U.S. patent application number 14/545756 was filed with the patent office on 2015-10-08 for methods for synthesizing 3-(substituted dihydroisoindolinone-2-yi)-2, 6-dioxopiperidine, and intermediates thereof.
This patent application is currently assigned to Nanjing Cavendish Bio-Engineering Technology Co., Ltd.. The applicant listed for this patent is Nanjing Cavendish Bio-Engineering Technology Co., Ltd., Rong Yan. Invention is credited to Yongxiang Xu, Rong Yan, Hao Yang.
Application Number | 20150284329 14/545756 |
Document ID | / |
Family ID | 41362841 |
Filed Date | 2015-10-08 |
United States Patent
Application |
20150284329 |
Kind Code |
A1 |
Yan; Rong ; et al. |
October 8, 2015 |
Methods for synthesizing 3-(Substituted
Dihydroisoindolinone-2-YI)-2, 6-Dioxopiperidine, and intermediates
thereof
Abstract
The present invention discloses methods for synthesizing
3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine and
intermediates thereof, namely, the synthesis of compounds of the
Formula (I), with each substitutional group defined in the patent
specification. Owing to the advantages of high productivity, little
influence to the environment and material accessibility, the
methods of the present invention is suitable for industrial
production. ##STR00001##
Inventors: |
Yan; Rong; (Nanjing, CN)
; Yang; Hao; (Nanjing, CN) ; Xu; Yongxiang;
(Nanjing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Yan; Rong
Nanjing Cavendish Bio-Engineering Technology Co., Ltd. |
Nanjing
Nanjing |
|
CN
CN |
|
|
Assignee: |
Nanjing Cavendish Bio-Engineering
Technology Co., Ltd.
Nanjing
CN
Yan; Rong
Nanjing
CN
|
Family ID: |
41362841 |
Appl. No.: |
14/545756 |
Filed: |
June 15, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13375610 |
Dec 1, 2011 |
9085530 |
|
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PCT/CN10/73437 |
Jun 1, 2010 |
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14545756 |
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Current U.S.
Class: |
548/465 ;
548/472; 548/477 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 209/48 20130101; C07D 209/46 20130101; C07D 405/04 20130101;
A61P 37/02 20180101 |
International
Class: |
C07D 209/46 20060101
C07D209/46; C07D 405/04 20060101 C07D405/04; C07D 209/48 20060101
C07D209/48 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 1, 2009 |
CN |
0910142160.9 |
Claims
1. The following intermediate compounds of Formula (IV):
##STR00184## wherein: One of R, R3, R4 and R5 is amino, protected
amino, nitro or halo, and the others are hydrogen; Y is: .dbd.O or
H; Z is: .dbd.O or H; and with the proviso that Y and Z are both
.dbd.O; or one of Y and Z is .dbd.O and the other of Y and Z is H;
A and B are each independently hydroxyl, C.sub.1-10 alkoxy,
aryloxy, aryl C.sub.1-4 alkoxy or NHR.sub.2, in which R.sub.2 is
hydrogen or amino protecting group; R1 is C.sub.1-4 alkyl or
hydrogen; and with the proviso that the following compounds are not
included: when R is nitro, A and B are both methoxy, benzyloxy,
hydroxyl or amino; when R is nitro, A is methoxy and B is amino;
when R is amino, A and B are both ethoxyl; when R is nitro, A is
amino and B is t-butoxyl.
2. The compound of claim 1 is the following intermediate compounds
of Formula (IV'): ##STR00185## the definitions of the substituted
groups in the compounds of Formula (IV') are the same as that in
claim 1.
3. The compound of claim 1 is the following intermediate compounds
of Formula (IV''): ##STR00186## the substituted groups in the
compounds of Formula (IV'') are as defined in claim 1.
4. The compound of claim 1 is the following intermediate compounds
of Formula (V): ##STR00187## wherein: the substituted groups in the
compounds of Formula (V) are as defined in claim 1, and with the
proviso that the following compounds are not included: when R is
amino or nitro, R1, R3, R4 and R5 are all hydrogen, and Y is
.dbd.O, and Z is .dbd.O or H.
5. The following intermediate compounds of Formula (VI):
##STR00188## wherein: the substituted groups in the compounds of
Formula (VI) are as defined in claim 1, and with the proviso that
the following compounds are not included: when R is nitro, R1, R3,
R4 and R5 are all hydrogen, and Y is .dbd.O, and Z is .dbd.O.
6. The compound of claim 1 is the following intermediate compounds
of Formula (VII): ##STR00189## wherein: the substituted groups in
the compounds of Formula (VII) are as defined in claim 1, and with
the proviso that the following compounds are not included: when R
is amino or nitro, R1, R3, R4 and R5 are all hydrogen, and Y is
.dbd.O, and Z is .dbd.O or H.
7. The compound of claim 1, which is selected from the following
intermediate compounds: ##STR00190## ##STR00191## ##STR00192##
8. The compound of claim 5, which is selected from the following
intermediate compounds: ##STR00193##
Description
TECHNICAL FIELD
[0001] The present invention is in the field of pharmaceutical
chemistry, and more specifically it relates to methods for
synthesizing 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and intermediates
thereof.
BACKGROUND ART
[0002] Lenalidomide, an analog of Thalidomide, is a kind of
immunomodulator with anti-vascular proliferation and anti-tumor
activities; its chemical name is
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
and its chemical structure is as following:
##STR00002##
[0003] Lenalidomide has the residue of dioxopiperidine and
dihydroisoindoline residue, as well as an asymmetric center in its
structure. At present Lenalidomide approved on the market are
racemic mixtures.
[0004] As is manifest in the article "Amino-substituted thalidomide
analogs: Potent inhibitors of TNF-.alpha. production" (Bioorganic
& Medicinal Chemistry Letters, Vol. 9, Issue 11, 7 Jun., 1999,
pp 1625-1630) and the Chinese Patent ZL97180299.8 by Muller etc.,
the method of preparing 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine is as following:
.alpha.-aminoglutarimide hydrochloride reacts with methyl
2-bromomethyl-3-nitrobenzoate, then hydrogenated over Pd/C to yield
lenalidomide.
##STR00003##
[0005] wherein, (a) under ultraviolet light (mercury lamp), NBS,
CCL.sub.4, refluxing; (b) Et.sub.3N, DMF, 80.degree. C.; (c)
H.sub.2, 10% Pd/C, MeOH. 7a X=4-NO.sub.2, 8a X=4-NH.sub.2. In
which, the synthesis of .alpha.-aminoglutarimide hydrochloride
begins with N-benzyloxycarbony-L-glutamine which reacts with
N,N'-carbonyldiimidazole (CDI) refluxing in THF to yield
N-benzyloxycarbony-aminoglutarimide; the key material of the
reaction is: methyl 2-bromomethyl-3-nitro benzoate, which is
converted from 2-methyl-3-nitrobenzoate by catalytic bromination in
the condition of carbon tetrachloride under ultraviolet light. The
catalytic and refluxing reaction needs long time and the yield is
low. Additionally, the mass production is unease to be realized due
to the difficulty of workers' labour protection against ultraviolet
produced by mercury lamp as catalytic light source.
[0006] In the US Patent application US2006/0052609 A1, Muller etc.
disclosed another synthetic method of 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine:
##STR00004##
[0007] In the US Patent application US2006052609A1 and the Chinese
Patent application CN97180299.8, the reaction product was purified
by column chromatography at least twice or more, which made
industrial operation complicated and made it difficult to
industrial scale-up production.
[0008] In the US Patent application US2006052609A1 and the Chinese
Patent application CN97180299.8, pressurized hydrogenation was both
utilized twice, which was of much more risk in industrial
operation.
[0009] In addition, when N-benzyloxycarbony-L-glutamine, as initial
material, reacted with N,N'-carbonyldiimidazole in THF refluxing
for 24 h to yield N-benzyloxycarbony-aminoglutarimide, low purity
of yield due to long reactive time for refluxing and high
temperature made extraction difficult.
[0010] On the other hand, the total yield was lower than 20% and
18% respectively reported in the US Patent application
US2006052609A1 and the Chinese Patent application. Also, in the
above two documents "lethal carbon tetrachloride" was reported to
be reactive solvent used for refluxing. Carbon tetrachloride had
serious destruction to ozone layer, which was forbidden to use by
UNEP. Because of the high toxicity of carbon tetrachloride, it was
difficult to dispose this substance, which is harmful to
environment.
SUMMARY OF INVENTION
[0011] The present invention provides a novel method for
synthesizing 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine and its
intermediates, which overcame the disadvantages mentioned above in
prior art.
[0012] One objective of the present invention is to provide a novel
method for synthesizing 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine.
[0013] Another objective of the present invention is to provide the
intermediates used to synthesize 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine.
DETAILED DESCRIPTION OF INVENTION
[0014] In one embodiment of the present invention, a novel method
for synthesizing the compound of Formula (I) is provided.
##STR00005##
[0015] Including the reaction of the compound of Formula (II) and
the compound of Formula (III) to yield the compound of Formula
(IV);
[0016] wherein:
[0017] One of R, R3, R4 and R5 is amino or protected amino
(carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,
fluorenylmethoxycarbonyl, etc.; acyl amides: such as acetyl,
phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl
and sulfinyl: such as phenylsulfonyl, p-toluenesulfonyl,
phenylsulfinyl, O-nitrophenylsulfinyl, etc.; referred to Greene T.
W. and WuTs P. G. M. Protective Groups in Organic Synthesis: P494-;
East China University Of Science And Technology Press, which is
hereby incorporated by reference in their entirety), nitro or halo
(for example F, Cl, Br or I), and the others are all hydrogen,
preferably, R3, R4 and R5 are hydrogen;
[0018] X is halo, such as: F, Cl, Br or I;
[0019] Y is .dbd.O or H;
[0020] Z is .dbd.O or H; with the proviso that Y and Z are both
.dbd.O; or one of Y and Z is .dbd.O and the other of Y and Z is
H;
[0021] R' is alkali metal ion or hydrogen (such as: H, Li.sup.+,
Na.sup.+, K.sup.+ or Cs.sup.+), or imine protecting group (such as
ethoxycarbonyl, etc.; referred to Greene T. W. and WuTs P. G. M.
Protective Groups in Organic Synthesis: P494-, East China
University Of Science And Technology Press, and Chemical Research
and Application: 2006, 18(11): 1349-1352), etc., preferably K.sup.+
or Cs.sup.+, and more preferably Cs.sup.+;
[0022] A and B are each independently hydroxyl, C.sub.1-10 alkoxy,
aryloxy, aryl C.sub.1-4 alkoxy or NHR.sub.2, and herein, R.sub.2 is
hydrogen or amino protecting group (carbamates: such as
carbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.;
acyl amides: such as acetyl, phenylacetyl, phthalyl, etc.; azanes:
such as allyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,
p-toluenesulfonyl, phenylsulfiny, O-nitrophenylsulfinyl, etc.;
referred to Protective Groups in Organic Synthesis: Greene T. W.,
WuTs P. G. M. East China University Of Science And Technology
Press: P494-); preferably, A and B are each independently hydroxyl,
methoxyl, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy,
t-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,
decyloxy; phenoxy or substituted phenoxy; phenyl C.sub.1-4 alkoxy,
such as benzyloxy, phenylethoxy, phenylpropoxy, etc., or
substituted phenyl C.sub.1-4 alkoxy; in terms of the substituted
phenoxy or substituted phenyl C.sub.1-4 alkoxy, the number of the
substituted groups is one or more; the substituted groups are
selected from the group consisting of C.sub.1-4 alkyl, halo, cyano,
and nitro, and the substituted groups may be the same or different,
optionally, the groups are substituted at 2, 3, 4, 5 or 6-position
of the benzene ring, for example 4-nitrobenzyloxyl,
2-chloro-4-nitrobenzyloxyl; amino, or benzylamino;
[0023] R1 is C.sub.1-4 alkyl or hydrogen; the said C.sub.1-4 alkyl
is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl; preferably, R1 is hydrogen or methyl.
[0024] The present invention provides the method of synthesizing
the compound of Formula (I) mentioned above, after yielding the
compound of Formula (IV), further including that if A and B are
both NHR.sub.2, the compound of Formula (IV) is heated and cyclized
in or out of the presence of formamide or methanesulfonic acid to
yield the compound of Formula (I); and with the proviso that when
R.sub.2 is not hydrogen, the compound of Formula (IV) undergoes
deprotection of amino groups and then cyclization mentioned above
to yield the compound of Formula (I);
[0025] when one of A and B is NHR.sub.2 and the other is hydroxyl,
the compound of Formula (IV) reacts in the presence of condensing
agent (such as thionyl chloride, dicyclohexylcarbodiimide (DCC),
phosphorus oxychloride, carbonyldiimidazole, etc.), to yield the
compound of Formula (I); and with proviso that when R.sub.2 is not
hydrogen, the compound of Formula (IV) undergoes deprotection of
amino groups and then cyclization mentioned above to yield the
compound of Formula (I);
[0026] when one of A and B is NHR.sub.2 and the other is C.sub.1-10
alkoxy, aryloxy, or aryl C.sub.1-4 alkoxy, the compound of Formula
(IV) is cyclized in alkaline condition (such as in the presence of
inorganic base, for example potassium carbonate, sodium carbonate,
or organic base, for example potassium tert-butoxide or sodium
methoxide, etc.), to yield the compound of Formula (I); and with
the proviso that when R.sub.2 is not hydrogen, the compound of
Formula (IV) undergoes deprotection of amino groups and then
cyclization mentioned above to yield the compound of Formula
(I);
[0027] when A and B are both hydroxyl, the compound of Formula (IV)
is cyclized in the presence of urea, or in the presence of
trifluoroacetamide, 1-hydroxy benzotriazole (HOBT) and
N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride
(EDCl), to yield the compound of Formula (I);
[0028] when A and B are both C.sub.1-10 alkoxy, aryloxy or aryl
C.sub.1-4alkoxy, the compound of Formula (IV) is cyclized in the
presence of alkali metal amide (such as lithium amide, sodium
amide, potassamide, preferred sodium amide), to yield the compound
of Formula (I);
[0029] when one of A and B is hydroxyl and the other is C.sub.1-10
alkoxy, aryloxy or aryl C.sub.1-4 alkoxy, the compound of Formula
(IV) is firstly esterified, and then cyclized in the presence of
alkali metal amide (such as lithium amide, sodium amide,
potassamide, preferred sodium amide), to yield the compound of
Formula (I); alternatively, the compound of Formula (IV) is firstly
ester hydrolyzed, and then cyclized in the presence of urea, or in
the presence of trifluoroacetamide, 1-hydroxy benzotriazole (HOBT)
and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDCl), to yield the compound of Formula (I); alternatively, the
compound of Formula (IV) is firstly ammonolyzed and then reacts in
the presence of condensing agent (such as thionyl chloride,
dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,
carbonyldiimidazole, etc.), to yield the compound of Formula (I);
alternatively, the compound of Formula (IV) is firstly acylated,
converting its hydroxyl to amino, and then cyclized in alkaline
condition (such as in the presence of inorganic base, for example
potassium carbonate, sodium carbonate, etc., or organic base, for
example potassium tert-butoxide or sodium methoxide, etc.), to
yield the compound of Formula (I);
##STR00006##
[0030] wherein, each substituted group in the Formula (IV) or (I)
is defined as above.
[0031] Optionally, the above-mentioned method for synthesizing the
compound of Formula (I) provided by the invention includes that,
after yielding the compound of Formula (IV), when A and B are both
C.sub.1-10 alkoxy, aryloxy, or aryl C.sub.1-4 alkoxy, the compound
of Formula (IV) is ammonolyzed to yield the monoamide compound of
Formula (IV'), and then the monoamide compound of Formula (IV') is
cyclized in alkaline condition (such as in the presence of
inorganic base, for example potassium carbonate, sodium carbonate,
etc., or organic base, for example potassium tert-butoxide or
sodium methoxide, etc.), to yield the compound of Formula (I); the
monoamide compound of Formula (IV') may alternatively continue to
be ammonolysed to yield eventually diamide of Formula (IV''), and
then diamide of Formula (IV'') is heated to be cyclized in or out
of the presence of formamide or methanesulfonic acid to yield the
compound of Formula (I);
##STR00007##
[0032] wherein, each substituted group in the Formula (IV), (IV'),
(IV'') and (I) is defined as above.
[0033] Optionally, the above-mentioned method for synthesizing the
compound of Formula (I) provided by the invention, after yielding
the compound of Formula (IV), when A and B are both C.sub.1-10
alkoxy, aryloxy, or arylC.sub.1-4alkoxy, further includes that the
compound of Formula (IV) is hydrolyzed to yield the monoamide
compound of Formula (V);
##STR00008##
[0034] wherein, each substituted group in the Formula (IV) and (V)
is defined as above.
[0035] The above-mentioned method for synthesizing the compound of
Formula (I) provided by the present invention, after yielding the
compound of Formula (V), further includes that the compound of
Formula (V) is cyclized (such as in the condition of acid anhydride
and heating) to yield the compound of Formula (VI);
##STR00009##
[0036] wherein, each substituted group in the Formula (V) and (VI)
is defined as above.
[0037] The above-mentioned method for synthesizing the compound of
Formula (I) provided by the present invention, after yielding the
compound of Formula (VI), further includes that the compound of
Formula (VI) is ring-opening ammonolyzed to yield the compound of
Formula (VII); then the compound of Formula (VII) reacts in the
presence of condensing agent (such as thionylchloride,
dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,
carbonyldiimidazole, etc.), to yield the compound of Formula
(I):
##STR00010##
[0038] wherein, each substituted group in the Formula (VI) and
(VII) is defined as above.
[0039] The present invention provided a novel method for
synthesizing the compound of Formula (I), which includes the
following steps:
##STR00011##
[0040] (1) the compound of Formula (II) reacts with the compound of
Formula (III) in the alkaline condition (such as in the presence of
inorganic base, for example potassium hydroxide, potassium
carbonate, sodium hydroxide, sodium carbonate, cesium hydroxide or
cesium carbonate, etc., otherwise organic base, for example
potassium tert-butoxide or sodium methoxide, etc.), to yield the
compound of Formula (IV);
##STR00012##
[0041] (2) when A and B are both NHR.sub.2, the compound of Formula
(IV) is heated and cyclized in or out of the presence of formamide
or methanesulfonic acid to yield the compound of Formula (I); and
with the proviso that when R.sub.2 is not hydrogen, the compound of
Formula (IV) undergoes deprotection of amino groups and then
cyclization mentioned above to yield the compound of Formula
(I);
[0042] when one of A and B is NHR.sub.2 and the other is hydroxyl,
the compound of Formula (IV) reacts in the presence of condensing
agent (such as thionyl chloride, dicyclohexylcarbodiimide (DCC),
phosphorus oxychloride, carbonyldiimidazole, etc.), to yield the
compound of Formula (I); and with the proviso that when R.sub.2 is
not hydrogen, the compound of Formula (IV) undergoes deprotection
of amino groups and then cyclization mentioned above to yield the
compound of Formula (I);
[0043] when one of A and B is NHR.sub.2 and the other is C.sub.1-10
alkoxy, aryloxy, or aryl C.sub.1-4alkoxy, the compound of Formula
(IV) is cyclized in alkaline condition (such as in the presence of
inorganic base, for example potassium carbonate, sodium carbonate,
etc., or organic base, for example potassium tert-butoxide or
sodium methoxide, etc.), to yield the compound of Formula (I); and
with the proviso that if R.sub.2 is not hydrogen, the compound of
Formula (IV) undergoes deprotection of amino groups and then
cyclization mentioned above to yield the compound of Formula
(I);
[0044] when A and B are both hydroxyl, the compound of Formula (IV)
is cyclized in the presence of urea, or in the presence of
trifluoroacetamide, 1-hydroxy benzotriazole (HOBT) and
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDCl), to yield the compound of Formula (I);
[0045] when A and B are both C.sub.1-10 alkoxy, aryloxy or aryl
C.sub.1-4alkoxy, the compound of Formula (IV) is cyclized in the
presence of alkali metal amide (such as lithium amide, sodium
amide, potassamide, preferred sodium amide), to yield the compound
of Formula (I);
[0046] when one of A and B is hydroxyl and the other is C.sub.1-10
alkoxy, aryloxy or aryl C.sub.1-4 alkoxy, the compound of Formula
(IV) is firstly esterified, and then cyclized in the presence of
alkali metal amide (such as lithium amide, sodium amide,
potassamide, preferred sodium amide), to yield the compound of
Formula (I); alternatively, the compound of Formula (IV) is firstly
ester hydrolyzed, and then cyclized in the presence of urea, or in
the presence of trifluoroacetamide, 1-hydroxybenzotriazole (HOBT)
and N-ethyl-N'-(3-dimethylamino propyl)-carbodiimide hydrochloride
(EDCl), to yield the compound of Formula (I); alternatively, the
compound of Formula (IV) is firstly ammonolyzed and then reacts in
the presence of condensing agent (such as thionyl chloride
dicyclohexylcarbodiimide (DCC), phosphorus oxychloride,
carbonyldiimidazole, etc.), to yield the compound of Formula (I);
alternatively, the compound of Formula (IV) is firstly acylated,
converting hydroxyl to amino, and then cyclized in alkaline
condition (such as in the presence of inorganic base, for example
potassium carbonate, sodium carbonate, etc., or organic base, for
example potassium tert-butoxide or sodium methoxide, etc.), to
yield the compound of Formula (I).
##STR00013##
[0047] wherein, each substituted group in the compounds of Formula
from (I) to (IV) mentioned above is defined as:
[0048] one of R, R3, R4 and R5 is amino or protected amino
(carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,
fluorenylmethoxycarbonyl, etc.; acyl amides: such as acetyl,
phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl
and sulfinyl: such as phenylsulfonyl, p-toluenesulfonyl,
phenylsulfiny, O-nitrophenylsulfinyl, etc.; referred to Greene T.
W. and WuTs P. G. M. Protective Groups in Organic Synthesis: P494-;
East China University Of Science And Technology Press), nitro or
halo (for example F, Cl, Br or I), and the others are hydrogen,
preferably, R3, R4 and R5 are hydrogen;
[0049] X is halo, such as: F, Cl, Br or I;
[0050] Y is .dbd.O or H;
[0051] Z is .dbd.O or H; and with the proviso that Y and Z are both
.dbd.O; or one of Y and Z is .dbd.O and the other is H;
[0052] R' is alkali metal ion or hydrogen, such as: H; Li.sup.+;
Na.sup.+; K.sup.+; Cs.sup.+; or imine group (such as
ethoxycarbonyl, etc.; referred to Greene T. W. and WuTs P. G. M.
Protective Groups in Organic Synthesis: P494-, East China
University Of Science And Technology Press, and referred to
Chemical Research and Application: 2006, 18(11): 1349-1352), etc.
preferably K.sup.+ or Cs.sup.+, and more preferably Cs.sup.+;
[0053] A and B are each independently hydroxyl, C.sub.1-10 alkoxy,
aryloxy, aryl C.sub.1-4 alkoxy or NHR.sub.2 in which R.sub.2 is
hydrogen or amino protecting group (carbamates: such as
carbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.;
acyl amides: such as acetyl, phenylacetyl, phthalyl, etc.; azanes:
such as allyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,
p-toluenesulfonyl, phenylsulfiny, O-nitrophenylsulfinyl, etc.;
referred to Protective Groups in Organic Synthesis: Greene T. W.,
WuTs P. G. M. East China University Of Science And Technology
Press: P494-); preferably, A and B are each independently hydroxyl,
methoxy, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy;
phenoxy or substituted phenoxy; phenyl C1-4 alkoxy, such as
benzyloxy, phenylethoxy, phenylpropoxy, etc., or substituted phenyl
C1-4 alkoxy; in terms of the substituted phenoxy or substituted
phenyl C1-4 alkoxy, the substituted groups are selected from the
group consisting of C.sub.1-4 alkyl, halo, cyano, nitro, and the
substituted groups are one or more, which could be the same or
different groups; optionally, the groups are substituted in 2, 3,
4, 5 or 6-position of the benzene ring, for example
4-nitrobenzyloxyl, 2-chloro-4-nitrobenzyloxyl; amino and
benzylamino.
[0054] R1 is C.sub.1-4 alkyl or hydrogen; the described C.sub.1-4
alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, and t-butyl; preferably, R1 is hydrogen or methyl.
[0055] Optionally, in the above-mentioned method for synthesizing
the compound of Formula (I) provided by the invention, the step (2)
is: when A and B are both C.sub.1-10 alkoxy, aryloxy, or
arylC.sub.1-4alkoxy, the compound of Formula (IV) is ammonolyzed to
yield the monoamide compound of Formula (IV'), and then the
monoamide compound of Formula (IV') is cyclized in alkaline
condition (such as in the presence of inorganic base, for example
potassium carbonate, sodium carbonate, etc., or organic base, for
example potassium tert-butoxide or sodium methoxide, etc.), to
yield the compound of Formula (I); the monoamide compound of
Formula (IV') may alternatively continue to be ammonolysed to yield
eventually diamide of Formula (IV''), and then diamide of Formula
(IV'') is heated to be cyclized in or out of the presence of
formamide or methanesulfonic acid, to yield the compound of Formula
(I);
##STR00014##
wherein, each other substituted group in the Formula (IV), (IV'),
(IV'') and (I) is defined as above.
[0056] Optionally, in the above-mentioned method for synthesizing
the compound of Formula (I) provided by the invention, the step (2)
is: when A and B are both C.sub.1-10 alkoxy, aryloxy, or
arylC.sub.1-4 alkoxy, the compound of Formula (IV) is hydrolyzed to
yield the monoamide compound of Formula (V);
##STR00015##
[0057] after yielding the compound of Formula (V), the compound of
Formula (V) is further cyclized (such as in the condition of acid
anhydride and heating) to yield the compound of Formula (VI);
##STR00016##
[0058] after yielding the compound of Formula (VI), the compound of
Formula (VI) is further ring-opening ammonolyzed to yield the
compound of Formula (VII); then the compound of Formula (VII)
reacts in the presence of condensing agent (such as
thionylchloride, dicyclohexylcarbodiimide (DCC), phosphorus
oxychloride, carbonyldiimidazole, etc.), to yield the compound of
Formula (I):
##STR00017##
[0059] wherein, each other substituted group in the Formula (IV),
(V), (VI) and (VII) is defined as above.
[0060] More preferably, the present invention provides a method for
preparing 3-(substituted
dihydroisoindolinone-2-yl)-2,6-dioxopiperidine, i.e. the compound
of Formula (I), including:
##STR00018##
[0061] wherein: in the formula (I),
[0062] substituted group R is amino, nitro or halo (such as F, Cl,
Br or I); R3, R4 and R5 are all hydrogen;
[0063] Y is .dbd.O; Z is H;
[0064] R1 is hydrogen or methyl;
[0065] (1) the following compound of Formula (II) is stirred in the
presence of potassium hydroxide, potassium carbonate, sodium
hydroxide, sodium carbonate, cesium hydroxide or cesium carbonate
for 5 minutes.about.6 hours; preferably, in the presence of
potassium hydroxide, potassium carbonate, cesium hydroxide or
cesium carbonate, and more preferably in the presence of cesium
hydroxide or cesium carbonate; the reaction time is preferably 10
minutes.about.4 hours, and more preferably 20 minutes.about.4
hours; then the corresponding compound of Formula (III) is added
into the reaction system to react with stirring, the reaction
temperature is -20.degree. C..about.80.degree. C.; the reaction
temperature is preferably 0.degree. C..about.50.degree. C., and
more preferably 10.degree. C..about.30.degree. C.; the reaction
time is 1 hour.about.72 hours, preferably 8 hours.about.48 hours,
and more preferably 12 hours.about.28 hours; the corresponding
compound of Formula (IV) is yielded in the reaction. in these
conditions:
TABLE-US-00001 Formula sequence Compound of Compound of Compound of
number Formula (II) Formula (III) Formula (IV) 1 ##STR00019##
##STR00020## ##STR00021## 2 ##STR00022## ##STR00023## ##STR00024##
3 ##STR00025## ##STR00026## ##STR00027## 4 ##STR00028##
##STR00029## ##STR00030##
[0066] (2) the compound of Formula (IV) in step (1) is cyclized in
the presence of alkali metal amide (such as lithium amide, sodium
amide, potassamide, preferred sodium amide); the reaction
temperature is -60.degree. C..about.80.degree. C., preferably
-40.degree. C..about.50.degree. C., and more preferably -30.degree.
C..about.20.degree. C.; the reaction time is 30 minutes.about.24
hours, preferably 1 hour.about.12 hours, and more preferably 2
hours.about.8 hours; the corresponding compounds of Formula (I) are
yielded in the reaction; alternatively, the compound of Formula
(IV) in step (1) is cyclized in the presence of urea; the reaction
temperature is 50.about.250.degree. C. preferably
100.about.200.degree. C., and more preferably 130.about.160.degree.
C.; the reaction time is 30 minutes.about.24 hours, preferably 1
hour.about.12 hours, and more preferably 2 hours.about.8 hours; the
corresponding compounds of Formula (I) are yielded in the
reaction;
[0067] in these conditions:
TABLE-US-00002 Formula sequence Compound of Compound of number
Formula (IV) conditions Formula (I) 1 ##STR00031## NaNH.sub.2 or
KNH.sub.2 ##STR00032## 2 ##STR00033## NH.sub.2CONH.sub.2
##STR00034## 3 ##STR00035## NaNH.sub.2 or KNH.sub.2 ##STR00036## 4
##STR00037## NH.sub.2CONH.sub.2 ##STR00038## 5 ##STR00039##
NaNH.sub.2 or KNH.sub.2 ##STR00040## 6 ##STR00041##
NH.sub.2CONH.sub.2 ##STR00042## 7 ##STR00043## NH.sub.2CONH.sub.2
##STR00044##
[0068] alternatively, the compound of Formula (IV) in step (1) is
ammonolyzed in alkaline condition to yield the monoamide compounds
of Formula (IV'); then the monoamide compound of Formula (IV') is
cyclized in the condition of alkali such as potassium
tert-butoxide, potassium carbonate etc. to yield the compound of
Formula (I); alternatively the monoamide compound of Formula (IV')
continues to be ammonolyzed to yield diamide compound of Formula
(IV''), and then the compound of Formula (IV'') is heated to be
cyclized to yield the compound of Formula (I);
[0069] in particular, preferred ammonolysis conditions are: the
compound of Formula (IV) is added into a single organic solvent or
mixture of two or more organic solvents containing saturated
ammonia such as ammonia water, ammonia/methanol,
ammonia/tetrahydrofuran, ammonia/dioxane or
ammonia/dimethylformamide; preferably ammonia/methanol or
ammonia/tetrahydrofuran; the reaction temperature is between
-20.degree. C. and the refluxing temperature, preferably
-10.degree. C..about.40.degree. C., and more preferably 0.degree.
C..about.20.degree. C.; the reaction time for preparing the
compound of Formula (IV') is 10 minutes.about.18 hours, preferably
2 hours.about.12 hours, more preferably 3 hours.about.8 hours; the
synthesis time of the compound of Formula (IV'') is 6
hours.about.72 hours, preferably 8 hours.about.32 hours, more
preferably 10 hours.about.24 hours;
[0070] optional reaction conditions of cyclization of the compound
of Formula (IV') are: in the presence of alkali, by cyclization the
compound of Formula (I) is yielded. In particular, when metal
organic base such as potassium tert-butoxide or sodium
tert-butoxide is selected, reaction temperature is between
-20.degree. C. and the refluxing temperature, preferably
-10.degree. C..about.50.degree. C., and more preferably 0.degree.
C..about.20.degree. C.; reaction time is 10 minutes.about.48 hours,
preferably 20 minutes.about.24 hours, Z) more preferably 30
minutes.about.6 hours. When inorganic base such as potassium
carbonate or sodium carbonate is selected, reaction solvent can be
acetonitrile or tetrahydrofuran, and reaction temperature can be
between 30.degree. C. and the refluxing temperature;
[0071] in these condition:
TABLE-US-00003 se- Formula quence Compound of Compound of Compound
of number Formula (IV) Formula (IV') Formula (I) 1 ##STR00045##
##STR00046## ##STR00047## 2 ##STR00048## ##STR00049## ##STR00050##
3 ##STR00051## ##STR00052## ##STR00053## 4 ##STR00054##
##STR00055## ##STR00056##
[0072] optional reaction conditions of synthesis of the compound of
formula (I) by cyclization of the compound of Formula (IV'') are:
in or out of the presence of formamide or methanesulfonic acid, by
heated cyclization the compound of Formula (I) is yielded. In
particular, the optional reaction temperature is 0.degree.
C..about.250.degree. C., preferably 60.degree. C..about.200.degree.
C. and more preferably 120.degree. C..about.18000; the reaction
time is 10 minutes.about.12 hours, preferably 1 hour.about.10
hours, more preferably 2 hours.about.8 hours;
[0073] in these conditions:
TABLE-US-00004 Formula sequence Compound of Compound of Compound of
number Formula (IV) Formula (IV'') Formula (I) 1 ##STR00057##
##STR00058## ##STR00059## 2 ##STR00060## ##STR00061## ##STR00062##
3 ##STR00063## ##STR00064## ##STR00065## 4 ##STR00066##
##STR00067## ##STR00068##
[0074] alternatively, the compound of Formula (IV) in the step (1)
is hydrolyzed to yield the compound of Formula (V), and the
reaction conditions in particular are: the compound of Formula (IV)
is posed in a mixture system of organic solvent (the solvent is
selected from acetonitrile, tetrahydrofuran, dioxane, methyl
tert-butyl ether, dichloromethane, etc., preferably, a single
solvent or mixture of two or more solvents of acetonitrile,
tetrahydrofuran, dioxane) and water in any optional ratio; in the
alkali system of potassium carbonate, sodium carbonate, sodium
hydroxide, potassium hydroxide or lithium hydroxide, at certain
temperature, by stirred reaction the compound of Formula (V) is
yielded, in which alkaline condition is preferably lithium
hydroxide, sodium hydroxide, sodium carbonate or potassium
carbonate, and more preferably potassium carbonate or sodium
carbonate. To yield the compound of Formula (V), the reaction
temperature can be between -20.degree. C. and the refluxing
temperature, preferably between room temperature and the refluxing
temperature, and more preferably 30.degree. C..about.50.degree. C.;
the reaction time is 30 minutes.about.24 hours, preferably 8
hours.about.24 hours, more preferably 12 hours.about.18 hours;
[0075] in these conditions:
TABLE-US-00005 sequence Formula number Compound of Formula (IV)
Compound of Formula (V) 1 ##STR00069## ##STR00070## 2 ##STR00071##
##STR00072## 3 ##STR00073## ##STR00074## 4 ##STR00075##
##STR00076##
[0076] after that, the obtained compound of Formula (V) is cyclized
to yield the compound of Formula (VI), and the specific reaction
procedure is: in dry surrounding a mixture of the compound of
Formula (V), acetic anhydride and catalytic amount of pyridine is
stirred by heating up and then the reactant is concentrated to
dryness to yield the compound of Formula (VI), wherein: to yield
the compound of Formula (VI), the reaction temperature is between
room temperature and 120.degree. C., preferably between 40.degree.
C..about.100.degree. C. and more preferably 5.degree.
C..about.80.degree. C.; the reaction time, in particular, is 1
minute.about.12 hours, preferably 10 minutes.about.6 hours, more
preferably 20 minutes.about.4 hours;
[0077] in these conditions:
TABLE-US-00006 sequence Formula number Compound of Formula (V)
Compound of Formula (VI) 1 ##STR00077## ##STR00078## 2 ##STR00079##
##STR00080## 3 ##STR00081## ##STR00082## 4 ##STR00083##
##STR00084##
[0078] subsequently, the compound of Formula (VI) undergoes
ring-opening ammonolysis to yield the compound of Formula (VII)
which is then cyclized in the presence of condensing agent (such as
thionyl chloride, dicyclohexylcarbodiimide (DCC), phosphorus
oxychloride, carbonyldiimidazole, etc.), to yield the compound of
Formula (I). In particular, the procedure of synthesis of the
compound of Formula (VII) from the compound of Formula (VI) is: in
dry surrounding, the compound of Formula (IV) is added into
supersaturated solution of ammonia/methanol,
ammonia/tetrahydrofuran, ammonia/dioxane or
ammonia/dimethylformamide; the above ammonia organic solvent system
can be a single organic solvent or mixture of two or more organic
solvents of methanol, tetrahydrofuran, dioxane or
dimethylformamide. To yield the compound of Formula (VII), stirred
reaction temperature is -40.degree. C..about.80.degree. C.,
preferably -20.degree. C..about.50.degree. C. and more preferably
-10.degree. C..about.30.degree. C.; the reaction time is 5
minutes.about.24 hours, preferably 30 minutes.about.12 hours, more
preferably 1 hours.about.6 hours. In dry condition and in the
reaction system of dimethylformamide, dimethylacetamide and
halogenated hydrocarbon, thionyl chloride is added drop by drop
into the compound of Formula (VII) to yield the compound of Formula
(I), in which the reaction temperature is -40.degree.
C..about.80.degree. C., preferably -30.degree. C..about.40.degree.
C. and preferably -20.degree. C..about.20.degree. C.; the reaction
time is 10 minutes.about.24 hours, preferably 30 minutes.about.6
hours, more preferably 30 minutes.about.3 hours;
[0079] in these conditions:
TABLE-US-00007 Formula sequence Compound of Compound of Compound of
number Formula (VI) Formula (VII) Formula (I) 1 ##STR00085##
##STR00086## ##STR00087## 2 ##STR00088## ##STR00089## ##STR00090##
3 ##STR00091## ##STR00092## ##STR00093## 4 ##STR00094##
##STR00095## ##STR00096##
[0080] The reaction routes of the reaction process mentioned above
are described in diagram A:
##STR00097##
[0081] The reaction routes of the reaction process mentioned above
are described in diagram B:
##STR00098##
The reaction routes of the reaction process mentioned above are
described in diagram C:
##STR00099##
[0082] In another aspection of the invention, the following
intermediate compounds of Formula (IV) are provided:
##STR00100##
[0083] wherein:
[0084] One of R, R3, R4 and R5 is amino or protected amino
(carbamates: such as carbobenzyloxy, t-butyloxycarbonyl,
fluorenylmethoxycarbonyl, etc.; acyl amide: such as acetyl,
phenylacetyl, phthalyl, etc.; azanes: such as allyl, etc.; sulfonyl
and sulfinyl: such as phenylsulfonyl, p-toluenesulfonyl,
phenylsulfinyl, O-nitrophenylsulfinyl, etc.; referred to T. W. and
WuTs P. G. M. Protective Groups in Organic Synthesis: P494-; East
China University Of Science And Technology Press), nitro or halo
(for example F, Cl, Br or I), and the others are hydrogen.
preferably, R3, R4 and R5 are hydrogen;
[0085] X is halo, such as: F, Cl, Br or I;
[0086] Y is .dbd.O or H;
[0087] Z is .dbd.O or H;
[0088] and with the proviso that Y and Z are both .dbd.O; or one of
Y and Z is .dbd.O and the other of Y and Z is H;
[0089] A and B are each independently hydroxyl, C.sub.1-10 alkoxy,
aryloxy, aryl C.sub.1-4 alkoxy or NHR.sub.2, in which R.sub.2 is
hydrogen or amino protecting group (carbamates: such as
carbobenzyloxy, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, etc.;
acyl amides: such as acetyl, phenylacetyl, phthalyl, etc.; azanes:
such as allyl, etc.; sulfonyl and sulfinyl: such as phenylsulfonyl,
p-toluenesulfonyl, phenylsulfinyl, O-nitrophenylsulfinyl, etc.;
referred to Protective Groups in Organic Synthesis: Greene T. W.,
WuTs P. G. M. East China University Of Science And Technology
Press: P494-); preferably, A and B are each independently hydroxyl,
methoxy, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy;
phenoxy or substituted phenoxy; phenyl C1-4 alkoxy, such as
benzyloxy, phenylethoxy, phenylpropoxy, etc., or substituted phenyl
C1-4 alkoxy; in terms of the substituted phenoxy or substituted
phenyl C1-4 alkoxy, the substituted groups are selected from the
group consisting of C.sub.1-4 alkyl, halo, cyano, nitro, and the
substituted groups are one or more, which could be the same or
different groups; optionally, the groups are substituted in 2, 3,
4, 5 or 6-position of the benzene ring, for example
4-nitrobenzyloxyl, 2-chlorine-4-nitrobenzyloxyl; amino and
benzylamino;
[0090] R1 is C.sub.1-4 alkyl or hydrogen; the described C.sub.1-4
alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl; preferably, R1 is hydrogen or methyl;
[0091] and with proviso that the following compounds are not
included: when R is nitro, A and B are both methoxy, benzyloxy,
hydroxyl or amino; when R is nitro, A is methoxy and B is amino;
when R is amino, A and B are both ethoxyl; when R is nitro, A is
amino and B is alkoxide.
[0092] Preferably, the present invention provides the compounds of
Formula (IV'):
##STR00101##
[0093] the definitions of the substituted groups in the compounds
of Formula (V') are identical to that in the compounds of Formula
(IV); more preferably, one of Y and Z is .dbd.O, and the other is
H.
[0094] Preferably, the present invention provides the compounds of
Formula (IV''):
##STR00102##
[0095] the definitions of the substituted groups in the compounds
of Formula (IV'') are identical to that in the compounds of Formula
(IV); more preferably, one of Y and Z is .dbd.O, and the other is
H.
[0096] Preferably, the present invention provides the compound of
Formula (V):
##STR00103##
[0097] wherein: the definitions of the substituted groups in the
compound of Formula (V) are identical to that in the compound of
Formula (IV); more preferably, one of Y and Z is .dbd.O, and the
other is H; and with the proviso that the following compounds are
not included: when R is amino or nitro, R1, R3, R4 and R5 are all
hydrogen, and Y is .dbd.O, and Z is .dbd.O or H.
[0098] Preferably, the present invention provides the compounds of
Formula (VI):
##STR00104##
[0099] wherein: the definitions of the substituted groups in the
compounds of Formula (VI) are identical to that in the compounds of
Formula (IV); more preferably, one of Y and Z is .dbd.O, and the
other is H; and with the proviso that the following compounds are
not included: when R is nitro, R1, R3, R4 and R5 are all hydrogen,
and Y is .dbd.O, and Z is .dbd.O.
Preferably, the present invention provides the compounds of Formula
(VII):
##STR00105##
[0100] wherein: the definitions of the substituted groups in the
compounds of Formula (VII) are identical to that in the compounds
of Formula (IV); more preferably, one of Y and Z is .dbd.O, and the
other is H; and with the proviso that the following compounds are
not included: when R is amino or nitro, R1, R3, R4 and R5 are all
hydrogen, Y is .dbd.O, and Z is .dbd.O or H.
[0101] Further preferably, the present invention provides the
compounds of following formula:
##STR00106## ##STR00107## ##STR00108##
[0102] By comparison with the existing synthesis routes, the
present invention has the following advantages:
[0103] 1. The raw materials used in the present invention are
accessible, whereas the raw materials used in original R&D
Corporation's route are commercially unavailable internally:
[0104] Initial materials: .alpha.-aminoglutarimide hydrochloride is
commercially unavailable internally. It is synthesized from
N-benzyloxycarbony-L-glutamine, which reacts with
N,N'-carbonyldiimidazole in THF refluxing to yield
N-benzyloxycarbony-aminoglutarimide. After that amino protection
group is removed and .alpha.-aminoglutarimide hydrochloride is
yielded by hydrogenation under certain pressure catalyzed with
Pd/C.
[0105] Key materials in reaction: methyl
2-bromomethyl-3-nitrobenzoate is synthesized from
2-methyl-3-nitrobenzoate, which is brominated by refluxing over 24
h in the presence of lethal carbon tetrachloride and in the
condition of ultraviolet light photocatalysis under mercury lamp.
Photocatalytic reaction has low yield and the difficulty in mass
production, as well as the difficulty in labour protection against
ultraviolet light emitted by the catalytic light source--mercury
lamp.
[0106] 2. Comparison of time length and degree of difficulty of
reaction, yield purity, as well as degree of extraction and
purification:
[0107] In both the US Patent application US2006052609A1 and the
Chinese Patent application CN97180299.8, the reaction product was
purified by column chromatography at least twice or more, which
made industrial operation complicated and made it difficult to
industrial scale-up production.
[0108] In both the US Patent application US2006052609A1 and the
Chinese Patent application CN97180299.8, pressurized hydrogenation
was utilized twice; In the present invention, only Pd/C and
ammonium formate are used in deprotection reduction, which is of
high security and mild conditions. By comparison with hydrogenation
under certain pressure, hydrogenation under atmospheric pressure is
of less risk, leading to enhanced production security.
[0109] When N-benzyloxycarbony-L-glutamine, as initial material,
reacted with N,N'-carbonyldiimidazole in THF refluxing for 24 h to
yield N-benzyloxycarbony-aminoglutarimide, low purity of yield
results from long reactive time and high temperature.
[0110] 3. Comparison of yield in each procedure and total
yield:
[0111] The total yield was lower than 20% and 18% respectively
reported in the US Patent application US2006052609A1 and the
Chinese Patent application.
[0112] In the present invention, the total yield of
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
synthesized from the original raw material,
4-nitro-2,3-dihydro-1H-isoindol-1-one and .alpha.-bromodimethyl
glutarate, averages from 35% to 40%, due to the short reaction
routes and simple methods.
[0113] 4. Toxicity of solvent and its influence on environment:
[0114] In the US Patent application US2006052609A1 and the Chinese
Patent application, carbon tetrachloride was reported to be
reaction solvent used for refluxing, which did extreme harm to
environment and made innocent treatment and labor protection
difficult.
[0115] In the present invention, derivatives of benzene or carbon
tetrachloride are unavailable to be as reaction solvent, which is
relatively eco-friendly.
DESCRIPTION OF EMBODIMENTS
[0116] The following examples will serve to further elaborate the
present invention seeing the above routes A, B and C, which
shouldn't be understood as a limitation in the scope of this
invention by the person skilled in the art. Any modification or
improvement based on the instruction well known in the art should
be in the scope of this invention, without departing from the
spirit and scope of the present invention.
Example 1
The synthesis of 4-nitro-2,3-dihydro-1H-isoindol-1-one
[0117] A mixture of methyl 2-bromomethyl-3-nitrobenzoate (20 g) and
methanol (200 ml) was stirred under ammonia gas for 30 min at room
temperature, and was kept in heat preservation for 2 hours. Crystal
grew in an ice bath for 2 hours, and then filtered, and dried to
give 11.7 g of light yellow crystal. yield: 90%. mp:
235.4.about.236.7.degree. C.
[0118] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 4.78 (s, 2H),
7.79 (t, 1H), 8.10 (d, 1H), 8.41 (d, 1H), 8.90 (S, 1H).
[0119] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.: 4.76
(s, 2H), 7.77 (t, 1H), 8.08 (d, 1H), 8.39 (d, 1H).
[0120] FAB(M+1): 179
[0121] Element analysis:
[0122] theoretical data: C, 53.94%; H, 3.39%; N, 15.72%.
[0123] measured data: C, 54.08%; H, 3.49%; N, 15.81%.
[0124] Test condition of HPLC: [0125] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0126] mobile phase: acetonitrile/0.1%
phosphate=30/70 [0127] appearance time of target yield: 5.810
minutes [0128] purity of target yield: 99.59%
Example 2
The synthesis of 4-amino-2,3-dihydro-1H-isoindol-1-one
[0129] A mixture of 4-nitro-2,3-dihydro-1H-isoindol-1-one (20 g),
ammonium formate (35 g) and 7.5% Pd/C (0.6 g) in methanol (60 ml)
was stirred for 2 hours by heating up to 35.degree. C. Pd/C was
filtered and the filtrate concentrated under reduced pressure. The
residue was recrystallized from water to give 15.3 g. of light
yellow solid. yield: 92%. mp: 195.6-197.degree. C.
[0130] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 4.31 (s, 2H),
6.76 (d, 1H), 7.14 (t, 1H), 6.86 (d, 1H), 5.30 (s, 2H), 8.26 (s,
1H)
[0131] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.: 4.14
(s, 2H), 6.79 (d, 1H), 6.93 (d, 1H), 7.16 (t, 1H)
[0132] FAB(M+1): 149
[0133] Element analysis: theoretical data: C, 64.85%; H, 5.44%; N,
18.91%.
[0134] measured data: C, 64.96%; H, 5.61%; N, 19.02%.
[0135] Test condition of HPLC: [0136] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; k=230 nm [0137] mobile phase: acetonitrile/0.1%
phosphate=15/85 or acetonitrile/0.01M ammonium acetate=10/90 [0138]
appearance time of target yield: 3.580 minutes; 4.790 minutes
[0139] purity of target yield: 99.66%
Example 3
The Synthesis of .alpha.-Bromodimethyl Glutarate
[0140] In a dry reaction flask, thionyl chloride 36 ml was added
into a stirred mixture of glutaric acid (30 g) and chloroform (90
ml) under reflux for 2 hours, and then bromine (36 g) was added
under reflux for over 16 hours. The reaction mixture was cooled,
into which methanol (75 ml) was then added by droplet in an ice
bath and stirred in heat preservation for 2 hours. The resulting
mixture was washed with 5% sodium bisulfate (150 ml), saturated
sodium bicarbonate (150 ml) and saturated sodium chloride (150 ml)
one by one. The organic layer was dried with anhydrous sodium
sulfate and after that sodium sulfate was removed by filter. The
filtrate was concentrated to dryness and distilled under reduced
pressure, to collect the fraction at 110-115.degree. C./5 mmHg. The
target yield is colorless liquid. weight: 41.3 g. yield: 76%.
[0141] FAB(M+1): 240
[0142] Test condition of HPLC: [0143] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0144] mobile phase: acetonitrile/0.1%
phosphate=50/50 [0145] appearance time of target yield: 7.750
minutes [0146] purity of target yield: 96.64%
Example 4
The synthesis of dimethyl
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate
[0147] A mixture of 4-amino-2,3-dihydro-1H-isoindol-1-one (5 g),
N-methylpyrrolidone (25 ml), cesium carbonate (11 g) and
.alpha.-bromodimethyl glutarate (9.7 g) was stirred under nitrogen
at room temperature over night. After adding water (75 ml) and
methylene chloride (50 ml), remove the aqueous phase and the
organic phase was extracted with 2 mol/L hydrochloric acid. The
aqueous hydrochloric acid solution was mixed with methylene
chloride (100 ml) and phases separated at pH7 adjusted by addition
of Na.sub.2CO.sub.3. The organic phase was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give a
yellow ticking substance (7.2 g) which could be used in next
reaction without further purification. yield: 70%
[0148] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 2.19 (m, 2H),
2.35 (t, 2H), 3.52 (s, 3H), 3.66 (s, 3H), 4.23 (s, 2H), 4.90 (m,
1H), 5.38 (s, 2H), 6.79 (d, 1H), 6.89 (d, 1H), 7.17 (t, 1H).
[0149] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.: 2.10
(m, 2H), 2.33 (t, 2H), 3.53 (s, 3H), 3.66 (s, 3H), 4.22 (s, 2H),
4.90 (m, 1H), 5.38 (s, 2H), 6.80 (d, 1H), 6.89 (d, 1H), 7.17 (t,
1H).
[0150] FAB(M+1): 307
[0151] Element analysis: theoretical data: C, 58.82%; H, 5.92%; N,
9.15%.
[0152] measured data: C, 58.74%; H, 6.06%; N, 9.06%.
[0153] Test condition of HPLC: [0154] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0155] mobile phase: acetonitrile/0.1%
phosphate=30/70 [0156] appearance time of target yield: 7.620
minutes [0157] purity of target yield: 92.1% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00008 [0157] Formula original yield/purity sequence raw
starting (HPLC by number material material target yield
normalization) 1 ##STR00109## ##STR00110## ##STR00111## yield:
68.3% purity: 93.5% 2 ##STR00112## ##STR00113## ##STR00114## yield:
73.7% purity: 91.4% 3 ##STR00115## ##STR00116## ##STR00117## yield:
59.3% purity: 89.1%
Example 5
The synthesis of
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0158] Under nitrogen in dry reaction flask was added sodium amide
(30 mmol 1.17 g) (obtained by adding metallic sodium (690 mg) into
liquid ammonia (-40.degree. C., 300 ml) and then adding catalytic
amount of ferric nitrate). The solution of dimethyl
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (3 g, 10
mmol) in anhydrous tetrahydrofuran (100 ml) was added by droplet
with the temperature maintaining at -40.degree. C. and the mixture
was stirred in heat preservation for 3 hours. ammonium chloride (5
g) (ammonia spillover is allowed) and water (300 ml) were added and
the resulting mixture was filtered. The crude was recrystallized
from isopropanol (15 ml) to give target yield (1.22 g).
[0159] Yield 48%. mp: 251.5.degree. C..about.252.5.degree. C.
[0160] .sup.1H-NMR: (500 MHz, DMSO-d.sub.6) .delta.:
2.02.about.2.04 (m, 1H), 2.27.about.2.34 (m, 1H), 2.60.about.2.63
(m, 1H), 2.88.about.2.95 (m, 1H), 4.16 (dd, 2H), 5.10 (dd, 2H),
6.80 (d, 1H), 6.92 (d, 1H), 7.19 (t, 1H), 10.19 (s, 1H) FAB(M+1):
260
[0161] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0162] measured data: C, 60.14%; H, 5.16%; N, 16.30%.
[0163] Test condition of HPLC: [0164] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0165] mobile phase: acetonitrile/0.1%
phosphate=10/90 [0166] appearance time of target yield: 11.81
minutes [0167] purity of target yield: 99.29% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00009 [0167] Formula yield/purity sequence starting (HPLC
by number material target yield normalization) 1 ##STR00118##
##STR00119## yield: 53% purity: 93.23% 2 ##STR00120## ##STR00121##
yield: 39.7% purity: 94.77%
Example 6
The synthesis of methyl
N-[4-amin-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-glutaminate
[0168] A mixture of dimethyl
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (30.6 g),
saturated dioxane/ammonia solution (150 ml) and lipase (14 g) was
stirred at 20.degree. C. for 3.about.5 hours. The reaction mixture
concentrated by reduced pressure at room temperature to remove
ammonia and then concentrated under reduced pressure to dryness.
The concentrate was stirred with methyl tert-butyl ether (100 ml)
and then white crystal was precipitated. After filter the residue
was dried under vacuum at room temperature to give 21.4 g of target
yield as a white crystal. yield: 73%. mp: 103-106.degree. C.
[0169] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 4.17 (d, 1H),
4.40 (d, 1H), 5.43 (s, 2H), 6.76 (d, 1H), 7.17 (t, 1H), 6.87 (d,
1H), 4.73 (m, 1H), 1.91 (m, 2H), 2.18 (t, 2H), 3.51 (s, 3H), 7.13
(s, 1H), 7.55 (s, 1H).
[0170] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D2O) .delta.: 4.17 (d,
1H), 4.40 (d, 1H), 6.76 (d, 1H), 7.17 (t, 1H), 6.87 (d, 1H), 4.73
(m, 1H), 1.91 (m, 2H), 2.18 (t, 2H), 3.51 (s, 3H).
[0171] FAB(M+1): 292
[0172] Test condition of HPLC: [0173] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0174] mobile phase: acetonitrile/0.1%
phosphate=10/90 [0175] appearance time of target yield: 19.900
minutes [0176] purity of target yield: 98.3% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00010 [0176] Formula yield/purity sequence starting (HPLC
by number material target yield normalization) 1 ##STR00122##
##STR00123## yield: 72% purity: 97.96% 2 ##STR00124## ##STR00125##
yield: 75.1% purity: 97.55% 3 ##STR00126## ##STR00127## yield:
64.1% purity: 96.74%
Example 7
The synthesis
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0177] A mixture of methyl
N-[4-amin-1-oxo-1,3-dihydro-2-hydro-isoindol-2-yl]-glutaminate (20
g) in acetonitrile (300 ml) was stirred with potassium carbonate
(9.4 g) under reflux for 5 hours. The reaction mixture was
concentrated to remove acetonitrile and was stirred with ethyl
acetate (100 ml) and water (50 ml). After filter, recrystallization
from isopropanol gave a light yellow solid (14.9 g). yield: 84%.
mp: 250.5-251.7.degree. C.
[0178] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.:
2.03.about.2.06 (m, 1H), 2.26.about.2.34 (m, 1H), 2.59.about.2.63
(m, 1H), 2.85.about.2.92 (m, 1H), 4.15 (dd, 2H), 5.09 (dd, 2H),
6.81 (d, 1H), 6.92 (d, 1H), 7.20 (t, 1H), 10.18 (s, 1H).
[0179] FAB(M+1): 260
[0180] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0181] measured data: C, 60.12%; H, 5.17%; N, 16.29%.
[0182] Test condition of HPLC: [0183] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0184] mobile phase: acetonitrile/0.1%
phosphate=10/90 [0185] appearance time of target yield: 11.73
minutes [0186] purity of target yield: 99.61% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00011 [0186] Formula yield/purity sequence starting (HPLC
by number material target yield normalization) 1 ##STR00128##
##STR00129## yield: 81% purity: 98.61% 2 ##STR00130## ##STR00131##
yield: 86% purity: 99.21% 3 ##STR00132## ##STR00133## yield: 71%
purity: 97.97%
Example 8
The synthesis of
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-gluta-
ramide
[0187] A mixture of dimethyl
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (30.6 g),
anhydrous acetonitrile (150 ml) and triethylamine (13.9 ml) was
stirred with benzyl chloroformate (17.1 g) under catalytic amount
of MAP under reflux for 4 hours. The reaction mixture was cooled to
room temperature and then mixed with water (500 ml). The resulting
mixture was then extracted with dichloromethane and dried over
anhydrous sodium sulphate, then concentrated under reduced pressure
to give a red sticky substance (66 g). The solution of residue in
supersaturated methanol-ammonia (250 ml) was stirred at
25.about.30.degree. C. for over 24 hours and white solid was
precipitated. Crystal grew in an ice bath for 2 hours. After filter
the cake was dried under reduced pressure to give 44.4 g of white
crystal. yield: 67%. mp: 190.about.192.degree. C.
[0188] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 4.29 (d, 1H);
4.56 (d, 1H), 7.56 (s, 1H), 6.59 (d, 1H), 7.34 (t, 1H), 6.88 (d,
1H), 4.70 (m, 1H), 2.01 (m, 2H), 2.20 (m, 1H), 2.02 (m, 1H), 6.59
(s, 1H); 6.74 (s, 1H), 4.38 (s, 2H), 7.14.about.7.40 (m, 7H).
[0189] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.: 4.29
(d, 1H); 4.56 (d, 1H), 6.59 (d, 1H), 7.34 (t, 1H), 6.88 (d, 1H),
4.70 (m, 1H), 2.01 (m, 2H), 2.20 (m, 1H), 2.02 (m, 1H), 4.38 (s,
2H), 7.14.about.7.40 (m, 5H).
[0190] FAB(M+1): 443
[0191] Test condition of HPLC: [0192] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0193] mobile phase: acetonitrile/0.1%
phosphate=40/60 [0194] appearance time of target yield: 6.980
minutes [0195] purity of target yield: 98.67% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00012 [0195] Formula yield/purity sequence starting (HPLC
by number material target yield normalization) 1 ##STR00134##
##STR00135## yield: 72% purity: 97.96% 2 ##STR00136## ##STR00137##
yield: 75.1% purity: 97.55% 3 ##STR00138## ##STR00139## yield:
64.1% purity: 96.74%
Example 9
The synthesis of
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0196]
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-
-glutaramide (30 g) was stirred with formamide (150 ml) for
3.about.4 hours by slowly heating up to 160.degree. C. The reaction
mixture was cooled to 0.degree. C. and then mixed with water (750
ml). After crystal growing for 1 hour, the resulting mixture was
filtered and dried to give 21.6 g of light yellow solid. The
solution of this residue in methanol (325 ml) was stirred with 5%
Pd/C (0.3 g) and formamide (22 g) at 30.degree. C. for 2 hours.
Pd/C was filtered and the filtrate concentrated under reduced
pressure to yield a yellow solid. Recrystallization and washing by
isopropanol and active carbon gave 12.75 g of light yellow solid.
yield: 72%. mp: 251.1.about.252.4.degree. C.
[0197] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 2.02 (m, 2H),
2.01.about.2.06 (m, 1H), 2.25.about.2.39 (m, 1H), 2.59.about.2.64
(m, 1H), 2.83.about.2.94 (m, 1H), 4.16 (dd, 2H), 5.08 (dd, 1H),
5.35 (s, 2H), 6.80 (d, 1H), 6.93 (d, 1H), 7.90 (t, 1H), 10.91 (s,
1H).
[0198] FAB(M+1): 260
[0199] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0200] measured data: C, 60.27%; H, 5.13%; N, 16.26%.
[0201] Test condition of HPLC: [0202] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0203] mobile phase: acetonitrile/0.1%
phosphate=10/90 [0204] appearance time of target yield: 11.77
minutes [0205] purity of target yield: 99.37% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00013 [0205] Formula yield/purity sequence starting (HPLC
by number material target yield normalization) 1 ##STR00140##
##STR00141## yield: 83% purity: 98.97% 2 ##STR00142## ##STR00143##
yield: 81% purity: 99.03% 3 ##STR00144## ##STR00145## yield: 76%
purity: 98.63%
Example 10
The synthesis of
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid
[0206] A mixture of dimethyl
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (5 g) and
tetrahydrofuran (14 ml) in 20% potassium carbonate solution (45 ml)
was stirred for 5 hours by heating up to 50.degree. C. The aqueous
phase was separated and concentrated to dryness under reduced
pressure. The concentrate was stirred with methanol (50 ml) for 30
min. After filter, the filtrate concentrated to dryness and was
mixed with isopropanol (50 ml) for crystal growing for 2 hours at
room temperature. The resulting mixture was filtered and dried
under reduced pressure to give 3.7 g of target yield as a white
solid. yield: 81%. Melting point test showed that the product began
to melt at 90.degree. C. and the final melting point was not
apparently observed.
[0207] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 2.01 (m, 2H),
2.20 (m, 2H), 3.78 (m, 1H), 4.55 (s, 2H), 5.30 (s, 2H), 6.73 (d,
1H), 6.85 (d, 1H), 7.12 (t, 1H), 10.99 (br, 2H).
[0208] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.: 1.88
(m, 2H), 2.09 (m, 2H), 3.71 (m, 1H), 4.49 (s, 2H), 6.76 (d, 1H),
6.90 (d, 1H), 7.15 (t, 1H).
[0209] FAB(M+1): 279
[0210] Element analysis: theoretical data: C, 56.11%; H, 5.07%; N,
10.07%.
[0211] measured data: C, 56.20%; H, 5.21%; N, 10.18%.
[0212] Test condition of HPLC: [0213] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0214] mobile phase: acetonitrile/0.1%
phosphate=15/85 [0215] appearance time of target yield: 5.260
minutes [0216] purity of target yield: 98.7% With the similar
methods, the compounds in the following table are obtained:
TABLE-US-00014 [0216] Formula yield/purity sequence starting raw
(HPLC by number material material target yield normalization) 1
##STR00146## K.sub.2CO.sub.3/H.sub.2O CH.sub.3OH ##STR00147##
yield: 84% purity: 97.9% 2 ##STR00148## K.sub.2CO.sub.3/H.sub.2O
EtOH ##STR00149## yield: 77% purity: 96.7% 3 ##STR00150##
K.sub.2CO.sub.3/H.sub.2O EtOH ##STR00151## yield: 68% purity:
93.3%
Example 11
The synthesis
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0217] A mixture of
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid (5 g)
and urea (1.08 g) in N, N-dimethylformamide (25 ml) was stirred and
heated under reflux for 3.about.4 hours. The reaction mixture
concentrated under reduced pressure at 60.degree. C. and then was
added into ice water by being stirred rapidly. After filter, the
cake was washed with isopropanol. The crude product was
recrystallized from isopropanol and active carbon to give 1.4 g of
off-white target compound. Yield: 30%. mp:
252.1.about.254.3.degree. C.
[0218] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.: 2.03 (m, 2H),
2.01.about.2.07 (m, 1H), 2.26.about.2.37 (m, 1H), 2.61.about.2.65
(m, 1H), 2.87.about.2.96 (m, 1H), 4.17 (dd, 2H), 5.09 (dd, 1H),
5.36 (s, 2H), 6.81 (d, 1H), 6.92 (d, 1H), 7.91 (t, 1H), 10.93 (s,
1H).
[0219] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D.sub.2O) .delta.:
2.02.about.2.05 (m, 1H), 2.32.about.2.36 (m, 1H), 2.60.about.2.65
(m, 1H), 2.83.about.2.88 (m, 1H), 4.17 (dd, 2H), 5.04 (dd, 1H),
6.82 (d, 1H), 6.94 (d, 1H), 7.20 (t, 1H).
[0220] FAB(M+1): 260
[0221] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0222] measured data: C, 60.30%; H, 5.20%; N, 16.18%.
With the similar methods, the compounds in the following table are
obtained:
TABLE-US-00015 Formula yield/purity sequence starting (HPLC by
number material target yield normalization) 1 ##STR00152##
##STR00153## yield: 33% purity: 99.37% 2 ##STR00154## ##STR00155##
yield: 31% purity: 98.55%
Example 12
The synthesis of
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-gluta-
ric anhydride
[0223] To a stirred mixture of
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid (30.6
g) and triethylamine (13.9 ml) in anhydrous acetonitrile (150 ml)
was added benzyl chloroformate (17.1 g) and catalytic amount of
DMAP under reflux for 4 hours. The resulting mixture was cooled to
room temperature and then added into water (500 ml). The mixture
was extracted with dichloromethane and dried over anhydrous sodium
sulphate. The resulting mixture was concentrated under reduced
pressure to give 66 g of red sticky substance. Then the substance
was added in acetic anhydride (250 ml) and heated to 50.degree. C.,
then pyridine (3 ml) was added and reacted at 70.degree. C. for 30
minutes. The reaction mixture was dried by reduced pressure and
added anhydrous methyl tert-butyl ether. Refinement gave 30 g of
white target yield. yield: 76%.
[0224] FAB(M+1): 395
With the similar methods, the compounds in the following table are
obtained:
TABLE-US-00016 sequence Formula number starting material target
yield yield 1 ##STR00156## ##STR00157## yield: 91% 2 ##STR00158##
##STR00159## yield: 87% 3 ##STR00160## ##STR00161## yield: 85% 4
##STR00162## ##STR00163## yield: 90% 5 ##STR00164## ##STR00165##
yield: 93.3%
Example 13
The synthesis of
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-isogl-
utamine
[0225] A mixture of
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-gluta-
ric anhydride (30 g) in dry tetrahydrofuran (300 ml) was stirred at
0 C. under supersaturated ammonia for 2 hours. After filter, the
cake was washed with ether and dried-under reduced pressure at room
temperature to give 27.3 g of white solid.
[0226] yield: 84%. purity: 95.61%.
[0227] FAB(M+1): 428
With the similar methods, the compounds in the following table are
obtained:
TABLE-US-00017 Formula yield/purity sequence starting (HPLC by
number material target yield normalization) 1 ##STR00166##
##STR00167## yield: 80% purity: 96.1% 2 ##STR00168## ##STR00169##
yield: 78% purity: 94.3% 3 ##STR00170## ##STR00171## yield: 75%
purity: 93.1% 4 ##STR00172## ##STR00173## yield: 75% purity: 95.3%
5 ##STR00174## ##STR00175## yield: 79% purity: 94.7%
Example 14
The synthesis of
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0228] To a stirred mixture of
3-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]-isogl-
utamine (10 g) in DMF (30 ml) was added thionyl chloride (5 g) by
droplet at -20.degree. C. for reaction in heat preservation for
2.about.3 hours. The resulting mixture was mixed in ice water
stirred rapidly. Then the mixture was extracted with ethyl acetate
(2.times.50 ml) and dried over anhydrous sodium sulfate. Sodium
sulfate was filtered and the filtrate concentrated to dryness under
reduced pressure. The concentrate was mixed in methanol (100 ml)
and stirred with 5% Pd/C (1 g) and ammonium formate (7 g) at
30.degree. C. for 2 hours. Pd/C was filtered and the filtrate
concentrated to dryness. The concentrate was recrystallized from
isopropanol and rinsed with water. Decompression drying gave 3.76 g
of target yield as a light yellow solid. yield: 62%. mp:
250.8.about.252.7.degree. C.
[0229] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6/D20) .delta.:
2.04.about.2.10 (m, 1H), 2.34.about.2.39 (m, 1H), 2.61.about.2.67
(m, 1H), 2.87.about.2.91 (m, 1H), 4.18 (dd, 2H), 5.08 (dd, 2H),
6.84 (d, 1H), 6.96 (d, 1H), 7.23 (t, 1H)
[0230] FAB(M+1): 260
[0231] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0232] measured data: C, 60.04%; H, 5.31%; N, 16.33%.
[0233] Test condition of HPLC: [0234] type and specification of
column: phenomenex Luna 5u C18 250 mm.times.4.6 mm; velocity: 1.0
ml/min; .lamda.=230 nm [0235] mobile phase: acetonitrile/0.1%
phosphate=10/90 [0236] appearance time of target yield: 11.767
minutes [0237] purity of target yield: 99.69%.
Example 15
The synthesis of
3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0238] To a mixture of
3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-isoglutamine (9 g)
in N,N-dimethylformamide (80 ml), was added thionyl chloride (6.6
g) by droplet below 0.degree. C. for stirred reaction in heat
preservation for 2.about.3 hours. The resulting solution was added
by droplet into mixture of ice and water and pH value was adjusted
to 7.about.8 with sodium carbonate. The mixture was stirred for 30
minutes and filtered to get light yellow crude. Refining with
methanol gave 6.6 g of target yield as a light yellow solid. yield:
78%.
[0239] FAB(M+1): 290
[0240] Element analysis: theoretical data: C, 53.98%; H, 3.83%; N,
14.53%.
[0241] measured data: C, 54.06%; H, 3.95%; N, 14.61%.
With the similar methods, the compounds in the following table are
obtained:
TABLE-US-00018 Formula yield/purity sequence starting (HPLC by
number material target yield normalization) 1 ##STR00176##
##STR00177## yield: 83% purity: 93.4% 2 ##STR00178## ##STR00179##
yield: 87% purity: 91% 3 ##STR00180## ##STR00181## yield: 77%
purity: 93.1% 4 ##STR00182## ##STR00183## yield: 81% purity:
92.2%
Example 16
The synthesis of
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0242] A mixture of
3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine
(7 g), 5% Pd/C (1.4 g) and ammonium formate (2.1 g) in methanol (35
ml) was stirred completely at room temperature for 2 hours. Pd/C
was filtered and the filtrate concentrated to dry under reduced
pressure. Recrystallization from heated isopropanol and washing
with water gave 5.6 g of yellow crystal. yield: 89%. mp:
252.3-254.0.degree. C.
[0243] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.:
2.00.about.2.08 (m, 1H), 2.27.about.2.32 (m, 1H), 2.58.about.2.64
(m, 1H), 2.86.about.2.96 (m, 1H), 4.15 (dd, 2H), 5.11 (dd, 2H),
6.80 (d, 1H), 6.91 (d, 1H), 7.19 (t, 1H), 11.00 (s, 1H).
[0244] FAB(M+1): 260
[0245] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0246] measured data: C, 60.17%; H, 5.21%; N, 16.26%.
[0247] Preparation with the same method: [0248]
(R)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine;
[0249] yield: 93%; purity 99.41%.
[0250] Preparation with the same method: [0251]
(S)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0252] yield: 91%; purity 99.73%.
Example 17
The synthesis of
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
[0253] A mixture of
3-(4-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
(5 g) in ammonium formate (30 ml) was stirred by heating up slowly
to reflux and then reacted under ammonia for 6.about.8 hours. The
reaction mixture concentrated to dryness under reduced pressure.
Recrystallization from heated isopropanol gave 3.96 g of target
yield. yield: 85%. Purity: 99.17%. mp: 251.6.about.253.9.degree.
C.
[0254] .sup.1H-NMR: (300 MHz, DMSO-d.sub.6) .delta.:
2.05.about.2.11 (m, 1H), 2.25.about.2.34 (m, 1H), 2.60.about.2.65
(m, 1H), 2.85.about.2.97 (m, 1H), 4.16 (dd, 2H), 5.12 (dd, 2H),
6.82 (d, 1H), 6.90 (d, 1H), 7.19 (t, 1H), 10.97 (s, 1H) FAB(M+1):
260
[0255] Element analysis: theoretical data: C, 60.22%; H, 5.05%; N,
16.21%.
[0256] measured data: C, 60.29%; H, 5.16%; N, 16.27%.
Example 18
The synthesis of
3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutaric acid
[0257] A mixture of 4-nitro-2,3-dihydro-1H-isoindol-1-one (80 g)
and cesium carbonate (219 g) in triethylamine (100 ml) was stirred
for over half an hour. Under nitrogen ethyl chloroformate (68 ml)
was added by droplet below 0.degree. C. and reacted by stirring at
room temperature for 3.about.5 hours. The resulting mixture was
added in ice water (1000 mL) and then light yellow solid was
precipitated. After filter, the cake was washed by iced water. The
aqueous phase was extracted with dichloromethane twice and the
combined extracts were dried with anhydrous sodium sulphate. After
filtered, the filtrate was concentrated to dry under reduced
pressure. The concentrated was diluted with n-hexane (120 ml) and
stirred to precipitate crystal. Filter and drying under reduced
pressure gave light yellow solid.
[0258] A mixture of D,L-glutamic acid (66.7 g) in tetrahydrofuran
(330 ml) was stirred with the intermediate prepared above in
batches at subzero temperature. Triethylamine (6.5 ml) was added in
the mixture to react for 20 min and then for 16.about.24 hours
under reflux. The reaction mixture was cooled and filtered. The
filtrate was concentrated to dryness under reduced pressure. The
concentrate was dissolved in dichloromethane (60 ml) and extracted
with saturated sodium bicarbonate solution. When pH of the
resulting mixture was adjusted to 2 by 2N hydrochloric acid, a
number of light yellow solid was precipitated, subsequently
extracted with dichloromethane, and washed with distilled water,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure, finally crystal grew by standing, filtered
and dried to give 94.2 g of title product as light yellow solid,
yield 79%. purity 95.81%.
[0259] FAB(M+1): 309.
[0260] Element analysis: theoretical data: C, 50.65%; H, 3.92%; N,
9.09%.
[0261] measured data: C, 50.54%; H, 4.01%; N, 9.04%.
INDUSTRIAL APPLICABILITY
[0262] The present processes have the following advantages:
[0263] i. The method for preparing key substrate needed in the
synthesis is simple and with low cost, which is suitable for
commercial process;
[0264] ii. Each step to the present invention is under mild
reaction conditions without hard long-time reflux.
[0265] iii. The products yielded in each step to the present
invention are of high purity, which simplify the extraction and
purification process without column chromatography or other
complicated extraction conditions.
[0266] iv. There is high yield in each reaction. When
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
is synthesized from the original raw material,
4-nitro-2,3-dihydro-1H-isoindol-1-one and .alpha.-bromodimethyl
glutarate, the total yield averages from 35% to 40%. Hence the
preparation methods are simple with low costs.
[0267] v. Only by three or four procedures can the key product be
yielded, which leads to short synthesis routes and simple
methods.
[0268] vi. The solvents used in each preparation procedure are easy
to be disposed for environment protection, which is relatively
eco-friendly.
* * * * *