U.S. patent application number 13/681485 was filed with the patent office on 2013-03-28 for novel process.
This patent application is currently assigned to Hoffmann-La Roche Inc.. The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Declan Costello, Gerard John Harnett, Pirmin Hidber, Ursula Hoffmann, Thomas McCarthy, Reinhard Reents, Dennis A. Smith, Timothy Smyth.
Application Number | 20130079541 13/681485 |
Document ID | / |
Family ID | 41394053 |
Filed Date | 2013-03-28 |
United States Patent
Application |
20130079541 |
Kind Code |
A1 |
Costello; Declan ; et
al. |
March 28, 2013 |
NOVEL PROCESS
Abstract
The present invention relates to a process for the preparation
of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate which is a useful pharmaceutical active compound.
Inventors: |
Costello; Declan; (Gort,
IE) ; Harnett; Gerard John; (County Clare, IE)
; Hidber; Pirmin; (Seengen, CH) ; Hoffmann;
Ursula; (Muttenz, CH) ; McCarthy; Thomas;
(Leixlip, IE) ; Reents; Reinhard; (Muenchenstein,
CH) ; Smith; Dennis A.; (County Clare, IE) ;
Smyth; Timothy; (County Limerick, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc.; |
Nutley |
NJ |
US |
|
|
Assignee: |
Hoffmann-La Roche Inc.
Nutley
NJ
|
Family ID: |
41394053 |
Appl. No.: |
13/681485 |
Filed: |
November 20, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12823157 |
Jun 25, 2010 |
|
|
|
13681485 |
|
|
|
|
Current U.S.
Class: |
558/257 |
Current CPC
Class: |
C07C 2601/14 20170501;
C07C 327/30 20130101 |
Class at
Publication: |
558/257 |
International
Class: |
C07C 327/30 20060101
C07C327/30 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 1, 2009 |
EP |
09164268.6 |
Claims
1. A process for the preparation of the compound of formula (I),
##STR00006## which comprises reacting a compound of formula (II),
##STR00007## with isobutyric anhydride and a reducing agent.
2. A process according to claim 1, wherein said reaction is carried
out with at least 0.10M of said reducing agent.
3. A process according to claim 1, wherein the said reducing agent
is selected from the group consisting of: phosphines, phosphinites,
phosphonites and phosphites.
4. A process according to claim 1, which further comprises the
oxidation of excess reducing agent with an oxidizing agent.
5. A process according to claim 4, wherein the oxidizing agent is
peroxymonosulfate or hydrogen peroxide.
6. A process according to claim 1, wherein the said reducing agent
is a phosphine.
7. A process according to claim 1, wherein the said reducing agent
is triphenyl phosphine.
8. A process according to claim 3 which further comprises the
removal of the phosphine oxide, phosphinate, phosphonate or
phosphate produced in said reaction using water/alcohol extraction
from an organic solvent.
9. A process according to claim 8, wherein said reducing agent is a
phosphine and the phosphine oxide produced in said reaction is
removed using water/alcohol extraction from an organic solvent.
10. A process according to claim 1 which further comprises
crystallizing the compound of formula (I) using a
solvent-antisolvent process with water as the antisolvent and the
solvent being a water-miscible solvent.
11. A process according to 10 wherein the water miscible solvent is
acetone, ethanol, isopropanol, propanol or mixtures thereof.
12. A process according to claim 1 which further comprises
crystallizing the compound of formula (I) by cooling a solution of
said compound of formula (I) in a non-polar solvent.
13. A process according to claim 1, which further comprises the
following steps: a) forming a solution of said compound of formula
(I) in acetone, ethanol, isopropanol or propanol at a temperature
of 40.degree. C. to 70.degree. C.; b) cooling the solution until
supersaturation; c) adding seed crystals of the compound of formula
(I); d) optionally aging the suspension; e) adding water while
stirring until the desired solvent/water ratio is obtained; f)
optionally further stirring the mixture; g) cooling the mixture to
a temperature below 0.degree. C. to effect the crystallization and
precipitation of the compound of formula (I) from the solution
thereof, and h) separating the crystalline compound of formula (I)
from the liquid component of the mixture.
14. The crystalline form of the compound of formula (I) as prepared
using the process of claim 13.
15. A process according to claim 4, wherein the oxidizing agent is
hydrogen peroxide.
Description
PRIORITY TO RELATED APPLICATION
[0001] This application is a continuation application of U.S. Ser.
No. 12/823,157 filed Jun. 25, 2010. This application claims the
benefit of European Patent Application No. 09164268.6, filed Jul.
1, 2009, which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for the
preparation of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate, which is a useful pharmaceutically active compound.
SUMMARY OF THE INVENTION
[0003] The present invention provides a process for the preparation
of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate.
DETAILED DESCRIPTION OF THE INVENTION
[0004] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below.
[0005] "(C.sub.1-8)alkyl" refers to a branched or straight
hydrocarbon chain containing from 1 to 8 carbon atoms, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl
and t-butyl, pentyl, hexyl, heptyl or octyl. (C.sub.1-6)alkyl is
preferred.
[0006] "(C.sub.1-6)alkoxy" means a moiety of the formula
--OR.sup.a, wherein R.sup.a is an (C.sub.1-6)alkyl moiety as
defined herein. Examples of alkoxy moieties include, but are not
limited to, methoxy, ethoxy, isopropoxy, and the like.
[0007] "Alcohol" refers to an (C.sub.1-8)alkyl as defined above
substituted by an hydroxy group. Examples of alcohols include, but
are not limited to, methanol, ethanol, isopropanol, propanol and
butanol. Methanol is preferred.
[0008] "(C.sub.3-8)cycloalkyl" refers to a single saturated
carbocyclic ring containing from 3 to 8 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0009] "Phenyl(C.sub.1-3)alkyl" refers to the group
R.sup.8ac--R.sup.8ad--, wherein R.sup.ac and R.sup.ad are,
respectively, "optionally substituted phenyl" and
"(C.sub.1-3)alkyl" as defined above.
[0010] "Phosphine" refers to a compound of formula PR.sub.3,
wherein each "R" may be the same or different and is independently
selected from (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, phenyl or
phenyl(C.sub.1-3)alkyl as defined above. Representative examples
include, but are not limited to, triphenylphosphine,
tricyclopentylphosphine, tricylcohexylphosphine, tributylphosphine
diethylphenylphosphine and tribenzylphosphine. Most preferably the
phosphine is triphenylphosphine.
[0011] "Phosphinite" refers to a compound of formula P(OR)R.sub.2,
wherein each R may be the same or different and is independently
selected from (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, phenyl and
phenyl(C.sub.1-3)alkyl as defined above. Representative examples
include, but are not limited to P,P-diphenyl-phosphinous acid
phenyl ester.
[0012] "Phosphonite" refers to a compound of formula P(OR).sub.2R,
wherein each R may be the same or different and is independently
selected from (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, phenyl and
phenyl(C.sub.1-3)alkyl as defined above. Representative examples
include, but are not limited to P-phenyl-phosphonous acid diphenyl
ester.
[0013] "Phosphite" refers to a compound of formula P(OR).sub.3,
wherein each R may be the same or different and is independently
selected from (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, phenyl and
phenyl(C.sub.1-3)alkyl as defined above. Most preferably the
phosphite is triisopropylphosphite.
[0014] The present invention provides a process for the preparation
of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate.
[0015]
S-[2-[1-(2-Ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiop-
ropionate is a compound having the following formula:
##STR00001##
[0016] The process comprises reacting a compound of formula
(II),
##STR00002##
with isobutyric anhydride and a reducing agent. Such a reaction is
an acylation reaction.
[0017] In an embodiment of the invention, the reducing agent is
selected from the group consisting of: phosphines, phosphinites,
phosphonites and phosphites.
[0018] In an embodiment of the invention, the reducing agent is a
phosphine.
[0019] In an embodiment, the reducing agent is selected from the
group consisting of: triisopropylphosphite, triphenylphosphine and
tributylphosphine.
[0020] In an embodiment of the invention, the reducing agent is
triphenylphosphine or tributylphosphine.
[0021] In an embodiment, the reducing agent is
triphenylphosphine.
[0022] In an embodiment, at least 0.10 M of the reducing agent is
used in the reaction.
[0023] In an embodiment of the invention, excess reducing agent is
oxidized with an oxidizing agent.
[0024] In an embodiment of the invention, the oxidizing agent is
potassium peroxymonosulfate or hydrogen peroxide.
[0025] In an embodiment of the invention, the oxidizing agent is
hydrogen peroxide.
[0026] In embodiments in which the reducing agent is a phosphine,
the acylation reaction produces a phosphine oxide. In embodiments
in which the reducing agent is a phosphinite, the reaction produces
a phosphinate. In embodiments in which the reducing agent is a
phosphonite, the reaction produces a phosphonate. In embodiments in
which the reducing agent is a phosphite, the reaction produces a
phosphate.
[0027] In an embodiment wherein the reducing agent is a phosphine,
a phosphinite, a phosphonite or a phosphite, the acylation reaction
is followed by the removal of the respective phosphine oxide,
phosphinate, phosphonate or phosphate with water/alcohol extraction
from an organic solvent.
[0028] Unless otherwise stated, the organic solvent used for
reactions referred to herein may be an ether-like solvent (e.g.
tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether,
t-butylmethyl ether or dibutyl ether, dimethyl acetal or dioxane),
an ester-like solvent (e.g. ethyl acetate, butyl acetate), an
aliphatic hydrocarbon solvent (e.g. hexane, heptane or pentane), a
saturated alicyclic hydrocarbon solvent (e.g. cyclohexane or
cyclopentane), an aromatic solvent (e.g. toluene or
t-butyl-benzene), a nitrile (e.g. acetonitrile), an amide (e.g.
dimethylformamide, N-methylpyrrolidine), a chlorinated solvent
(e.g. dichloromethane), or dimethyl sulfoxide.
[0029] In an embodiment, the solvent for reactions is heptane or
toluene.
[0030] Unless otherwise stated, the organic solvent used for
extractions referred herein may be an ether-like solvent (e.g.
methyltetrahydrofuran, diisopropyl ether, t-butylmethyl ether or
dibutyl ether, dimethyl acetal or dioxane), an ester-like solvent
(e.g. ethyl acetate, butyl acetate), an aliphatic hydrocarbon
solvent (e.g. hexane, heptane or pentane), a saturated alicyclic
hydrocarbon solvent (e.g. cyclohexane or cyclopentane), or an
aromatic solvent (e.g. toluene or t-butyl-benzene).
[0031] In an embodiment, the solvent for extractions is
heptane.
[0032] The compound of formula (II) can be prepared according to
scheme 1.
##STR00003##
[0033] In the above scheme, X is I, Br, Cl or F. In particular, the
process comprises reacting a cyclohexanecarboxylic acid derivative
of formula (IV) with a halogenating agent, such as PX.sub.3,
PX.sub.5, SOX.sub.2 or NCX, to obtain the acyl halide of formula
(III). The halogenating step is preferably carried out in the
presence of tri-(C.sub.1-C.sub.5)alkylamine. Furthermore, the
process comprises reacting the compound of formula (III) with
bis(2-aminophenyl)disulfide to acylate the amino groups of the
bis(2-aminophenyl)disulfide in the presence of a base (e.g.
N-methylmorpholine, di-N-methylpiperazine, pyridine), thus
producing the compound of formula (II).
[0034] In an embodiment, the halogenating agent is chosen from the
group consisting of: thionyl chloride, phosphorus pentachloride,
oxalyl chloride, phosgene, diphosgene, triphosgene, phosphorus
tribromide, cyanuric fluoride, and cyanuric chloride.
[0035] In an embodiment, the halogenating agent is thionyl chloride
or phosgene.
[0036] In an embodiment of the invention, the compound formula
(III) is one wherein X is Cl.
[0037] Furthermore the invention may comprise the step of
crystallizing
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate.
[0038]
S-[2-[1-(2-Ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiop-
ropionate can be crystallized by a combined cooling and
solvent-anti-solvent process. The solvent and anti-solvent should
be miscible. Both addition modes--anti-solvent to
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate solution (preferred) or
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate solution to anti-solvent--are possible. With water as the
anti-solvent, the solvent should be a water-miscible solvent.
Examples of such solvents include but are not restricted to
acetone, ethanol, isopropanol, propanol, and mixtures thereof.
[0039] In an embodiment,
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate is crystallized from ethanol (solvent) and water
(anti-solvent).
[0040] For the crystallization,
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate is dissolved at elevated temperature in ethanol (preferably
between 40.degree. C. and 70.degree. C.) and cooled until
supersaturation is achieved (preferably to room temperature).
S-[2-[1-(2-Ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate seed crystals are added, preferably as a suspension in
ethanol/water 1:1 (m/m). After seeding, the suspension is aged for
an appropriate time (preferably 60 minutes). Subsequently, and
while stirring, water is added until the desired ethanol to water
ratio is achieved (preferentially ethanol:water=7:3 (m/m)). After
complete addition, the crystallization mixture is stirred for about
30 min, cooled to the final temperature (preferentially -10.degree.
C.) and further aged at the same temperature. The crystals are
isolated by filtration and washed with a mixture of ethanol-water
(preferably ethanol:water 3:1 (m/m). Subsequently, the wet crystals
are dried, most preferably at 40.degree. C., under reduced pressure
until the weight is constant
[0041] Alternatively, the mode of addition can be changed. The hot
solution of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
atein ethanol is added to the water phase preferably containing
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate seed crystals. In this case, the ethanol:water ratio can be
smaller than 7:3 (m/m), preferably 6:4 (m/m) or even smaller. The
suspension is further processed as described above.
[0042]
S-[2-[1-(2-Ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiop-
ropionate can also be crystallized by cooling a solution of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate in a non-polar solvent such as hexane(s), cyclohexane, heptane,
or pentane. Most preferably,
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate is crystallized from heptane.
[0043] In another embodiment, the process of the present invention
further comprises the following steps: [0044] a) forming a solution
of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate in acetone, ethanol, isopropanol or propanol at a temperature
of 40.degree. C. to 70.degree. C.; [0045] b) cooling the solution
until supersaturation, preferably to room temperature; (wherein
supersaturation is well understood by the person skilled in the
art, see J. W. Mullin, "Crystallization", fourth edition,
Butterworth-Heinemann, 2001, ISBN 0 7506 4833 3, pages 123-131);
[0046] c) adding seed crystals of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate; [0047] d) optionally aging the suspension, preferably for at
least 10 min, most preferably for 60 minutes; [0048] e) adding
water while stirring until the desired solvent/water ratio is
obtained, preferably the solvent/water ratio is between 9:1 and 1
to 9, more preferably 8:2 and 2:8 most preferably 7:3 (m/m); [0049]
f) optionally further stirring the mixture; [0050] g) cooling the
mixture to a temperature below 0.degree. C., more preferably
between 0.degree. C. and -20.degree. C., most preferably to
-10.degree. C., to effect the crystallization and precipitation of
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate from the solution thereof, [0051] h) separating the crystalline
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate from the liquid component of the mixture, preferably the
crystalline
S-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]2-methylthiopropion-
ate is filtered out.
[0052] In an embodiment, the invention relates to a crystalline
form of the compound of formula (I) as produced using the above
process.
[0053] The starting materials and reagents which do not have their
synthetic route explicitly disclosed herein are generally available
from commercial sources or are readily prepared using methods well
known to the person skilled in the art. For instance, the compound
of formula (IV) can be prepared according to the procedures
described in Shinkai et al., J. Med. Chem. 43:3566-3572 (2000), WO
2007/051714 or WO 2008/074677.
[0054] In general, the nomenclature used in this Application is
based on AUTONOM.TM. 2000, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature.
Chemical structures shown herein were prepared using MDL ISIS.TM.
version 2.5 SP2. Any open valency appearing on a carbon, oxygen or
nitrogen atom in the structures herein indicates the presence of a
hydrogen atom.
EXAMPLES
[0055] The following examples are provided for the purpose of
further illustration and are not intended to limit the scope of the
claimed invention.
[0056] The following abbreviations and definitions are used: Ar
(argon); acid chloride (1-(2-ethyl-butyl)-cyclohexanecarbonyl
chloride); amidodisulfide
(N,N'-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide-
]); amidothiophenol
(1-(2-ethylbutyl)-N-(2-mercaptophenyl)-cyclohexanecarboxamide);
thioester
(S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]-phenyl]2-methylthiopropi-
onate); DTDA (2,22-dithiodianiline); eq. (equivalent); g (gram);
EtOH (ethanol); IPC (in process control); GC (gas chromatography);
h (hour); M (Molarity [moles/L]); MeOH (methanol); ml (milliliter);
NMM(N-methylmorpholine); RT (room temperature); TBP
(tributylphosphine); TEP (triethylphosphite); TPP
(triphenylphosphine), TPPO (triphenylphosphine oxide),
methylthioether
(1-(2-ethylbutyl)-N-[2-(methylthio)phenyl]-cyclohexanecarboxamide),
ethylthioether
(1-(2-ethylbutyl)-N-[2-(ethylthio)phenyl]-cyclohexanecarboxamide,
isopropylthioether
(1-(2-ethylbutyl)-N-[2-(isopropylthio)phenyl]-cyclohexanecarboxamide.
Example 1
Use of Triphenylphosphine in Toluene at Reflux
##STR00004##
[0058] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g NMM (115
mmol, 1.15 eq) was added. The dark brown suspension was heated to
100.degree. C. and the suspension became a clear solution. 24.5 g
acid chloride (100 mmol, 1.0 eq, Assay: 94.2 (% mass)) was added to
this solution over a period of 30 minutes at 100.degree. C. The
reaction mixture was heated at reflux (115.degree. C.) and then
stirred for 7 h under reflux.
[0059] The reaction mixture was cooled to RT and extracted with 20
g water twice. The toluene phase was completely evaporated at
50.degree. C. under reduced pressure. To the residue was added 59 g
toluene (68 ml).
[0060] 14.2 g of TPP (54 mmol, 0.54 eq) was dissolved in 36 g
toluene (42 ml) followed by the addition of the above
amidodisulfide solution in toluene at 25.degree. C. 9.82 g
isobutyric anhydride (62 mmol, 0.621 eq) was added and rinsed with
9 g toluene (10 ml). The reaction mixture was heated to reflux
(115.degree. C.) and then stirred for 6 h under reflux. An
IPC-sample showed 38.6% TPPO, 0% amidothiophenol, 0% amidodisulfide
and 61.0% thioester.
[0061] The reaction mixture was completely evaporated at 50.degree.
C. under reduced pressure. To the residue was added 109 g heptane
(160 ml). The solution was warmed to 40.degree. C. and extracted
four times with each a mixture of 89 g MeOH (112 ml) and 48 g water
(48 ml). The phases were allowed to separate for 10 minutes after
each extraction. The aqueous phases were discarded.
[0062] The thioester heptane solution was completely evaporated at
50.degree. C. under reduced pressure. To the oily residue was added
117 g EtOH (148 ml) and the suspension was heated at 50.degree. C.
until the solution was clear. A lab filter unit with external
heating (50.degree. C.) was charged with an activated charcoal
filter pad.
[0063] The reddish-brown thioester solution in ethanol was filtered
at 50.degree. C. through the above filter unit within approx. 20
minutes and became light brown. The flask and the filter unit were
washed with 16 g EtOH (20 ml). The solution was filtered through a
polishing filter (Millipore.RTM.) at 50.degree. C. into an
Erlenmeyer flask. The flask and the filter unit were rinsed with 16
g EtOH (20 ml). Obtained were ca. 170 g EtOH-solution (assay
thioester 19.8%, 87.8% yield)
[0064] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g EtOH (20 ml).
[0065] The clear solution was cooled to RT and seeded with a
suspension of thioester (0.3 mmol, 0.003 eq) seeding crystals in
2.0 g EtOH/water 1:1 (m/m) (2.3 ml). The seeded solution was
stirred until a well mixed suspension was obtained (60 minutes),
and then, while stirring, water was added with the use of a
Dosimat.RTM. (Metrohm.RTM. automatic dispenser) within 60 minutes
at RT. After complete addition the crystallization mixture was
stirred for 30 minutes and then cooled to -10.degree. C. (T.sub.i)
within 3.5 h and further stirred for min. 60 minutes at this
temperature. The suspension was isolated by filtration on paper and
the isolated crystals were washed with a mixture of 36 g EtOH (45
ml) and 15 g water (cooled to -10.degree. C.). The wet crystals
(approx. 45 g) were dried at 45.degree. C. under reduced pressure
for 16 h until the weight was constant. 32.9 g thioester (83.9
mmol, yield 83.9%) were obtained.
Example 2
Use of Tributylphosphine in Toluene at Reflux
[0066] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g NMM (115
mmol, 1.15 eq) was added. The dark brown suspension was heated to
100.degree. C. and the suspension became a clear solution. 23.9 g
acid chloride (100 mmol, 1.0 eq, Assay: 96.7 (% mass)) was added to
this solution over a period of 30 minutes at 100.degree. C. The
reaction mixture was heated to reflux (115.degree. C.) and then
stirred for 6 h under reflux.
[0067] The reaction mixture was cooled to RT and washed with 20 g
water twice. The toluene phase was completely evaporated at
50.degree. C. under reduced pressure. To the residue was added 59 g
toluene (68 ml).
[0068] The above toluene solution was transferred into another
vessel and rinsed with 17 g toluene (20 ml). To this toluene
solution was added at room temperature via dropping funnel 9.81 g
isobutyric anhydride (62 mmol, 0.62 eq). The dropping funnel was
rinsed with 9 g (10 ml) toluene. Subsequently 11.5 g TBP (54 mmol,
0.54 eq.) was added via dropping funnel within 25 minutes at RT.
The dropping funnel was rinsed with 10 g (12 ml) toluene. After 3
hours additional 0.08 g isobutyric anhydride (0.5 mmol, 0.005 eq)
was added and the reaction mixture was stirred for another 90
minutes. An IPC-sample showed 0.52% amidothiophenol, 0%
amidodisulfide and 90.8% thioester.
[0069] The reaction mixture was completely evaporated at
40-85.degree. C. under reduced pressure. To the residue was added
109 g heptane (160 ml). The heptane solution was washed at room
temperature four times with each a mixture of 89 g MeOH (112 ml)
and 48 g water (48 ml). The phases were allowed to separate for 10
minutes after each extraction. The aqueous phases were
discarded.
[0070] The thioester heptane solution was completely evaporated at
45-60.degree. C. under reduced pressure. To the oily residue was
added 117 g EtOH (148 ml) and the suspension was heated at
50.degree. C. until the solution was clear. A lab filter unit with
external heating (50.degree. C.) was charged with an activated
charcoal filter pad and a 0.45 .mu.m membrane (Millipore.RTM.)
filter.
[0071] The reddish-brown thioester EtOH solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 32 g EtOH (40 ml). Obtained were 180 g EtOH-solution
(containing 18.8% thioester, 86.9% yield)
[0072] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g EtOH (20 ml).
[0073] The clear solution was cooled to RT and seeded with a
suspension of thioester (0.3 mmol, 0.003 eq.) seeding crystals in
2.0 g EtOH/water 1:1 (m/m) (2.3 ml). The seeded solution was
stirred until a well mixed suspension was obtained (60 minutes),
and then, while stirring, 72 g water was added with the use of a
Dosimat.RTM. (Metrohm automatic dispenser) within 60 minutes at RT.
After complete addition the crystallization mixture was stirred for
30 minutes and then cooled to -10.degree. C. (T.sub.i) with a ramp
of 10.degree. C./h and further stirred for 60 minutes at this
temperature. The suspension was isolated by filtration on paper and
the isolated crystals were washed with a mixture of 36 g EtOH (45
ml) and 15 g water (cooled to -10.degree. C.). The wet crystals
(40.7 g) were dried at 45.degree. C. under reduced pressure for 16
h until the weight was constant. 33.0 g thioester (assay 99.1%,
83.8 mmol, yield 83.8%) were obtained.
Example 3
Use of Triethylphosphite (TEP) in Toluene at Reflux
[0074] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g NMM (115
mmol, 1.15 eq) was added. The dark brown suspension was heated to
100.degree. C. and the suspension became a clear solution. 23.9 g
acid chloride (100 mmol, 1.0 eq, Assay: 96.7 (% mass)) was added to
this solution over a period of 30 minutes at 100.degree. C. The
reaction mixture was heated to reflux (115.degree. C.) and then
stirred for 6 h under reflux.
[0075] The reaction mixture was cooled to RT and washed twice with
20 g water twice. The toluene phase was completely evaporated at
50.degree. C. under reduced pressure. To the residue was added 59 g
toluene (68 ml).
[0076] The above toluene solution was transferred into another
vessel and rinsed with 17 g toluene (20 ml). To the toluene
solution was added at room temperature via dropping funnel 9.81 g
isobutyric anhydride (62 mmol, 0.62 eq). The dropping funnel was
rinsed with 17 g (20 ml) toluene. Subsequently 9.16 g TEP (54 mmol,
0.54 eq.) was added via dropping funnel within 25 minutes at RT.
The dropping funnel was rinsed with 10 g (12 ml) toluene. The
reaction mixture was heated to 60.degree. C. and stirred for 20
minutes at this temperature. An IPC-sample showed 0%
amidothiophenol, 0% amidodisulfide, 87.9% thioester and 5.0%
ethylthioether.
[0077] The reaction mixture was completely evaporated at
40-85.degree. C. under reduced pressure. To the residue was added
109 g heptane (160 ml). The heptane solution was washed at room
temperature four times with each a mixture of 89 g MeOH (112 ml)
and 48 g water (48 ml). The phases were allowed to separate for 10
minutes after each extraction. The aqueous phases were
discarded.
[0078] The thioester heptane solution was completely evaporated at
45-60.degree. C. under reduced pressure. To the oily residue was
added 117 g EtOH (148 ml) and the suspension was heated at
50.degree. C. until the solution was clear. A lab filter unit with
external heating (50.degree. C.) was charged with an activated
charcoal filter pad and a 0.45 .mu.m membrane (Millipore.RTM.)
filter.
[0079] The reddish-brown thioester EtOH solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 32 g EtOH (40 ml).
[0080] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g EtOH (20 ml).
[0081] The clear solution was cooled to RT and seeded with a
suspension of thioester (0.3 mmol, 0.003 eq.) seeding crystals in
2.0 g EtOH/water 1:1 (m/m) (2.3 ml). The seeded solution was
stirred until a well mixed suspension was obtained (60 minutes),
and then, while stirring, 72 g water was added with the use of a
Dosimat.RTM. (Metrohm automatic dispenser) within 60 minutes at RT.
After complete addition the crystallization mixture was stirred for
30 minutes and then cooled to -10.degree. C. (T.sub.i) with a ramp
of 10.degree. C./h and further stirred for 60 minutes at this
temperature. The suspension was isolated by filtration on paper and
the isolated crystals were washed with a mixture of 36 g EtOH (45
ml) and 15 g water (cooled to -10.degree. C.). The wet crystals
(38.6 g) were dried at 45.degree. C. under reduced pressure for 16
h until the weight was constant. 33.2 g thioester (assay 99.5%,
84.4 mmol, yield 84.4%) were obtained. 0.48% of ethylthioether was
observed.
Example 4
Use of TEP in Toluene Under Reflux
[0082] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g NMM (115
mmol, 1.15 eq) was added. The dark brown suspension was heated to
100.degree. C. and the suspension became a clear solution. 23.9 g
acid chloride (100 mmol, 1.0 eq, Assay: 96.7 (% mass)) was added to
this solution over a period of 30 minutes at 100.degree. C. The
reaction mixture was heated at reflux (115.degree. C.) and then
stirred for 6 h under reflux.
[0083] The reaction mixture was cooled to RT and washed twice with
each 20 g water. The toluene phase was completely evaporated at
50.degree. C. under reduced pressure. To the residue was added 59 g
toluene (68 ml).
[0084] The above toluene solution was transferred into another
vessel and rinsed with 17 g toluene (20 ml). To the toluene
solution was added at room temperature via dropping funnel 9.81 g
isobutyric anhydride (62 mmol, 0.62 eq). The dropping funnel was
rinsed with 17 g (20 ml) toluene. Subsequently 9.16 g TEP (54 mmol,
0.54 eq.) were added via dropping funnel within 20 minutes at
24-30.degree. C. The dropping funnel was rinsed with 10 g (12 ml)
toluene. The reaction mixture was heated to 30.degree. C. and
stirred for 30 minutes at that temperature. An IPC-sample showed 0%
amidothiophenol, 0% amidodisulfide, 87.6% thioester and 5.2%
ethylthioether
[0085] The toluene solution was washed at room temperature 5 times
with each 100 g water (100 ml). The phases were always allowed to
separate for 5 minutes. The aqueous phases were discarded.
[0086] The thioester toluene solution was completely evaporated at
45-60.degree. C. under reduced pressure. To the oily residue was
added 117 g EtOH (148 ml) and the suspension was heated at
50.degree. C. until the solution was clear. A lab filter unit with
external heating (50.degree. C.) was charged with an activated
charcoal filter pad and a 0.45 .mu.m membrane (Millipore.RTM.)
filter.
[0087] The reddish-brown thioester EtOH solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 32 g EtOH (40 ml).
[0088] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g EtOH (20 ml).
[0089] The clear solution was cooled to RT and seeded with a
suspension of thioester (0.3 mmol, 0.003 eq.) seeding crystals in
2.0 g EtOH/water 1:1 (m/m) (2.3 ml). The seeded solution was
stirred until a well mixed suspension was obtained (60 minutes),
and then while stirring 72 g water was added with the use of a
Dosimat.RTM. (Metrohm.RTM. automatic dispenser) within 60 minutes
at RT. After complete addition the crystallization mixture was
stirred for 30 minutes and then cooled to -10.degree. C. (T.sub.i)
with a ramp of 10.degree. C./h and further stirred for 60 minutes
at this temperature. The suspension was isolated by filtration on
paper and the isolated crystals were washed twice with each a
mixture of 36 g EtOH (45 ml) and 15 g water (cooled to -10.degree.
C.). The wet crystals (43.9 g) were dried at 45.degree. C. under
reduced pressure for 16 h until the weight was constant. 33.1 g
thioester (assay 99.5%, 84.5 mmol, yield 84.5%) were obtained.
0.41% of ethylthioether was observed.
Example 5
With Triethylphosphite (Reaction at -20.degree. C.), No
Triethylphosphate Extraction
[0090] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g NMM (115
mmol, 1.15 eq) was added. The dark brown suspension was heated to
100.degree. C. and the suspension became a clear solution. 24.1 g
acid chloride (100 mmol, 1.0 eq, Assay: 95.8 (% mass)) was added to
this solution over a period of 30 minutes at 100.degree. C. The
reaction mixture was heated at reflux (115.degree. C.) and then
stirred for 6 h under reflux.
[0091] The reaction mixture was cooled to RT and washed twice with
each 20 g water. The toluene phase was completely evaporated at
50.degree. C. under reduced pressure. To the residue was added 59 g
toluene (68 ml).
[0092] The above toluene solution was transferred into another
vessel and rinsed with 17 g toluene (20 ml). To the toluene
solution was added at room temperature via dropping funnel 9.82 g
isobutyric anhydride (62 mmol, 0.62 eq). The dropping funnel is
rinsed with 28 g (32 ml) toluene. Subsequently the reaction mixture
was cooled to -20.degree. C. T.sub.i and 9.16 g TEP (54 mmol, 0.54
eq.) were added via syringe pump within 60 minutes at -20.degree.
C. T.sub.i. The reaction mixture was stirred for 60 minutes. An
IPC-sample showed 2.1% amidothiophenol, 0% amidodisulfide, 93.4%
thioester and 2.1% ethylthioether.
[0093] The reaction mixture was completely evaporated at
45-60.degree. C. under reduced pressure. To the oily residue was
added 117 g ethanol (148 ml) and the suspension was heated at
50.degree. C. until the solution was clear. A lab filter unit with
external heating (50.degree. C.) was charged with an activated
charcoal filter pad and a 0.45 .mu.m membrane (Millipore.RTM.)
filter.
[0094] The reddish-brown thioester ethanol solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 32 g ethanol (40 ml).
[0095] The filtered thioester ethanol solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g ethanol (20 ml).
[0096] The clear solution was cooled to 20.degree. C. and seeded
with a suspension of thioester (0.3 mmol, 0.003 eq.) seeding
crystals in 2.0 g ethanol/water 1:1 (m/m) (2.3 ml). The seeded
solution was stirred until a well mixed suspension was obtained (60
minutes), and then, while stirring 72 g water was added with the
use of a Dosimat.RTM. (Metrohm.RTM. automatic dispenser) within 60
minutes at 20-24.degree. C. After complete addition the
crystallization mixture was stirred for 30 minutes and then cooled
to -10.degree. C. (T.sub.i) with a ramp of 10.degree. C./h and
further stirred overnight at this temperature. The suspension was
isolated by filtration on paper and the isolated crystals were
washed twice with each a mixture of 36 g ethanol (45 ml) and 15 g
water (cooled to -10.degree. C.). The wet crystals (43.7 g) were
dried at 45.degree. C. under reduced pressure for 6 h until the
weight was constant. 34.1 g thioester (assay 98.7%, 86.4 mmol,
yield 86.3%) were obtained. 0.32% of ethylthioether was
observed.
Example 6
Use of Triisopropylphosphite (TIP) at 0.degree. C., No
Triisopropylphosphate Extraction
[0097] In a double jacket vessel under argon 13.4 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g N-methyl
morpholine (115 mmol, 1.15 eq) was added. The dark brown suspension
was heated to 100.degree. C. and the suspension became a clear
solution. 24.1 g acid chloride (100 mmol, 1.0 eq, Assay: 95.9 (%
mass)) was added to this solution over a period of 30 minutes at
100.degree. C. The reaction mixture was heated at reflux
(115.degree. C.) and then stirred for 6 h under reflux.
[0098] The reaction mixture was cooled to 25.degree. C. and washed
twice with each 20 g water. The toluene phase was completely
evaporated at 50.degree. C. under reduced pressure. To the residue
was added 59 g toluene (68 ml).
[0099] The above toluene solution was transferred into another
vessel and rinsed with 17 g toluene (20 ml). To the toluene
solution was added at room temperature via dropping funnel 9.82 g
isobutyric anhydride (62 mmol, 0.62 eq). The dropping funnel was
rinsed with 28 g (32 ml) toluene. Subsequently the reaction mixture
was cooled to -2 to 0.degree. C. T.sub.i and 11.84 g
triisopropylphosphite (54 mmol, 0.54 eq.) were added via syringe
pump within 60 minutes at 0.degree. C. T.sub.i. The reaction
mixture was stirred for 30 minutes. An IPC-sample showed <0.1%
amidothiophenol, 0.17% amidodisulfide, 95.7% thioester and 1.6%
isopropylthioether.
[0100] The reaction mixture was completely evaporated at
45-60.degree. C. under reduced pressure. To the oily residue was
added 117 g ethanol (148 ml) and the suspension was heated at
50.degree. C. until the solution was clear. A lab filter unit with
external heating (50.degree. C.) was charged with an activated
charcoal filter pad and a 0.45 .mu.m membrane (Millipore.RTM.)
filter.
[0101] The reddish-brown thioester ethanol solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 32 g ethanol (40 ml).
[0102] The filtered thioester ethanol solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g ethanol (20 ml).
[0103] The clear solution was cooled to 20.degree. C. and seeded
with a suspension of thioester (0.3 mmol, 0.003 eq.) seeding
crystals in 2.0 g ethanol/water 1:1 (m/m) (2.3 ml). The seeded
solution was stirred until a well mixed suspension was obtained (60
minutes), and then, while stirring 72 g water was added with the
use of a Dosimat.RTM. (Metrohm.RTM. automatic dispenser) within 60
minutes at 20-24.degree. C. After complete addition the
crystallization mixture was stirred for 30 minutes and then cooled
to -10.degree. C. (T.sub.i) with a ramp of 10.degree. C./h and
further stirred overnight at this temperature. The suspension was
isolated by filtration on paper and the isolated crystals were
washed twice with each a mixture of 36 g ethanol (45 ml) and 15 g
water (cooled to -10.degree. C.). The wet crystals (55.1 g) were
dried at 45.degree. C. under reduced pressure over the weekend.
34.7 g thioester (assay 99.5%, 88.6 mmol, yield 88.6%) were
obtained. 0.10% of isopropylthioether was observed.
Example 7
Pretreatment of Quenched Amidodisulfide Reaction Mixture with
Isobutyric Anhydride at 80.degree. C. Before Reduction with TIP
[0104] In a double jacket vessel under argon 4.0 g DTDA (16.2 mmol,
0.54 eq) was suspended in 19.5 g toluene (22.5 ml). 3.49 g N-methyl
morpholine (34.5 mmol, 1.15 eq) was added. The dark brown
suspension was heated to 100.degree. C. and the suspension became a
clear solution. 7.15 g acid chloride (30 mmol, 1.0 eq, Assay: 96.8
(% mass)) was added to this solution over a period of 30 minutes at
100.degree. C. The reaction mixture was heated at reflux
(115.degree. C.) and then stirred for 6 h under reflux.
[0105] The reaction mixture was cooled to 25.degree. C. and washed
twice with each 6 g water. The toluene phase was completely
evaporated at 50.degree. C. under reduced pressure. To the residue
was added 17.7 g toluene (20.4 ml).
[0106] The above toluene solution was transferred into another
vessel and rinsed with 11.8 g toluene (13.6 ml). To the toluene
solution was added at room temperature 3.08 g isobutyric anhydride
(19.5 mmol, 0.65 eq). The reaction mixture was stirred for 60
minutes at 20.degree. C., 60 minutes at 50.degree. C. and 3 hours
30 minutes at 80.degree. C. Subsequently the reaction mixture was
cooled to 10.degree. C. T.sub.i and 3.2 g triisopropylphosphite
(14.6 mmol, 0.49 eq.) were added via syringe pump within 60 minutes
at 10.degree. C. T.sub.i. The reaction mixture was stirred for 90
minutes, after which additional 377 mg triisopropylphosphite were
added. After further 3 hours of stirring, an IPC-sample showed 0%
amidothiophenol, 0% amidodisulfide, 90.4% thioester and 0.36%
isopropylthioether.
Example 8
Use of TPP in Dichloromethane at Room Temperature
[0107] In a double jacket vessel under argon 31.0 g DTDA (125 mmol,
0.54 eq) is suspended in 146 g toluene. 26.9 g NMM (266 mmol, 1.15
eq) was added. The dark brown suspension was heated to 100.degree.
C. and the suspension became a clear solution. 54.9 g acid chloride
(232 mmol, 1.0 eq, Assay: 97.3 (% mass)) was added to this solution
over a period of 30 minutes at 100.degree. C. The reaction mixture
was heated at reflux (115.degree. C.) and then stirred for 7 h
under reflux.
[0108] The reaction mixture was cooled to RT and extracted twice
with each 45 g water. The toluene phase was completely evaporated
at 50.degree. C. under reduced pressure. To the residue was added
180 g methylene chloride).
[0109] 32.8 g of TPP (125 mmol, 0.54 eq) was dissolved in 111 g
dichloromethane followed by the addition of the above
amidodisulfide solution in dichloromethane at 25.degree. C. 22.8 g
isobutyric anhydride (144 mmol, 0.621 eq) were added and rinsed
with 29 g dichloromethane. The reaction mixture was stirred at room
temperature for 36 h (results after 2 hours: 4.3% amidothiophenol,
<0.1% amidodisulfide; results after 36 hours: 1.7%
amidothiophenol, <0.1% amidodisulfide).
[0110] The reaction mixture was completely evaporated at 50.degree.
C. under reduced pressure. To the residue was added 224 g heptane.
The solution was warmed to 40.degree. C. and extracted 4 times with
a mixture of 199 g MeOH and 110 g water. The phases were always
allowed to separate for 10 minutes. The aqueous phases were
discarded.
[0111] The thioester heptane solution was completely evaporated at
50.degree. C. under reduced pressure. To the oily residue was added
262 g EtOH and the suspension was heated at 50.degree. C. until the
solution was clear. A lab filter unit with external heating
(50.degree. C.) was charged with an activated charcoal filter
pad.
[0112] The reddish-brown thioester EtOH solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 34 g EtOH. The solution was filtered over a polishing
(Millipore.RTM.) filter at 50.degree. C. into an Erlenmeyer
flask.
[0113] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
34 g EtOH.
[0114] The clear solution was cooled to RT and seeded with a
suspension of 262 mg thioester seeding crystals in 4.4 g EtOH/water
1:1 (m/m). The seeded solution was stirred until a well mixed
suspension was obtained (60 minutes), and then, while stirring 160
g water was added with the use of a Dosimat.RTM. (Metrohm.RTM.
automatic dispenser) within 60 minutes at RT. After complete
addition the crystallization mixture was stirred for 30 minutes and
then cooled to -10.degree. C. (T.sub.i) within 3.5 h and further
stirred for min. 60 minutes at this temperature. The suspension was
isolated by filtration on paper and the isolated crystals are
washed with a mixture of 80 g EtOH and 34 g water (cooled to
-10.degree. C.). The wet crystals (approx. 98 g) are dried at
40.degree. C. under reduced pressure for 16 h until the weight was
constant. 78.8 g thioester (assay 97.1%, yield 83.7%, 0.4%
amidothiophenol) are obtained.
Example 9
Use of TPP in Toluene at Room Temperature
[0115] In a double jacket vessel under argon 31.0 g DTDA (125 mmol,
0.54 eq) was suspended in 146 g toluene. 26.9 g NMM (266 mmol, 1.15
eq) was added. The dark brown suspension was heated to 100.degree.
C. and the suspension became a clear solution. 54.9 g acid chloride
(232 mmol, 1.0 eq, Assay: 97.3 (% mass)) was added to this solution
over a period of 30 minutes at 100.degree. C. The reaction mixture
was heated at reflux (115.degree. C.) and then stirred for 7 h
under reflux.
[0116] The reaction mixture was cooled to RT and extracted twice
with each 45 g water. The toluene phase was completely evaporated
at 50.degree. C. under reduced pressure. To the residue was added
132 g toluene).
[0117] 32.8 g of TPP (125 mmol, 0.54 eq) was dissolved in 80 g
toluene followed by the addition of the above amidodisulfide
solution in toluene at 25.degree. C. 22.8 g isobutyric anhydride
(144 mmol, 0.621 eq) are added and rinsed with 20 g toluene. The
reaction mixture was stirred at room temperature for 24 h (results
after 3 hours: 10.6% amidothiophenol, <0.1% amidodisulfide;
results after 24 hours: 4.9% amidothiophenol, <0.1%
amidodisulfide).
[0118] The reaction mixture was completely evaporated at 50.degree.
C. under reduced pressure. To the residue was added 224 g heptane.
The solution was warmed to 40.degree. C. and extracted 4 times with
a mixture of 199 g MeOH and 110 g water. The phases are always
allowed to separate for 10 minutes. The aqueous phases are
discarded.
[0119] The thioester heptane solution was completely evaporated at
50.degree. C. under reduced pressure. To the oily residue was added
262 g EtOH and the suspension was heated at 50.degree. C. until the
solution was clear. A lab filter unit with external heating
(50.degree. C.) was charged with an activated charcoal filter
pad.
[0120] The reddish-brown thioester EtOH solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit are washed
with 34 g EtOH. The solution was filtered over a polishing
(Millipore.RTM.) filter at 50.degree. C. into an Erlenmeyer
flask.
[0121] The filtered thioester EtOH solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
34 g EtOH.
[0122] The clear solution was cooled to RT and seeded with a
suspension of 262 mg thioester seeding crystals in 4.4 g EtOH/water
1:1 (m/m). The seeded solution was stirred until a well mixed
suspension was obtained (60 minutes), and then, while stirring 160
g water was added with the use of a Dosimat.RTM. (metrohm automatic
dispenser) within 60 minutes at RT. After complete addition the
crystallization mixture was stirred for 30 minutes and then cooled
to -10.degree. C. (T.sub.i) within 3.5 h and further stirred for
min. 60 minutes at this temperature. The suspension was isolated by
filtration on paper and the isolated crystals are washed with a
mixture of 80 g EtOH and 34 g water (cooled to -10.degree. C.). The
wet crystals (approx. 119 g) are dried at 40.degree. C. under
reduced pressure for 16 h until the weight was constant. 81 g
thioester (assay 98.4%, yield 88.2%, 1.0% amidothiophenol) are
obtained.
Example 10
Use of Excess TPP in Toluene Followed by H.sub.2O.sub.2
Oxidation
[0123] In a double jacket vessel under argon 13.5 g DTDA (54 mmol,
0.54 eq) was suspended in 65 g toluene (75 ml). 11.6 g
N-methylmorpholine (115 mmol, 1.15 eq) was added. The dark brown
suspension was heated to 100.degree. C. and the suspension becomes
a clear solution. 23.7 g acid chloride (100 mmol, 1.0 eq, assay:
97.3% (% mass)) was added to this solution over a period of 30
minutes at 100.degree. C. The reaction mixture was heated to reflux
(115.degree. C.) and then stirred for 5 h under reflux.
[0124] The reaction mixture was cooled to 25.degree. C. and
extracted twice with each 20 g water. The toluene phase was
completely evaporated at 50.degree. C. under reduced pressure. To
the residue was added 59 g toluene (68 ml).
[0125] 14.7 g Triphenylphosphine (56 mmol, 0.56 eq) was dissolved
in 36 g toluene (42 ml) and the above amidodisulfide solution in
toluene was added at 25.degree. C. 9.82 g isobutyric anhydride (62
mmol, 0.621 eq) was added and rinsed with 9 g toluene (10 ml). The
reaction mixture was heated to reflux (115.degree. C.) and then
stirred for 5 h under reflux. An IPC-sample showed 36.7% TPPO,
0.16% amidothiophenol, 0% amidodisulfide and 60.2% thioester.
[0126] The reaction mixture was completely evaporated at 50.degree.
C. under reduced pressure. To the residue was added 109 g heptane
(160 ml). The suspension was warmed to 25-30.degree. C. and a
mixture of 89 g methanol (112 ml) and 48 g water (48 ml) was added.
3.4 g H.sub.2O.sub.2 (10% solution in water) (10 mmol, 0.10 eq.)
was added and the biphasic mixture was stirred for 30 minutes. The
aqueous phase was removed and the organic phase was extracted three
times with each a mixture of 89 g methanol (112 ml) and 48 g water
(48 ml). The phases were allowed to separate for 10 minutes after
each extraction. The aqueous phases were discarded.
[0127] The thioester solution was completely evaporated at
50.degree. C. under reduced pressure. To the oily residue was added
117 g ethanol (148 ml) and the suspension was heated at 50.degree.
C. until the solution was clear. A lab filter unit with external
heating (50.degree. C.) was charged with an activated charcoal
filter pad.
[0128] The reddish-brown thioester solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and became light brown. The flask and the filter unit were washed
with 16 g ethanol (20 ml). The solution was filtered through a
polishing filter at 50.degree. C. into an Erlenmeyer flask. The
flask and the filter unit was rinsed with 16 g ethanol (20 ml).
[0129] The filtered thioester ethanol solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g ethanol (20 ml).
[0130] The clear solution was cooled to 20.degree. C. and seeded
with a suspension of thioester (0.3 mmol, 0.003 eq) seeding
crystals in 2.0 g ethanol/water 1:1 (m/m) (2.3 ml). The seeded
solution was stirred until a well mixed suspension was obtained (60
minutes), then, while stirring, water was added with the use of a
Dosimat.RTM. within 60 minutes at 24.degree. C. After complete
addition the crystallization mixture was stirred for 30 minutes and
then cooled to -10.degree. C. (T.sub.i) within 3.5 h and further
stirred for 60 minutes at this temperature. The suspension was
isolated by filtration on paper and the isolated crystals were
washed with a mixture of 36 g ethanol (45 ml) and 15 g water
(cooled to -10.degree. C.). The wet crystals (approx. 45 g) were
dried at 45.degree. C. under reduced pressure for 16 h until the
weight was constant. 34.0 g thioester (assay 99.7%, 87 mmol, yield
87.0%) were obtained.
Example 11
Use of Excess TPP in Heptane Followed by H.sub.2O.sub.2
Oxidation
[0131] In a double jacket vessel under argon 13.4 g 2,2'-dithio
dianiline (54 mmol, 0.54 eq) was suspended in 51 g heptane (75 ml).
11.6 g N-methyl morpholine (115 mmol, 1.15 eq) was added. The dark
brown suspension was heated to 100.degree. C. and the suspension
became a clear solution. 23.7 g CAT-acid chloride (CAT13) (100
mmol, 1.0 eq, Assay: 97.3 (% mass)) was added to this solution over
a period of 30 minutes at 100.degree. C. The reaction mixture was
heated to 113.degree. C. under pressure (max 2 bar) and then
stirred for 7 h at this temperature.
[0132] The reaction mixture was cooled to 25.degree. C. and
extracted twice with each 20 g water. The heptane phase was heated
to reflux at normal pressure and azeotroped using a Dean-Stark-trap
until the heptane phase was dry. The heptane phase was cooled to
room temperature.
[0133] 14.7 g triphenyl phosphine (56 mmol, 0.56 eq) and 24 g
heptane (35 ml) were charged to the above solution in heptane at
25.degree. C. 9.82 g isobutyric anhydride (62 mmol, 0.621 eq) were
added and rinsed with 7 g heptane (10 ml). The reaction mixture was
heated at reflux (100.degree. C.) and then stirred for 5 h under
reflux. An IPC-sample showed 10.8% TPPO, 0% amidothiophenol, 0%
amidodisulfide and 84.3% thioester.
[0134] The reaction mixture was cooled to 35.degree. C. and diluted
with 27 g heptane (40 ml) and a mixture of 89 g methanol (112 ml)
and 37 g water. 11.3 g of 3% H.sub.2O.sub.2-solution (10 mmol, 0.10
eq.) were added and the biphasic mixture was stirred for 30 minutes
at 35.degree. C. The aqueous phase is separated and the organic
phase was extracted 4 times with each a mixture of 89 g methanol
(112 ml) and 48 g water (48 ml). The phases were always allowed to
separate for 10 minutes. The aqueous phases were discarded.
[0135] The thioester heptane solution was completely evaporated at
50.degree. C. under reduced pressure. To the oily residue was added
117 g ethanol (148 ml) and the suspension is heated at 50.degree.
C. until the solution was clear. A lab filter unit with external
heating (50.degree. C.) was charged with an activated charcoal
filter pad.
[0136] The reddish-brown thioester ethanol solution was filtered at
50.degree. C. through above filter unit within approx. 20 minutes
and becomes light brown. The flask and the filter unit were washed
with 16 g ethanol (20 ml). The solution was filtered over a polish
filter at 50.degree. C. into an Erlenmeyer flask. The flask and the
filter unit was rinsed with 16 g ethanol (20 ml).
[0137] The filtered thioester ethanol solution was transferred into
the double jacket vessel at 50.degree. C. The flask was rinsed with
16 g ethanol (20 ml).
[0138] The clear solution was cooled to 18-20.degree. C. and seeded
with a suspension of thioester (0.3 mmol, 0.003 eq) seeding
crystals in 2.0 g ethanol/water 1:1 (m/m) (2.3 ml). The suspension
was stirred until a well mixed suspension is obtained (60 minutes),
subsequently and while stirring water was added with the use of a
Dosimat.RTM. within 60 minutes at 24.degree. C. After complete
addition the crystallization mixture was stirred for 30 minutes and
then cooled to -10.degree. C. (T.sub.i) within 3.5 h and further
stirred for min. 60 minutes at this temperature. The suspension was
isolated by filtration on paper and the isolated crystals were
washed with a mixture of 36 g ethanol (45 ml) and 15 g water
(cooled to -10.degree. C.). The wet crystals (42.5 g) were dried at
45.degree. C. under reduced pressure for 16 h until the weight was
constant. 34.6 g of thioester (88.9 mmol, yield 88.9%) were
obtained.
Example 12
Extraction of TPPO with a Multi Stage Centrifugal Extractor (Model
Used LX526 from Rousselet & Robatel)
##STR00005##
[0140] In a double jacket vessel 114 kg DTDA (459 mol, 0.54 eq) and
99 kg NMM (979 mol, 1.15 eq) was suspended in 555 kg toluene (640
l). The suspension was heated to 100.degree. C. and the suspension
became a clear solution. 197 kg acid chloride (854 mol, 1.0 eq,
assay corrected) was added to this solution over a period of 30
minutes at 100.degree. C. The reaction mixture was heated at reflux
(115.degree. C.) and then stirred for 6 hours under reflux.
[0141] The reaction mixture was transferred to another double
jacket vessel and rinsed with 43 kg toluene (49 l). The reaction
mixture was cooled to RT and extracted with 171 kg water twice. 100
kg solvent was evaporated at 50.degree. C. under reduced pressure.
At constant volume 500 kg toluene (434 l) was added to the residue
while evaporating solvent.
[0142] 121 kg of TPP (461 mol, 0.54 eq) was dissolved in 282 kg
toluene (325 l) followed by the addition of the above
amidodisulfide solution in toluene at 25.degree. C. 84 kg
isobutyric anhydride (531 mol, 0.62 eq) was added. The reaction
mixture was heated to reflux (115.degree. C.) and then stirred for
6 hours under reflux.
[0143] The reaction mixture was completely evaporated at 50.degree.
C. under reduced pressure. To the residue was added 930 kg heptane
(1348 l). The solution was warmed to 40.degree. C. and extracted
with a mixture of 181 kg MeOH (229 l) and 98 kg water (98 l). The
aqueous phase was discarded.
[0144] The heptane solution (feed 1200 l/h) was extracted at
40.degree. C. with methanol/water (65/35) (feed 800 l/h) via a 6
stage centrifugal extractor at 1800 rpm. The vessel was rinsed with
104 kg heptane (150 l) and the heptane was extracted against
methanol/water (65/35) in the extractor under the same
conditions.
[0145] The thioester heptane solution was completely evaporated at
55.degree. C. under reduced pressure. To the oily residue was added
1258 kg EtOH (1593 l) and the suspension was heated at 50.degree.
C. until the solution was clear. A 16'' filter unit with external
heating (50.degree. C.) was charged with three activated charcoal
filter modules.
[0146] The reddish-brown thioester solution in ethanol was filtered
at 50.degree. C. through the above filter unit and an additional
polishing filter (5 .mu.m) within approx. 2 hours and became
yellowish. The vessel and the filters were rinsed with 156 kg EtOH
(198 l).
[0147] The clear solution was cooled to RT and seeded with a
suspension of 1 kg thioester (2.6 mol, 0.003 eq) seeding crystals
in 17 kg EtOH/water 1:1 (m/m). The seeded solution was stirred
until a well mixed suspension was obtained (60 minutes), and then,
while stirring, 615 kg water (615 l) was added within 60 minutes at
RT. After complete addition the crystallization mixture was stirred
for 30 minutes and then cooled to -10.degree. C. (T.sub.i) within
3.5 hours and further stirred for min. 60 minutes at this
temperature.
[0148] The suspension was separated on a centrifuge and the
isolated crystals were washed with a mixture of 307 kg EtOH (390 l)
and 128 kg water (cooled to -10.degree. C.).
[0149] The wet crystals (approx. 378 kg) were dried in a spherical
dryer at 45.degree. C. under reduced pressure for 11 hours. 298.8
kg thioester (assay 99.5%, 763 mol, yield 89.3%) were obtained.
* * * * *