Note: Descriptions are shown in the official language in which they were submitted.
~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
-
.
1075701
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
1CHC 12 H H H H H H
. 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
4 CHC12 CH3 CH3 H H 3H7 H
CH2Cl CH3 CH3 H H H H
6 CBr3 CH3 CH3 H H H H
7 CH2Br CH3 CH3 CH3 CH3 H H
8 CHC12 CH3 CH3 C2H5 H H H
9 CC13 CH3 H H H CH3 H
CC13 C2H5 H C2H5 H H H
11 CHC12 CH3 CH3 CH3 3 H
12 CHC12 CH3 t C4Hg H H H H
13 CHC12 H H CH3 3 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
36 C2H5S H H C2H5 H H H
1037 C2H5S CH3 H H H CH3 H
: 38 C3H7S CH3 CH3 C2H5 H H H
39 i-C3H S CH3 CH3 C2H5 H H H
CH3S CH3 H C2H5 H H H
41 4HgS CH3 H C2H5 H H H
42 C6H13 CH3 CH3 H H H H
43 CHC12 C3H7 H H H H H
44 CHC12 CH3OCH2 H H H H H
CH2Cl CH3 CH3 H H 3 7 H
46 CHC12 CH3 CH3 CH3 CH2OH H H
2047 CH2C1 5 11 H CH3 C 3 H H
48 CH2C1 2,6-dimethyl- H CH3 3 H H .-
heptyl
49 CH2Cl n-C3H7 CH3 CH3 3 H
CH2C1 2 5 C2H5 CH3 3 H H
51 2Cl n-C3H7 n~C3H7 CH3 3 H H
Aromatic-Substituted Oxazolidines
., :
:. 52 CHC12 m NO2 C6H4 H CH3 3 H H
53 CC13 C6H5 H H H H H
54 CHBrCH3 C6H5 H H H H H
CCL2-CH3 C6H5 H H H H H
56 CHBr2 C6H5 H H H H H
57 CCl~CC12 C6H5 H H H H H
.. . .
--6--
~ . . . . . . . .
~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
CHC12 C6H5 H C2H5 H H H
61 CHC12 C2H5 H H 6 5 H
62 CC13 C2H5 H H 6 5 H
63 CHC12 CH3 3 6 5 H
64 CH2Cl CH3 3 6 5 H
CHBrCH2Br p-CH3-C6H4 H H H H H
66 CC12CH P 3 6 4 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
71 CHC12 C6H5 H H H CH3 H
72 2Cl C6H5 H CH3 CH3 CH3 H
73 CHC12 C6H5 H CH3 CH3 CH3 H
74 CC13 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
81 CHC12 C6H5 H CH3 CH3 H H
82 CC13 CH3 3 3 6 5 H
~i .
107S70~
TABLE I (cont.)
Compound R - R2 R3 4 R5 6_ _ _
83 2BR CH3 3 3 6H5 H
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
88 CHC12 CH3 CH3 CH2OH 6 5 H
89 CHC12 CH3 CH3 CH2OCNHCH3 H C6H5 H
CHC12 CH3 CH3 CH2OCCHC12 H C6H5 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
.
-8-
~ .
.
;. . ~ - ~ . ~ - -
,
: .. .
- . . : . - . - . ~ . :
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-
.... . . . .
. .
1075701
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
R2
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-- -'
,
- '
107S701
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
H2N 1 1 - OH
R6 R4
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,
-11 -
.~
. ~ , . . .
~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~
/CH3
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
- -12-
, ~ . - .
.
- -: `' ' : - .
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.
:.
-13-
1075701
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
-14-
~ 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
-15-
.. . .
- . . . . .
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.
- -16-
,
- , - ~
- ' ' - . . -, . . -
1075701
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.
:~ . ' :' ' , , '
107 5701
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.
.
-18-
B
1075701
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)~
. ' .
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