).
In the compounds of group (b) above, the following em-bodiments are intended for the various substituent groups: For R, "haloal~yl" prefer*bly includes those members which contain from 1 to 6 c~rbon atoms, inclusive, in both straight chain and branched chain configurations and the term halo includes chloro and bromo as mono, di, tri and tetra substitut~ons. As examplsry of the alkyl portion within the preferred embodiment are the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, l,l-dimethylbutyl, amyl, isoamyl, n-hexyl and isohexyl.
For R, "chloroalkenyl" preferably includes those members which contain from 2 to 4 carbon atoms and at ~east one olefinic double bond and the chloro substitu@n~s are present as mono-,di-, tri-, or tetra- substitutions, such as tri-chlorovinyl. For Rl, R2, R3, R4 and R5, "lower ~lkyl" in each lnstance preferPbly lncludes -.
those members which contain from 1 to 4 carbon atoms, inclusive, in both straight chain and branched chain configurations, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl tert.-butyl and the like. For purposes of clarity, those com-pounds will be hereafter referred to as the "aromatic-substituted oxazolidines". A preferred type of aromatic-substituted oxazoli-dine is that in which Rl and R2 are both lower alkyl (Rl and Rz may be the same or different) and R5 iS phenyl.
Compounds of these types have been found to possess activity as herbicidal antidotes and, in some cases, as herbi-cides, and are disclosed in several publications including, for instance, Belgian Patents 782,120; 806,038 and 806,040, German Offenlegungsschrift 2,341,810. Aromatic-substituted oxazolidines are further shown in Canadian patent application 245,696 of Eugene G. Teach, filed February 13, 1976.
Representative examples of compounds of these types are included in Table I, hereinbelow. --TABLE I
~ j5 R C N ¦
~0 Rl R2 Compound Number R 1 2 3 4 5 6 Aliphatic-Substituted Oxazolidines . 2 CH3 CH3 H H H H
3 CHCl CH3 CH3 H H CH3 H
~ :
~'' .
._. - - : .
. : - . - .
:. , . - j ~.
- .... , . , . . .. ` . . ..
~075701 TABLE I (cont.) Number R Rl R2 R3 4 R5 R6 CH2Cl CH3 CH3 H H H H
6 CBr3 CH3 CH3 H H H H
7 CH2Br CH3 CH3 CH3 CH3 H H
12 CHC12 CH3 t C4Hg H H H H
; 14 CBr3 H H C2H5 H H H
CHC12 CH3 i C3H7 H H H H
16 CBr3 CH3 C2H5 H H H H
17 CBr3 C2H5 H H H H H
18 CH3cHBr CH3 CH3 H H CH3 H
, CH3CHBr C2H5 H H H CH3 H
2020 CH2Br CH3 CH3 C2H5 H H H
21 CH2Br CH3 H H H H H
22 CH3(CHBr)4 CH3 CH3 H H H H
. 23 2CH2 CH3 CH3 H H H H
~ 24 CH2BrCHBr CH3 4 9 H H H
s 25 CHBr2 C2H5 H H H H H
s 26 (CH ) CB C2H5 H H H CH3 H
~ 27 CC13 CH3 H H H H H
.i1 28 CH2BrC(CH3)Br CH3 H H H CH3 H
; 29 CH2BrCH2 CH3 CH3 H H H H
; 3030 Cl(CH2)3 CH3 CH3 H H H H
., ' :~ _5_ :--' .
TABLE I (cont.) 107~701 .
Number R Rl R2 R3 4 5 6_ 31 CH3CHClCH2 CH3 CH3 H H H H
32 C2H5CHBr CH3 CH3 H H CH3 H
33 C3H7CHBr CH3 CH3 H H H H
34 CH2ClCH2CH2 CH3 CH3 H H CH3 H
CH2Br(CH2)4 CH3 CH3 H H CH3 H
: 38 C3H7S CH3 CH3 C2H5 H H H
39 i-C3H S CH3 CH3 C2H5 H H H
41 4HgS CH3 H C2H5 H H H
CH2Cl CH3 CH3 H H 3 7 H
48 CH2C1 2,6-dimethyl- H CH3 3 H H .-heptyl 49 CH2Cl n-C3H7 CH3 CH3 3 H
51 2Cl n-C3H7 n~C3H7 CH3 3 H H
Aromatic-Substituted Oxazolidines ., :
:. 52 CHC12 m NO2 C6H4 H CH3 3 H H
54 CHBrCH3 C6H5 H H H H H
56 CHBr2 C6H5 H H H H H
57 CCl~CC12 C6H5 H H H H H
.. . .
~ . . . . . . . .
~07~701 TABLE I (cont.) Compound R R R R R R
Number R 1 2 3 4 5 6 _ _ _ _ _ _ 58 CH2Cl m-ClC6H4 H H H H H
59 CH2Br m-ClC6H4 H H H H H
64 CH2Cl CH3 3 6 5 H
CHBrCH2Br p-CH3-C6H4 H H H H H
67 CHC12 m-CH3O-C6H4 H H H H H
68 2CH3 m-CH3O-C6H4 H H H H H
69 CH2Cl ~ H H H H H
CC12CH3 ~ H H H H H
72 2Cl C6H5 H CH3 CH3 CH3 H
CH2Cl , 2 C6H3 H H H H H
76 CHC12 , 2 6H3 H H H H H
77 2CH3 , 2 C6H3 H H H H H
78 CH2Cl H H H H C6H5 H
79 CH2-CH2Br H H H 6 5 H
CHC12 m-OH-C6H H H H H H
~i .
107S70~
TABLE I (cont.) Compound R - R2 R3 4 R5 6_ _ _ 84 CHC12 o-Cl-C H H H H H H
CH2Cl p-Cl-C H H H H H H
86 CHC12 p-Cl-C6H H H H H H
87 CCl=CC12 p-Cl-C H H H H H H
In one preferred embodiment of the alkyl-substituted oxazolidines, Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy-alkyl or lower alkylol.
According to the prior art, oxazolidines were generally prepared by the condensation of alkanolamines wi$h a suitable aldehyde or ketone in a solvent such as benzene, with water being removed from the reaction product. Such a method is describea, for instance, in the article by Bergmann et al., JACS 75 358 - -(1953). In order to produce N-substituted oxazolidines of the types mentioned herein, the product of this reaction was further --treated with an acia chloride in the presence of a hydrogen chloriae acceptor, such as triethylamine. This reaction was conducted in the anhydrous state, the water having been removed . ' .
after the condensation of the alkanolamine with the carbonyl compound. Processes of this type, for example, are described in the above-mentioned Belgian patents and U.S. patent 3,707,541.
~, , 30 .
~ .
.
;. . ~ - ~ . ~ - -, : .. .
- . . : . - . - . ~ . :
iO75~701 Substituted ox~zolidines produced in this m~nner ~re fre~uently cont~minPted with by-products, gener~lly resulting from the re~ction of the ~cid chloride w~th by-products or resc-tion intermedi~tes formed during the condens~tion step. These by-products h~ve often proved difficult to seper~te either because of their quantity or their che~icel beh~vior, or both. In the production of substituted ox~zo~ idines on P sm~ll sc~le, such PS
for l~bor~tory or testing purposes~ the desired product c~n be obt~ined in the subst~nti~lly pure st~te with sufficient purifi-c~tion. Such purificPtion steps, however, m~y result in suffi-cient product loss es to be detriment~l if the desired product is to be produced on ~ l~rger scPle, for inst~nce, commerci~lly.
Furthermore, the elimin~tion or reduction of such purific~tion steps would be ~dv~ntPgeous in a co~erciPl f~cility since the inst~lled ~nd/or oper~ting cost could be reduced by the cost of - eauipment and/or solvent not reauired.
It is ~n ob3ect of the present invention to provide ~n improved process for the production of N-substituted oxazolidines.
Another object of the present invention is to provide ~ process for the production of N-substituted ox~zolidines of ~deau~te purity.
Yet ~ further object of the present invention is to provide ~ process for the production of N-substituted ox~zoli-dines re~uiring fewer purific~tion steps thPn previously.
Still ~nother ob3ect of the present invention is to provide P process for the production of N-substituted ox~zolidines in which the production of undesir~ble by-products c~n be mini-mized.
~ -9-.... . . . .
. .
Summary of the Invention The present invention comprises a process for the pro-duction of N-substituted oxazolidines having the formula 3 ~ R6 R C N
~0 R
in which:
a) R is Cl-C10 haloalkyl, Cl-C10 alkyl or lower alkyl-thio; Rl and R2 are independently hydrogen, Cl-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are indepen-dently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, j or in which:
b) R is haloalkyl or chloroalkenyl, Rl is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy - or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or dichloro-` acetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of Rl or R5 is phenyl, substituted phenyl or naphthyl, com-~ prising reacting an oxazolidine having the formula :, ' R3 R4 5 >~ R6 HN
.''' ~ ~
. 30 Rl R2 ''. O
with a compound having the formula R C - X, in which X is a --10-- -' , - ' halogen, in ~he presence of a hydrogen chloride acceptor and water.
In a preferred embodiment, the invention herein com-prises a process for production of N-su~stituted oxazolidines having the above formula comprising the steps of:
a) Reacting an alXanolamine having the formula IR5 l3 with a carbonyl compound having the rormula il Rl C R2 to produce a reaction product com-- prising an oxazolidine and water; and b) reacting the oxazolidine in the presence of water and a hydrogen chloride acceptor, with a compound having the formula q in which X is a halogen.
t R X
In another aspect, the invention comprises a process - for the production of N-substituted oxazolidines having the aforesaid formula comprising:
a) Reacting an alkanolamine having the formula l3 - H N - C - O~
. 2 R6 R4 with a carbonyl compound having the formula n Rl - ~ R2 to produce a reaction product comprising an oxazolidine ~: and water, .~
. ~ , . . .
~075701 b) removing w~ter from the re~ction product of (~);
~nd c) re~cting the ox~zolldine from step (b) with ~ com-pound hPving the formul~ R- ~ - X , in which X is ~ h~logen, in the presence of ~ hydrogen chloride ~cceptor Pnd w~ter.
This v~riPtion of the process is the method by which the ~rom~tic-substituted ox~zolidines ~re prepared ~nd i8 ~180 suit~ble for the production of the filiphPtic-substituted ox~zoli-dines.
Det~iled Description of the Invention As is known in the prior ~rt, when an ~lk~nolamine is -~ condensed with ~n ~ldehyde or ketone, the resulting product is anoxazolidine. However, the ox~zolidine is gener~lly believed to be in t~utomeric eauilibrium wth ~ Schiff b~se. For exsmple, the rePction of eth~nolamine with scetone in the presence of ~ solvent such PS benzene produces a mixture of 2,2-dimethylox~zolidine Pnd a Schiff bPse h~ving the formul~
CH20H CH~N=C \ , plus water.
C~l~
Longer ch~in ~lk~nolAmines, in which the hydroxyl group is ~tt~ched I to the cPrbon ~tom ~dj~cent to the ~mino group, rePct in ~ simil~r; 20 f~shion~ resulting in ox~zolidines cont~ining v~rious substituentson the ring. Gener~lly both the desired ox~zol~dine ~nd the - undesired Schiff b~se ~re present in the re~ction mixture. In : the prior ~rt, w~ter is removed from the re~ction mixture by strippng or distill~tion ~nd the rem~ining products re~cted in ~n , ~ . - .
.
- -: `' ' : - .
1075'701 Pnhydrous system with ~n ~cid chloride to produce ~n N-substituted ox~zolidine, plus hydrogen chloride.
However, the Schiff b~se will Plso re~ct with the ~cid chloride, producing undesir~ble by-products of v~rious types, believed to be prim~rily esters. These must be sep~r~ted from the desired N-substituted ox~zolidine in order for the l~tter to be used either commerciPlly or otherwise. In ~ number of c~ses, good sep~r~tion is difficult to schieve: in others, it c~n be ~chieved, but m~y reauire sever~l purific~tion steps.
It h~s now been found, however, if, contrPry to the prior ~rt pr~ctice, the rePction of the 02~zolidine ~nd acid chloride is conducted in the presence of wPter, the purity of the substituted ox~zolidine obtPined is substPnti~l~y gre~ter, per-- mitting purific~tion with ~ewer steps. Addition~lly, the yield of the desired oxazolidine mey ~lso be incre~sed.
In general, the process is conducted by re~cting the ox~zolidine with the ~cid chloride in the presence of water ~nd ~ hydrogen chloride ~cceptor, such as sodium hydroxide. The hydrogen chloride ~cceptor is generally present in ~ concentr~tion of between ~bout 5 ~nd ~bout 5~/0.
In one embodiment, the w~ter produced during condens~-tion of the ~ nol~mine with the ~ldehyde or ketone is ret~ned in the re~ction system ~nd the totPl rePction products (including the ox~olidine ~nd w~ter) ~re cont~cted with ~n ~cid chloride in the presence of ~ hydrogen chloride ~cceptor.
In ~nother embodiment, w~ter is removed from the con-dens~tion re~ction products, but is re-introduced into the system in the form of ~n ~aueous solution of ~ hydrogen chloride ~cceptor ~ such ~s sodium hydroxide.
:.
In ~nother preferred embodiment, ~n ~aueous solution of c~ustic contPining ~bout 5 - 5~/0 NPOH i~ ~dded to the system prior to ~ddition of the ~cid chloride, The strong b~se serves to function PS the hydrogen chloride ~cceptor in the following step ~nd is ~lso believed to be effective in lowering the water v~por pressure over the re~ction system, promoting the form~tion of the ox~olidine from the diol intermediAte, r~ther th~n the Schiff b~se. If the concentr~tion of the N~OH is greater thPn 20qo~ sodium chloride will be precipit~ted from the system. re-~uiring dilution of the mixture before purific~tion or remov~l by filtr~tion or simil~r me~ns.
Another Pdv~nt~ge of the present process is th~t since the rePction of the ox~zolidine ~nd the ~cid chloride ~re con-ducted in ~ueous solution, it is not necess~ry to utili~e com-p~r~tively expensive hydrogen chloride Pcceptors such ~s triethyl~-mlne, although these c~n be used ~s they will serve to effectu~te ` this reaction. The hydrogen chloride acceptor utilized m~y be - less expensive subst~nce, for example, ~ we~k CPUStiC solution, or ~nother ~lk~li met~l hydroxide such ~s pot~ssium hydroxide (in ~aueous solution). Most common hydrogen chloride ~cceptors are miscible with or soluble in w~ter under the conditions employed;
however, w~ter-immiscible hydrogen chloride ~cceptors such as dimethyl~niline m~y be used. As mentioned above, if ~n squeous c~ust~c solution is added to the re~ction product prior to the ~ddition of the ~cid chloride, this c~ustic will ~lso serve to function ~s the hydrogen chloride ~cceptor.
i . Prefer~bly, the re~ction is run ~t low temper~tures, such ~s -5 to ~5C. However, the re~ction c~n be run ~t somewh~t higher temPer~tures, for ex~mple, up to ~bout 25C, though ~t ~ 10 75~70 ~
these temper~tures the product yield m~y be somewhat less, The ~lk~nolPmine used c~n be ~ny lower Plk~nolsmine, thPt is one hsv-ing from ~bout 2 to ~bout 6 c~rbon ~toms, provided th~t the hydroxyl group ~nd ~mino group Pre ~tt~ched to sd~cent c~rbon ~toms. The c~rbonyl compound can be ~ny suit~ble ~ldehyde or ketone of the formuls RlCOR2 in which Rl ~nd R2 sre as previously defined.
The following ex~mples ~re illustr~tive of the u~e of the process of the present invention.
PrepsrAtion of 2,2-dimethyl-3-dichloro~cetyl ox~zolidine (Compound 2 ~n the T~ble) Ex~mple 1 (Prior Art) 5.1 grPms of 2,2-dimethyl oxszolidine dissolved in 50 - ml of benzene ~5 tre~ted with 5.5 g. of triethyl~mine ~nd 7.4 g.
of dichloro~cetyl chloride w~s ~dded dropwise with stirring ~nd cooling in an ice b2th. The mixture w~s poured into w~ter, the ben~ene solution sepPr~ted, dried over anhydrous m~gnesium sulf~te ~nd the solvent stripped under v~cuum. The product w~s a wPxy .
solid which h~d ~ melting point of 113-115C on recryst~ zation from diethyl ether.
Ex~mple 2 122 ml (122 g.) eth~nolamine, 150 ml scetone ~nd 600 ml benzene were introduced into ~ 2-liter re~ctor. The mixture w~s he~ted to reflux~ water w~s stripped off, the resction mixture was ~llowed to cool, and 200 ml of 37~/0 N~OH And 175 ml of w~ter were ~dded. The mixture wss m~intPined Pt sbout 5C while 100 ml of dichloro~cetyl chlor~de w~s ~dded. The ~ixture w~s let st~nd for 1 hour, then ~n ~dditionsl 93 ~1 of dichloro~cetyl chloride w~s added. The pH of the mixture dropped to below 13 ~nd 25 ml of 2~b N~OH w~s ~dded, bringing the pH up to 13.8. The .. . .
- . . . . .
107570~
re~ction product w~s neutr~lized with concentrated hydrochloric ~cid: benæene was stripped off ~nd the product filtered ~nd dr-ed.
There w~s obt~ined 282 g. (66.~/~ of theoretic~l) of ~ solid, m.p. 117.5-119.5C.
Ex~ple 3 122 ml (122 g) eth~nol~mine, 150 ml (116 g) ~cetone ~nd 600 ml benzene were in~roduced into ~ 2-liter reactor. The re~ction proceeded ~t ~ temper~ture of ~bout 33-34C. The re~ction mixture was stirred for 1 hour, 200 ml of 3~/O N~OH were added, the temper~ture lowered to ~bout 5C with ~n ~cetone-ice b~th ~nd the m~xture stirred for 3 more hours. 110 ml (168.5 g) of dichlo-ro~cetyl chloride w~s Pdded over ~ period of 1 hour, followed by 25 ml of 33% N~OH Pnd ~ second portion of 110 ml of dichloro~cetyl chloride (slowly ~dded). The re~ction product w~s neutr~lized with concentr~ted hydrochloric ~cid. Water (190 ml) w~s added to dissolve the sodium chloride formed, benzene w~s stripped off ~nd the product filtered ~nd drled. There w~s obt~ined 347 g (8270 of theoretic~l) m.p. 117.5-119C.
Prepar~tion of 2,2,5-trimethyl-3-dichloro~cet~l oxazo~idine (Compound 3 in the T~ble) Ex~mple 4 (Prior Art) 18 ml of P benzene solution containing 4.6 g of 2,2,5-trimethyl oxazolidine w~s ~dded to 25 ml of benzene ~nd 4.5 g of triethylamine. Five ~nd nine-tenths (5.9) gr~ms of dichloro-- ~cetyl chloride w~s ~dded dropwise with stirring ~nd cooling in ~n ice b~th. When re~ction w~s complete the mixture w~s poured into w~ter ~nd the benzene l~yer sep~r~ted, dried over ~nhydrous m~gnesium sulf~te Pnd the benzene removed under v~cuum. Yield w~s 7.7 g of ~n oil, n30 ~ 1.4950.
, - , - ~
- ' ' - . . -, . . -Ex~mple 5 150 g (162 ml) of isoprop~nol~mine, density 0.961, wPs mixed with 150 ml (116 g) ~cetone and 600 ml benzene. W~ter w~s stripped off~ the re~ction mixture cooled down ~nd 200 ml of 20qo of N~OH ~nd 175 ml of w~ter were mixed with the products Subseauently, 202 ~1 (310 g) of 96% pure dichloroPcetyl chloride w~s ~dded. Te~perPture w~s m~intained ~t 5C. The re~ction product w~s neutr~lized with concentr~ted hydrochloric ~cid, tr~nsferred to P separ~tory funnel ~nd w~shed once with distilled w~ter. Benzene w~s stripped off. 343 g of 2,2,5-trimethyl-3-dichloro~cetyl ox~zolidine were recovered (76% of theoretic~l), melting point 77-84C.
Ex~mple 6 150 g (162 ml) of isoprop~nol~mine, 150 ml (116 g) of ~cetone ~nd 600 ml of benzene were introduced into a 2-liter re~ctor. The products were ~eated to 40 ~nd stirred for ~n hour.
200 ml of 3370 sodium hydroxide w~s added and the resulting mix-ture ætirred for two more hours. The resulting mixture w~s chilled ~t 5C with an ice b~th using acetone and 110 ml of dichloro~cetyl chloride w~s slowly ~dded over ~ period of one hour. The mlxture w~s allowed to st~nd for one Pnd ~ half hours more,then 110 Pdd~tion~l ml of dichloro~cetyl chloride were ~dded over ~nother hour's time, together with ~n addition~l 10 ml of 3370 N~OH. The pH of the re~ction product wPs 11.1. The re~ction products were neutrPlized with hydrochloric ~cid until the pH w~s about 3. Water (185 ml) was added to dissolve the 25~ sodium chloride formed. Benzene w~s stripped o f under v~cuum.
The product w~s filtered, stripped ~nd dried without further cryst~llizPt~on. 346.2 g were recovered (7770 of theoretic~l), melting point 87-88C.
:~ . ' :' ' , , ' Preparation of 2,2-dimethyl-3-dichloroacetyl-5-phenyl oxazolidine (Compound 63 of the table).
Example 7 (Prior Art~
100 grams of 1-phenyl-2-amino ethanol was dissolvet in 250 ml of benzene and 45 g of acetone was added. The mixture was heated at reflux for several hours while about 15 ml of water was remo~ed with a modified Dean-Stark apparatus. The mlxture was cooled and 75 ml of triethylamine was added, followed by 108 g of dichloroacetyl chloride added dropwise with stirring and cooling in a room temperature water bath. The solution was allowed to stand over anhydrous magnesium sulfate, and the sol-vent stripped under vacuum. The thick o~l, wt. 170 g., crystal-~Q lized on standing and was triturated with dry ether to give 132 g (6370 of theoretical) of the desired compound, a-white solid, m.p.
99.5-100.5C.
` Example 8 One liter of benzene containing 531.6 g of l-phenyl-
2-amino ethanol and 250 g of acetone was heated at reflux and ~I5 water was removed in a modified Dean-Star~ apparatus. When about 70 ml of water was collected, the mixture was cooled to 5 in an isopropanol-dry ice bath and 470 g of 50qO NaOH solution was added, followed by 630 g of dichloroacetyl chloride in 500 ml of benzene at a rate which kept the temperature at 1-3C. When -Z~ addition W~8 complete the mixture was allowed to warm to room temperature and neutrallzed to pH with concentrated HCl. At this ` point a precipitate appeared and was filtered off, giving 458 g of -solid, m.p. 103-105C. The benzene solution was washed with water, dried and ~he benzene stripped, giving 374 g of solid, Z5 m.p. 81-91C. This was triturated with ether to give a solid, m.p. 102-103C. This was combined with the first product to ; give a total of 778 g of product, 8 7070 yield.
.
B
As can been seen from the examples, the use of either embodiment of the present invention in the preparation of alkyl-substituted oxazolidines, produced a product of greater purity than the use of the prior art technique of operating in an anhydrous system. In the preparation of 2,2-dimethyl-3-dichloro-acetyl oxazolidine, removal of water from the system, followed by its re-introduction ln the form of an aqueous caustic solution (as in Example 2) produced a much purer product than the prior art technique of Example 1 and the product did not require re-crystallization. When the water was retained in the system (Example 3) a product of similarly improved purity was obtained, furthermore, in higher yield.
Similar results are seen by comparing the production of 2,2,5-trimethyl-3-dichloroacetyl oxazolidine in Examples 4-6.
Both methods according to the invention resulted in a crystalline product, whereas the earlier technique produced an oil, a much more impure product. Re;aining the water in the system (Example 6) produced the product of highest purity.
Similarly in the preparation of an aromatic-substituted oxazolidine, the expedient of removing water from the system i~ and then re-introducing it as a solution of NaOH resulted in a ;~ greater yield of a purer product (Example 8) then the earlier techni~ue (Example 7)~
. ' .
' ' ~
.
B
As can been seen from the examples, the use of either embodiment of the present invention in the preparation of alkyl-substituted oxazolidines, produced a product of greater purity than the use of the prior art technique of operating in an anhydrous system. In the preparation of 2,2-dimethyl-3-dichloro-acetyl oxazolidine, removal of water from the system, followed by its re-introduction ln the form of an aqueous caustic solution (as in Example 2) produced a much purer product than the prior art technique of Example 1 and the product did not require re-crystallization. When the water was retained in the system (Example 3) a product of similarly improved purity was obtained, furthermore, in higher yield.
Similar results are seen by comparing the production of 2,2,5-trimethyl-3-dichloroacetyl oxazolidine in Examples 4-6.
Both methods according to the invention resulted in a crystalline product, whereas the earlier technique produced an oil, a much more impure product. Re;aining the water in the system (Example 6) produced the product of highest purity.
Similarly in the preparation of an aromatic-substituted oxazolidine, the expedient of removing water from the system i~ and then re-introducing it as a solution of NaOH resulted in a ;~ greater yield of a purer product (Example 8) then the earlier techni~ue (Example 7)~
. ' .
' ' ~
Claims (15)
1. A process for the production of N-substituted oxazolidines having the formula in which:
a) R is C1-C10 haloalkyl, C1-C10 alkyl or lower alkyl-thio; R1 and R2 are independently hydrogen, C1-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3,R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, or in which:
b) R is haloalkyl or chloroalkenyl, R1 is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituent are mono- or dichloro, nitro, methyl, methoxy or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or di-chloroacetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydro-gen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of R1 or R5 is phenyl, substituted phenyl or naphthyl, comprising the step of reacting an oxazolidine having the formula with a compound having the formula , in which X is a halogen, in the presence of a hydrogen chloride acceptor and water.
a) R is C1-C10 haloalkyl, C1-C10 alkyl or lower alkyl-thio; R1 and R2 are independently hydrogen, C1-C12 alkyl, lower alkoxyalkyl or lower alkylol; and R3,R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol, or in which:
b) R is haloalkyl or chloroalkenyl, R1 is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituent are mono- or dichloro, nitro, methyl, methoxy or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxymethyl, N-methyl carbamoyloxymethyl or di-chloroacetoxymethyl; R4 is hydrogen or lower alkyl; R5 is hydro-gen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of R1 or R5 is phenyl, substituted phenyl or naphthyl, comprising the step of reacting an oxazolidine having the formula with a compound having the formula , in which X is a halogen, in the presence of a hydrogen chloride acceptor and water.
2. A process according to Claim 1 in which R is C1-C10 haloalkyl, C1-C10 alkyl, or lower alkylthio; R1 and R2 are independently hydrogen, C1-C10 alkyl, lower alkoxyalkyl or lower alkylol; and R3, R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkoxy-alkyl or lower alkylol.
3. A process according to Claim 1 in which R is haloalkyl, alkyl or lower alkylthio and R1, R2, R3, R4, R5 are independently hydrogen, lower alkyl, lower alkoxyalkyl or lower alkylol.
4. A process according to Claim 1 in which R is haloalkyl or chloroalkenyl, R1 is hydrogen, lower alkyl, phenyl, naphthyl, or substituted phenyl wherein the substituents are mono- or dichloro, nitro, methyl, methoxy or hydroxyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, hydroxy-methyl, N-methyl carbamoyloxymethyl or dichloroacetoxymethyl; R5 iæ hydrogen, lower alkyl or phenyl; and R6 is hydrogen, provided that at least one of R1 or R5 is phenyl, substituted phenyl or naphthyl.
5. A process according to Claim 1 in which R is halo-alkyl or chloroalkenyl; R1 is hydrogen, lower alkyl, phenyl, naph-thyl, or substituted phenyl wherein the substituents are mono-or dichloro, nitro, methyl, methoxy, or hydroxyl; R2, R3 and R4 are independently hydrogen or lower alkyl; R5 is hydrogen, lower alkyl or phenyl; and R6 is hydrogen; provided that at least one of R1 or R5 is phenyl, substituted phenyl or naphthyl.
6. A process according to Claim 4 or Claim 5 in which R1 and R2 are both lower alkyl and R5 is phenyl.
7. A process according to any oc Claim 1 in which the temperature is between about -5 and about +5°C.
8. A process according to any of Claim 1 in which the hydrogen chloride acceptor is an alkali metal hydroxide.
9. A process according to any of Claim 1 in which the hydrogen chloride acceptor is sodium hydroxide.
10. A process according to Claim 1 in which the N-substituted oxazolidine is 2,2-dimethyl-3-dichloroacetyl oxazoli-dine .
11. A process according to Claim 1 in which the N-substituted oxazolidine is 2,2,5-trimethyl-3-dichloroacetyl oxazolidine.
12. A process according to Claim 1 in which the N-substituted oxazolidine is 2,2-dimethyl-3-dichloroacetyl, 5-n-propyl oxazolidine.
13. A process according to Claim 1 in which the N-substituted oxazolidine is 2,2-dimethyl-3-dichloroacetyl-5-phenyl oxazolidine.
14. A process according to Claim 1 in which the oxazolidine was previously prepared by the reaction of an alkanolamine having the formula with a carbonyl compound having the formula producing water and the oxazolidine, and in which the water of this previous reaction was retained in contact with the oxazolidine product.
15. A process according to Claim 1 in which the oxazolidine was prepared in a previous step by reacting an alkanolamine having the formula with a carbonyl compound having the formula producing water and an oxazolidine reaction product, the water was re-moved from the system, and an aqueous solution of sodium hydroxide was added to the oxazolidine acylation step.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60847575A | 1975-08-28 | 1975-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1075701A true CA1075701A (en) | 1980-04-15 |
Family
ID=24436651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA258,154A Expired CA1075701A (en) | 1975-08-28 | 1976-07-30 | Production of n-substituted oxazolidines |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5925788B2 (en) |
| BE (1) | BE845577A (en) |
| BG (1) | BG27551A3 (en) |
| BR (1) | BR7605610A (en) |
| CA (1) | CA1075701A (en) |
| CH (1) | CH624946A5 (en) |
| CS (1) | CS191316B2 (en) |
| DD (1) | DD127680A5 (en) |
| DE (1) | DE2637580C2 (en) |
| FR (1) | FR2322141B1 (en) |
| HU (1) | HU174379B (en) |
| IL (1) | IL50192A (en) |
| IT (1) | IT1066346B (en) |
| NL (1) | NL181274C (en) |
| PL (1) | PL100986B1 (en) |
| RO (1) | RO69421A (en) |
| SU (2) | SU814276A3 (en) |
| YU (2) | YU40284B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225570A (en) * | 1987-08-13 | 1993-07-06 | Monsanto Company | 5-heterocyclic-substituted oxazolidine dihaloacetamides |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1419330A1 (en) * | 1962-06-09 | 1970-02-19 | Hoechst Ag | Optical brighteners |
| BE757717A (en) * | 1969-10-21 | 1971-04-01 |
-
1976
- 1976-07-30 CA CA258,154A patent/CA1075701A/en not_active Expired
- 1976-08-03 IL IL50192A patent/IL50192A/en unknown
- 1976-08-20 RO RO7687340A patent/RO69421A/en unknown
- 1976-08-20 DE DE2637580A patent/DE2637580C2/en not_active Expired - Lifetime
- 1976-08-20 CH CH1064076A patent/CH624946A5/en not_active IP Right Cessation
- 1976-08-21 JP JP51100109A patent/JPS5925788B2/en not_active Expired
- 1976-08-23 BR BR7605610A patent/BR7605610A/en unknown
- 1976-08-25 YU YU2076/76A patent/YU40284B/en unknown
- 1976-08-25 PL PL1976191993A patent/PL100986B1/en unknown
- 1976-08-26 BG BG034079A patent/BG27551A3/en unknown
- 1976-08-26 IT IT51031/76A patent/IT1066346B/en active
- 1976-08-26 DD DD194486A patent/DD127680A5/en unknown
- 1976-08-26 BE BE7000872A patent/BE845577A/en not_active IP Right Cessation
- 1976-08-27 NL NLAANVRAGE7609563,A patent/NL181274C/en not_active IP Right Cessation
- 1976-08-27 SU SU762391502A patent/SU814276A3/en active
- 1976-08-27 HU HU76SA2966A patent/HU174379B/en unknown
- 1976-08-27 CS CS765587A patent/CS191316B2/en unknown
- 1976-08-27 FR FR7625928A patent/FR2322141B1/en not_active Expired
-
1978
- 1978-04-27 SU SU782607602A patent/SU727145A3/en active
-
1982
- 1982-10-14 YU YU02318/82A patent/YU231882A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL50192A0 (en) | 1976-10-31 |
| NL7609563A (en) | 1977-03-02 |
| JPS5925788B2 (en) | 1984-06-21 |
| IT1066346B (en) | 1985-03-04 |
| BG27551A3 (en) | 1979-11-12 |
| SU727145A3 (en) | 1980-04-05 |
| DE2637580C2 (en) | 1990-08-02 |
| BR7605610A (en) | 1977-08-09 |
| DD127680A5 (en) | 1977-10-05 |
| HU174379B (en) | 1979-12-28 |
| IL50192A (en) | 1978-10-31 |
| CS191316B2 (en) | 1979-06-29 |
| PL100986B1 (en) | 1978-11-30 |
| SU814276A3 (en) | 1981-03-15 |
| BE845577A (en) | 1977-02-28 |
| FR2322141A1 (en) | 1977-03-25 |
| RO69421A (en) | 1981-06-30 |
| DE2637580A1 (en) | 1977-03-17 |
| JPS5236662A (en) | 1977-03-22 |
| FR2322141B1 (en) | 1980-04-04 |
| NL181274C (en) | 1987-07-16 |
| YU231882A (en) | 1983-02-28 |
| CH624946A5 (en) | 1981-08-31 |
| YU207676A (en) | 1983-02-28 |
| YU40284B (en) | 1985-12-31 |
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