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Sommaire du brevet 2294342 

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Disponibilité de l'Abrégé et des Revendications

L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Brevet: (11) CA 2294342
(54) Titre français: PROCEDE DE SYNTHETISATION D'INTERMEDIAIRES DE CARBAPENEM A CHAINE LATERALE
(54) Titre anglais: PROCESS FOR SYNTHESIZING CARBAPENEM SIDE CHAIN INTERMEDIATES
Statut: Réputé périmé
Données bibliographiques
(51) Classification internationale des brevets (CIB):
  • C07D 495/08 (2006.01)
  • C07D 207/12 (2006.01)
  • C07D 207/16 (2006.01)
  • C07D 409/12 (2006.01)
  • C07F 9/572 (2006.01)
(72) Inventeurs :
  • BRANDS, KAREL M. J. (Etats-Unis d'Amérique)
  • WILLIAMS, JOHN M. (Etats-Unis d'Amérique)
  • DOLLING, ULF H. (Etats-Unis d'Amérique)
  • JOBSON, RONALD B. (Etats-Unis d'Amérique)
  • DAVIES, ANTONY J. (Etats-Unis d'Amérique)
  • COTTRELL, IAN F. (Etats-Unis d'Amérique)
  • CAMERON, MARK (Etats-Unis d'Amérique)
  • ASHWOOD, MICHAEL S. (Etats-Unis d'Amérique)
(73) Titulaires :
  • MERCK SHARP & DOHME CORP. (Etats-Unis d'Amérique)
(71) Demandeurs :
  • MERCK & CO., INC. (Etats-Unis d'Amérique)
(74) Agent: NORTON ROSE FULBRIGHT CANADA LLP/S.E.N.C.R.L., S.R.L.
(74) Co-agent:
(45) Délivré: 2006-03-14
(86) Date de dépôt PCT: 1998-07-02
(87) Mise à la disponibilité du public: 1999-01-21
Requête d'examen: 2000-03-13
Licence disponible: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Oui
(86) Numéro de la demande PCT: PCT/US1998/013738
(87) Numéro de publication internationale PCT: WO1999/002531
(85) Entrée nationale: 1999-12-13

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
60/052,032 Etats-Unis d'Amérique 1997-07-09
9810184.3 Royaume-Uni 1998-05-13

Abrégés

Abrégé français

L'invention concerne un procédé de synthétisation d'un composé de formule (1). Un composé de formule (2) est mis à réagir tout d'abord avec un chlorure diphénylphosphinique, afin d'activer le groupe acide carboxylique, puis avec un chlorure méthanesufonyle, afin de produire un composé de formule (4). Ce composé de formule (4) est ensuite mis à réagir avec une source de sulfure d'un métal de groupe II dans de l'eau, afin de produire un composé de formule (1).


Abrégé anglais



A process of synthesizing a compound of formula (1)
is described. A compound of formula (2) is reacted with
diphenylphosphinic chloride to activate the carboxylic acid
group, and then reacted with methanesulfonyl chloride to
produce a compound of formula (4). Compound (4) is then
reacted with a group II metal sulfide source in water to
produce a compound of formula (1).

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.



-27-

CLAIMS

1. A process for synthesizing a compound of the formula 1:
Image
wherein X is a protecting group selected from the group consisting of:
t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl,
triethylsilyl,
o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-
butyloxycarbonyl (t-BOC), 2,2,2-trichloroethyloxycarbonyl benzhydryl, o-
nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl,
2,2,2-
trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C 1-10 alkylphosphoryl,
diarylphosphoryl and di-ar-C 1-10 alkylphosphoryl,
comprising
(a) reacting a compound of the formula 2:
Image


-28-

:wherein X is as defined above with diphenylphosphinic chloride in a solvent
in
the presence of excess base to produce a compound of the formula 3:
Image
(b) reacting said compound 3 with methanesulfonyl chloride in a solvent in the
presence of a slight molar excess of pyridine, collidine or lutidine to
produce a
compound of formula 4:
Image
(c) combining said compound 4 with an alkali metal sulfide or non-alkali metal
sulfide in water to produce a compound of said formula 1.

2. A process of producing a compound of the formula 5:



-29-

Image
wherein X is a protecting group selected from the group consisting of:
t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl,
triethylsilyl,
o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-
butyloxycarbonyl (t-BOC), 2,2,2-trichloroethyloxycarbonyl benzhydryl, o-
nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl,
2,2,2-
trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C 1-10 alkylphosphoryl,
diarylphosphoryl and di-ar-C 1-10 alkylphosphoryl,
R1 and R2 are independently selected from hydrogen, aryl and heteroaryl, said
aryl and heteroaryl groups being unsubstituted or substituted with from 1-3
groups selected from the group consisting of: C 1-4 alkyl, C 1-4 alkoxy, C 1-4
alkylthio, halo, hydrogen, CO2H, CO2C1-4 alkyl, NH2, NHCl4 alkyl, N(C1-4
alkyl)2, SO3H, CN, NHC(O)C1-4 alkyl, SO2NH2, SO2C1-4 alkyl, aryl and
heteroaryl; comprising: (a) reacting a compound of the formula 2:
Image



-30-

wherein X is as defined above with diphenylphosphinic chloride in a solvent in
the presence of excess base to produce a compound of the formula 3:
Image
(b) reacting said compound 3 with methanesulfonyl chloride in a solvent in the
presence of a slight molar excess of pyridine, collidine or lutidine to
produce a
compound of formula 4:
Image
(c) combining said compound 4 with an alkali metal sulfide or non-alkali metal
sulfide in water to produce a compound of formula 1:



-31-


Image
(d) reacting said compound 1 with NHR1R2 wherein R1 and R2 are as defined
above to produce a compound of said formula 5.

3. A process in accordance with claim 1 or 2, wherein X is selected from t-
BOC,
p-nitrobenzyloxycarbonyl and diisopropylphosphoryl.

4. A process in accordance with claim 3 wherein X represents
diisopropylphosphoryl.

5. A process in accordance with claim 2 wherein said compound 1 and said
NHR1R2, in (d) are reacted in the presence of an organic acid to produce said
compound of formula 5.

6. A process in accordance with claim 5 wherein the organic acid is selected
from formic acid, acetic acid and propionic acid.

7. A process in accordance with claim 5 wherein said compound 1 and
said NHR1R2 in (d) are reacted in an organic solvent.

8. A process in accordance with claim 7 wherein the organic solvent is
methylene chloride.

9. A process in accordance with claim 1 or 2, wherein the base in (a) is a
trialkylamine.




-32-


10. A process in accordance with claim 9 wherein the trialkylamine is selected
from the group consisting of diisopropylethylamine and triethylamine.

11. A process in accordance with claim 1 or 2, wherein said compound 3 is
reacted with said methanesulfonyl chloride in the presence of pyridine to
produce said compound of formula of formula 4.

12. A process in accordance with claim 1 or 2, wherein said compound 3 is
reacted with said methanesulfonyl chloride in the presence of collidine to
produce said compound of formula of formula 4.

13. A process in accordance with claim 1 or 2, wherein said compound 3 is
reacted with said methanesulfonyl chloride in the presence of lutidine to
produce
said compound of formula of formula 4.

14. A process in accordance with claim 1 or 2, wherein said compound 4 is
reacted with a non-alkali metal sulfide to produce said compound of formula 1.

15. A process in accordance with claim 14 wherein the non-alkali metal
sulphide, in water, is reacted with said compound 4 to produce said compound
of formula 1 at a temperature of 10°C to room temperature.

16. A process in accordance with claim 2 wherein
NHR1R2 is selected from the group consisting of:



-33-


Image

17. A process in accordance with claim 14 or 15 wherein the non-alkali metal
sulfide is selected from a sulfide of calcium, barium and magnesium.

18. A process in accordance with claim 17 wherein the non-alkali metal sulfide
is calcium sulfide.

19. A process in accordance with claim 17 wherein the non-alkali metal sulfide
is barium sulfide.

20. A process in accordance with claim 1 wherein:
X represents diisopropylphosphoryl and said compound 4 is reacted with CaS in
water to produce a compound of said formula 1.

21. A process in accordance with claim 1 wherein:
X represents diisopropylphosphoryl and said compound 4 is reacted with Na2S
in water to produce a compound of said formula 1.



-34-


22. A process in accordance with claim 2 wherein the amine HNR1R2 is
m-aminobenzoic acid.

23. A process in accordance with claim 2, further comprising reacting a
compound of formula 5 with an acid to produce a compound of formula 6:
Image

24. A process in accordance with claim 23 in which said reacting of said
compound of formula 5 with an acid is in the presence of trialkylphosphine or
triarylphosphine.

25. A process in accordance with claim 24 in which the trialkylphosphine is
tri-
n-butylphosphine.

26. A process in accordance with claim 23 in which the reacting is in a
solvent
selected from the group consisting of C 1-5 alcohols, C 1-3 alkanoic acids,
toluene,
acetonitrile and ethyl acetate.

27. A process in accordance with claim 23, wherein said compound of formula 2
is a compound of formula 2':



-35-


Image
and is reacted with said diphenylphosphinic chloride to produce said compound
of formula 3 which is a compound of formula 3':
Image
said compound 3' is reacted with mesyl chloride to produce said compound of
formula 4 which is a compound of formula 4':
Image
said compound 4' is reacted with a member selected from the group consisting
of Na2S, K2S, CaS and BaS to produce a compound of formula 1':


-36-


Image
said compound 1' is reacted with m-aminobenzoic acid to produce said
compound of formula 5 which is a compound of formula 5':
Image
and said compound 5' is reacted with acid to produce said compound of formula
6 which is a compound of formula 6':
Image
or a salt or solvate thereof.

28. A process in accordance with claim 27 in which said reacting of said



-37-


compound 5' with acid is in the presence of trialkylphosphine or
triarylphosphine.

29. A process in accordance with claim 28 in which the trialkylphosphine is
tri-
n-butylphosphine.

30. A process in accordance with claim 28 or 29 in which said reacting of said
compound 5' with acid is in the presence of a solvent selected from the group
consisting of C 1-5 alcohols, C 1-3 alkanoic acids, toluene, acetonitrile and
ethyl
acetate.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-1-
TITLE OF THE INVENTION
PROCESS FOR SYNTHESIZING CARBAPENEM
SIDE CHAIN INTERMEDIATES
BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of carbapenem
side chains, and in particular, to side chains or portions thereof containing
a pyrrolidine group, which is bonded to the carbapenem nucleus through
a thioether linkage. Typically, the pyrrolidine is a portion of the side
chain, and is substituted at the two position with any of a variety of
substituents.
Conventionally, these intermediate compounds are prepared
from a 4-hydroxyproline derivative of the formula:
HO
CONR~R2
N
R
Such synthetic schemes typically require the extensive use of protecting
groups.
Similarly, a method of converting trans-4-hydroxy-L-proline
to a thiolactone of the formula:
O
S
N
C(O)CH3
has been described. However, this thiolactone is unsuitably protected for
synthesis of carbapenem antibiotics.

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-2-
EP 551 993 Al published on July 21, 1993 relates to a
synthesis which utilizes active esterifying agents and base, followed by
treatment with hydrogen sulfide, or an alkali metal salt of hydrogen
sulfide, and base.
The present invention is an improvement over these other
processes, utilizing a sulfide source which surprisingly improves the
process when commercial quantities are synthesized.
SUMMARY OF THE INVENTION
A process for synthesizing a compound of the formula 1:
p O
1
is described wherein P is a protecting group
comprising
(a) reacting a compound of formula 2:
H 0,,,~,,
C02H
I
P
2
wherein P is as previously defined with diphenylphosphinic chloride to
produce a compound of formula 3:

CA 02294342 1999-12-13
WO 99102531 PCT/US98/13738
-3-
HO,,,~,,.
N C~O~P
O p ' /
3
(b) reacting compound 3 with methanesulfonyl chloride to
produce a compound of formula 4:
H3CSO3 0,,~,,,
~C,O~P
Ipl II
P O
and
(c) combining compound 4 with an alkali metal sulfide or
non-alkali metal sulfide in water to produce a compound of formula 1.
More particularly, the process described herein relates to a
process for producing a compound of the formula 5:
HS
'~C(O)NR'Rz
N
P
5

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-4-
wherein P is a protecting group;
R~ and R2 are independently selected from hydrogen, aryl and
heteroaryl, said aryl and heteroaryl groups being unsubstituted or
substituted with from 1-3 groups selected from the group consisting of:
C 1 _q. alkyl, C ~ _4 alkoxy, C 1 _4 alkylthio, halo, hydroxy, C02H,
C02C1_4 alkyl, NH2, NHCl_4 alkyl, N(Cl_4 alkyl)2, S03H, CN,
NHC(O)C1_4 alkyl, S02NH2, S02C1_4 alkyl, aryl and heteroaryl;
comprising: (a) reacting a compound of the formula 2:
H 0,,,,,,.
~C02H
N
P
2
wherein P is as previously defined with diphenylphosphinic chloride to
produce a compound of the formula 3:
HO,,,,,,
~C.O~P
ii II
P O O
3
(b) reacting compound 3 with methanesulfonyl chloride to
produce a compound of formula 4:

CA 02294342 1999-12-13
WO 99/0253I PCT/US98/13738
-5-
H3CSO3 gin,,,,,
C.O~P
P O O
4
(c) combining compound 4 with an alkali metal sulfide or
non-alkali metal sulfide in water to produce a compound of formula 1:
P O
1
and
(d} reacting compound 1 with NHR1R2 wherein R~ and R2 are as
previously defined to produce a compound of formula 5:
DETAILED DESCRIPTION OF THE INVENTION
The invention is described using the following definitions
unless otherwise specified.
Alkyl and the alkyl portions of substituent groups include
monovalent hydrocarbon chains containing from 1-4 carbon atoms which
are straight or branched as appropriate.
Aryl refers to 6-10 membered mono- and bicyclic ring
systems, containing carbon atoms with alternating (resonating) double
bonds. Preferred aryl groups are phenyl and naphthyl.
Heteroaryl refers to aromatic 5-10 membered mono- and
bicyclic ring systems, containing from 1-4 heteroatoms, O, S or N.

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-6-
Preferred nitrogen containing monocyclic heteroaryl groups include
pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl
and l, 2, 4-triazolyl. Preferred heteroaryl groups containing oxygen as
the only heterotom include furanyl. Preferred heteroaryl groups
containing sulfur as the only heterotom include thienyl.
Preferred bicyclic heteroaryl groups include benzthiazolyl,
benzimidazolyl, quinolinyl and isoquinolinyl, indolyl and isoindolyl.
When substituted, the aryl and heteroaryl groups may be
substituted with 1-3 groups selected from the group consisting of: Cl-4
alkyl, C 1-4 alkoxy, C 1 _4 alkylthio, halo, hydroxy, C02H, C02C 1 _4 alkyl,
NH2, NHC 1 _4 alkyl, N(C 1 _4 alkyl)2, NHC(O)C 1 _4 alkyl, S03H, CN,
S02NH2, S02C1-4 alkyl, aryl and heteroaryl.
When necessary, the substituents which are optionally
present on aryl and heteroaryl can be in protected form.
Examples of suitable protecting groups include the following
without limitation: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,
trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyl-
oxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2-
trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl,
2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl,
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl-
silyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C,_,o alkylphosphoryl,
diarylphosphoryl and di-ar-C,_,o alkylphosphoryl. Preferred silyl
protecting groups are trimethylsilyl and triethylsilyl. Preferred carboxyl
protecting groups are p-nitrobenzyl and allyl. Preferred phosphoryl based
protecting groups include diisopropylphosphoryl.
Many other suitable hydroxyl and carboxyl protecting
groups are known in the art. See, e.g., Greene, T. W., et al. Protective
Groups in Or anic Synthesis, John Wiley & Sons, Inc., 1991.
P represents a protecting group on the proline nitrogen atom.
Thus, in one aspect of the invention, P represents a member selected from
the group consisting of: t-butylmethoxyphenylsilyl, t-butoxydiphenyl-
silyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitro-

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
_7_
benzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC),
2,2,2-trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl,
2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl,
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)
ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C,-,o alkylphosphoryl,
diarylphosphoryl and di-ar-C,_,o alkylphosphoryl.
More particularly, P represents a protecting group which is
selected from the group consisting of: t-BOC, diisopropylphosphoryl and
p-nitrobenzyloxycarbonyl.
Most particularly, P represents diisopropylphosphoryl.
Compound 2 used herein as a starting material is N
protected trans-4-hydroxy-L-proiine. The 2-carboxyl group is activated
using the compound diphenylphosphinic chloride, which is reacted with
I S compound II in a solvent in the presence of excess base. Solvents which
are useful herein include dichloromethane, acetonitrile, toluene,
fluorobenzene, tetrahydrofuran, or mixtures thereof. Bases which are
useful for this reaction include trialkylamines. Preferred trialkylamines
include diisopropylethylamine (DIPEA) and triethylamine.
Typically an amount of diphenylphosphinic chloride which
is about equimolar to the starting compound can be used. The reaction
between compound 2 and diphenylphosphinic chloride is typically run at
reduced temperature, below about 0°C to as low as about -40°C.
Preferably, the reaction temperature is maintained at about -10°C.
Compound 3, with the diphenylphosphinyloxycarbonyl
group at position two, is reacted with methanesulfonyl chloride (MsCl)
to produce compound 4. This reaction is conducted in a solvent, in the
presence of a slight molar excess of pyridine, collidine, lutidine and the
like, using a slight molar excess of MsCI. This mesylation reaction may
be conducted over about 1-4 hours, at a reduced temperature, e.g., about
0°C to as low as about -40°C. Preferably, the reaction
temperature is
maintained at about -10°C.
Compound 4 is thereafter combined with an alkali metal
sulfide or non-alkali metal sulfide and water to form the thiolactone 1.

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
_g_
Essentially the reaction can be conducted at about -10°C to about
room
temperature. Preferably the sulfide and water are added quickly, and the
reaction is aged for several hours at ambient temperature.
As used herein, "alkali metal sulfide" refers to the group I
metal sulfides, such as the sulfides of sodium and potassium. Preferably
the alkali metal sulfide is Na2S.
As used herein, "non-alkali metal sulfides" and "alkaline
earth metals" are used interchangeably to include the group II alkaline
earth metal sulfides selected from the group consisting of: magnesium,
calcium and barium. Preferred are calcium and barium.
The preferred non-alkali metal sulfide, most notably CaS,
provides an unexpected advantage in that side products of the reaction
have low solubility in water, and thus can be removed as a precipitate.
In a preferred aspect of the process described herein, the
amine HNR'RZ is m-aminobenzoic acid.
In another preferred aspect of the process, the compound of
formula 5 is reacted with an acid to produce a compound of formula 6:
HS
~C(O)NR~R2
N
H
6
More particularly, a compound of formula 2'
H 0,,,
C02H
N
P(O)(OiPr)2
2'
is reacted with diphenylphosphinic chloride to produce a compound of
formula 3'

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-9-
H 0,,,
.~C02P(O)(Ph)2
N
P(O)(OiPr)2
3'
compound 3' is reacted with mesyl chloride to produce compound 4'
MsO,,,
.~ C02P(O)(Ph)2
N
P(O)(OiPr)2
4'
compound 4' is reacted with a member selected from the group consisting
of: Na2S, K2S, CaS and BaS to produce a compound of formula 1':
(iPrO)2P(O) ~N~~!~O
S
1'
compound 1' is reacted with m-aminobenzoic acid to produce 5'

CA 02294342 2003-11-27
-10-
C02 H
HS
?--~C(O)NH
N
P(O)(OiPr)z
s'
and compound 5' is reacted with acid to produce a compound of formula
6'
C02H
HS
'~C(O)NH
N
H
6'
or a salt or solvate thereof.

CA 02294342 2003-11-27
10a -
In a preferred aspect of the invention, the thiolactone
compound 1 is reacted with the amine HNR1R2 in the presence of an
organic acid to produce compound 5. Examples of suitable organic acids
include formic acid, acetic acid and propionic acid. Most preferably, the
reaction is conducted in the presence of acetic acid. Preferably, this
reaction is carried out in the presence of an organic solvent, such as
methylene chloride.
After the conversion of compound 4' to compound 1', the
latter is combined with ammonia or a primary or secondary amine to form
compounds of formula 5', which can be deprotected to give compound 6'
or salt thereof. In the isolation of 6' solvents, such as C~_5 alcohols, C1_3
alkanoic acids, toluene, acetonitrile, ethyl acetate and others may be
added to improve crystallization, or otherwise facilitate isolation.

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-11-
Also, addition of a trialkyl or triaryl phosphine, e.g., tri-n-butylphosphine,
at this stage may be useful in reducing the formation of disulfides
corresponding to compound (' and/or improving the rejection of other
impurities.
Most primary and secondary amines HNR1R2 wherein Rl
andlor RZ represent H, aryl or heteroaryl react with compound 1 upon
slight heating. Generally, the reaction proceeds from about RT to about
100°C over a few minutes to several hours.
The acid that is used to convert compound 5' to compound
G' can be varied within wide limits. For example, concentrated HCl can
be used and is preferred.
The invention described herein can be conducted in
essentially a single reaction vessel, thus allowing for economical
production of compounds 6' from compound 2.
The invention is further illustrated with the following non-
limiting examples.
EXAMPLE ONE
~1 S. 4S~-5-DIISOPROPYLPHOSPHORYL-2-THIA-5-
AZAB ICYCLO f 2.2.11 HEPTAN-3-ONE
HO,,,,.
N/ _ CO H diphenylphosphinic
2 chloride
P(O)(OiPr)2
1-2
HO,,,,, O
methanesulfonyl
P \ ~ chloride
P(O)(OiPr)2
1-3

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-12-
MsO,,,,, O
CO2 P \ / CaS/H20
Slurry
1_4 ~ \
P(O)(OiPr)2
(iPrO)2(O)P~ O
1-1
The following starting materials were utilized:
Startin Material uantit


Diisopropylphosphoryl 5.0 g, 16.93 mmol
h drox roline


Diiso ro leth lamine 6.34 mL, 36.44 mmol


Diphenylphosphinic 3.36 mL, 17.61 mmol
chloride


P ridine 1.48 mL, 18.29 mmol


Methanesulfon 1 chloride1.43 mL, 18.46 mmol


Calcium sulfide 1.49 , 20.66 mmol


Dichloromethane 100 mL


Water 350 mL


The mesylate mixed anhydride was formed according to
WO 97/06154 published on February 20, 1997, incorporated herein by
reference, and stirred with cooling at -15°C for 15 min.
Calcium sulfide (1.49 g) was added as a solid and washed
with water (30 mL), resulting in a three phase reaction mixture. The
mixture was stirred rapidly and the cooling bath removed, allowing the
mixture to reach room temperature.
r

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-13-
The solids quickly went into solution, and a white solid
precipitate was formed.
The mixture was stirred for 45 min and then filtered through
a coarse filter. The solid on the filter was washed with dichloromethane
and the filtrate separated.
The organic layer (approx. 200 mL) was washed with 1 M
HCl (50 mL), and 8% NaHC03 (50 mL). The aqueous bicarbonate layer
was back extracted and the combined extracts were washed with brine
and the layers weighed. The presence of the title compound (4.04 g) was
confirmed by HPLC.
EXAMPLE TWO
HO,,~I
~ H diphenylphosphinic
N chloride
t-BOC O
2-2
HO,,~,. O
methanesulfonyl
chloridc
N
t-BOC O
2-3

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MsO,,,, O
O-P \ ~ CaS
--
N ~ \ H2o
t-BOC O
2-4
t-BOC O
2-1
A. Synthesis of trans-N-t-butoxycarbonyl-2-
dinhenylphosphinyloxvcarbonyl-4-h~~~roline
H 0,,~,I DIpEA
OH dry THF
-2o°c
diphenylphosphmic
t-BOC ~ chloride
2-2
HO
O-P~ \
II
o b
2-3
A solution of compound 2-2 (35.0 g, 151 mmol.) and DIPEA
(60 mL, 344 mmol) in dry THF ( 1.0 L) was combined over 20 min with a

CA 02294342 1999-12-13
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solution of diphenylphosphinic chloride (37.5 g, 155 mmol) in THF (50
mL) at -20°C. The reaction mixture was stirred at -20°C for 90
minutes
to produce compound 2-3, which can be isolated and characterized or
used in the next part without isolation.
B. Synthesis of trans-N-t-butoxycarbonyl-2-diphenylphosphinyl
oxycarbonyl-4-methanesulfonxloxy-L-proline
HO,,,, O
\ ~ methanesulfonyl
0-P chloride
N ~ ~ \
t-BOC O
2-3
MsO,
O-P~ \
II
o b
2-4
Without isolation and characterization, after stirring the
reaction mixture from part A for 90 minutes at -20°C, pyridine (13.0
mL,
161 mmol) was added followed by a solution of methanesulfonyl chloride
( 19.8 g, 171 mmol) in THF (50 mL) over 15 minutes. The reaction
mixture was stirred at -20°C for 2 hours and allowed to warm to -
5°C
over an additional 30 minutes producing compound 2-4. The
methanesulfonyl substituted compound can be isolated and characterized,
or used in the next reaction without isolation and characterization.

CA 02294342 1999-12-13
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C. Synthesis of N-t-butoxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-
3-one
MsO,,,, O
O-P \ ~ CaS/H20
\ Slurry
t-BOC O
2-4
t-BOC O
2-1
After allowing the reaction from part B to warm to -5°C,
a slurry of CaS (45.0 g, 187 mmol) in H20 (60 mL) is added in one
portion. The mixture is allowed to warm to room temperature and is
stirred for 6 hrs. The resulting suspension is filtered and the filtrate is
then partitioned between toluene and water. The organic Iayer is washed
with HCl (2.0 M), NaHC03 ( 1.0 M) and brine, dried over MgS04 and
concentrated in vacuo.
EXAMPLE THREE
HS
t-BOC O
~C(O}NR 1 R2
N
2-1
t-BOC
3-5

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WO 99/02531 PCT/US98/13738
-17-
The thiolactone 2-1 from Example Two without isolation,
can be combined with the amine shown below in column one to produce
the cis N-protected 4-thiol substituted proline derivative shown below in
column two.
TABLE ONE
Amine Product (3)
(3_1) HS
NH4Cl ~''C(O)NH2
N
i
t-BOc
3-5-1
(3-2)
HS
NH2 ~C(O)NH
N
I
t-BOC
3-5-2
(3-3)
NH2 HS
~C(O)NH ~
N C02H
C02H t-BOC
3-5-3

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-1$-
(3-4)
HS
~C(O)NH
N S C02H
H2N ~S ~C02H
t-BOC
3-5-4
(3-5)
HS
NH2 ~C(O)NH ~
N C02H
t'(O)(OiPr)
C02H
3-5-5
(1) 4.0 eq. of NH4C1 in Et3N; solvent CH30H;
reaction time: 30 min at RT;
(2) 1.25 eq. of aniline; solvent toluene; reaction time:
2 hrs at 100°C;
(3) 1.25 eq. of 3-aminobenzoic acid; solvent toluene;
reaction time: 2 hrs at 100°C;
(4) 1.25 eq. of 5-amino-2-carboxythiophene; solvent
toluene; 2 hrs at 100°C;
(5) P represents diisopropylphosphoryl. (iPr = isopropyl).
EXAMPLE FOUR
Using the procedures set forth in Example Two, Part A, the
compounds of column one are reacted with diphenylphosphinic chloride
to produce the compounds in column two.

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-I9-
TABLE TWO
HO,,,,,,,
HO,,,,
C02P(O)(Ph)2
C02H N
N
O~O ~ O O
4-3-1 / N02
N02 ph - phenyl
4-2-1
HO~~,,,, HO,,,,,,
C02H ~ C02P{O)(Ph)2
N N
\ ~O \
O O ~ O
/ /
4-2-2 4-3-1
HO,,,,,,, HO,,,~,.
~'C02H ~C02P(O)(Ph)2
N N
0 0 0
4-2-3 I 4-3-3
SUBSTITUTE SHEET (RULE 26)

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-20-
EXAMPLE FIVE
Using the procedures set forth in Example One, Part B, the
compounds of column one are reacted with methanesulfonyl chloride to
produce the compounds in column two.
TABLE THREE
5-4-1
MsO,,
~C02P(O)(Ph)2
4-3-1 N
O~O
N02
Ph = phenyl
5-4-2
4-3-2 MsO,,,,,
~
C02P(O)(Ph)2
N
O~O

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WO 99/02531 PCT/US98/13738
-21-
5-4-3
MsO,,,,,,,
4-3-3
~C02P(O)(Ph)2
N
~O~
O
EXAMPLE SIX
Using the procedures set forth in Example Two, Part C, the
compounds of column one are reacted with CaS in water to produce the
compounds in column two.
TABLE FOUR
6-1-1
NOZ
w
5-4-1
OII
Ol~N. / O
S

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WO 99/02531 PCT/US98/13738
-22-
G-1-2
5_4.2 OII
OJ~N.~O
I S
fi-1-3
5-4-3
OJ~N / O
S
EXAMPLE SEVEN
Using the procedures set forth in Example Three, the
compounds of column one are reacted with the amine in column two to
produce the compounds in column three.

CA 02294342 1999-12-13
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TABLE FIVE
Amine NHR1R2 P rrolidine
7_5_1 1
HS
(1)
~C(O)NH2
6-1-1 NH4Cl N
\
O
/ N02
7-5-2 1
(2) . H S
NH2 ~C(O)NH-Ph
6-1-1 N
~O \
/ O
/ N02
Ph = Phenyl
7-5-3 1
(3) HS
NH ~C(O)NH
6-1-1 N
\ C02H
O~O
/ C02H
/ N02

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WO 99/02531 PCT/US98/13738
-24-
7_5_4 1
(4) H S
~C(O)NH
N s C02H
6-1-1
H2N S C02H O'~'O \
N 02
7-5-5 I
HS
(1)
6-1-2 ~C(O)NH2
NH4Cl N
O
7_5_6 1
(2) HS
6-1-2 NH2 ~C(O)NH-Ph
N
/ p p
/
Ph = Phenyl
7_5_7 1
(3) HS
._
6-1-2 NH2 ~C(O)NH
N
O ~ C02H
C02 H O

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-25-
7_5_8 1
(q.) H S
~C(O)NH
6-1-2 / N S C02H
H2N S/\C02H O~O w
7_5-9 1
HS
(1)
~C(O)NH2
6-1-3 ~ NH4Cl N
~O~
O
7-5-10 1
(2) HS
NH2 ~'~'C(O)NH-Ph
6-1-3 N
/ O O~
Ph = Phenyl
7-5-11 l
(3) HS
NH ~'C(O)NH
N
6-1-3 l
O~ C02H
/ O
C02H

CA 02294342 1999-12-13
WO 99/02531 PCT/US98/13738
-26-
(4) 7-5-12 1
HS
- _ ~ , C(O)NH ~ I
613 H2N S~C02H N S~C02H
O~O
(3)
7-5-13 '
NH2 HS
1-1 ~ ~C(O)NH ~
I / N
CO H
CO H ~(O)(piPr)
2
1: Tri-n-butylphosphine may be added.
While certain preferred embodiments have been described
herein in detail, numerous alternative embodiments are contemplated as
falling within the scope of the invention.

Dessin représentatif
Une figure unique qui représente un dessin illustrant l'invention.
États administratifs

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , États administratifs , Taxes périodiques et Historique des paiements devraient être consultées.

États administratifs

Titre Date
Date de délivrance prévu 2006-03-14
(86) Date de dépôt PCT 1998-07-02
(87) Date de publication PCT 1999-01-21
(85) Entrée nationale 1999-12-13
Requête d'examen 2000-03-13
(45) Délivré 2006-03-14
Réputé périmé 2012-07-03

Historique d'abandonnement

Il n'y a pas d'historique d'abandonnement

Historique des paiements

Type de taxes Anniversaire Échéance Montant payé Date payée
Enregistrement de documents 100,00 $ 1999-12-13
Le dépôt d'une demande de brevet 300,00 $ 1999-12-13
Requête d'examen 400,00 $ 2000-03-13
Taxe de maintien en état - Demande - nouvelle loi 2 2000-07-04 100,00 $ 2000-06-09
Taxe de maintien en état - Demande - nouvelle loi 3 2001-07-02 100,00 $ 2001-06-05
Taxe de maintien en état - Demande - nouvelle loi 4 2002-07-02 100,00 $ 2002-05-31
Taxe de maintien en état - Demande - nouvelle loi 5 2003-07-02 150,00 $ 2003-06-30
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Taxe de maintien en état - Demande - nouvelle loi 7 2005-07-04 200,00 $ 2005-06-29
Taxe finale 300,00 $ 2005-12-13
Taxe de maintien en état - brevet - nouvelle loi 8 2006-07-04 200,00 $ 2006-06-16
Taxe de maintien en état - brevet - nouvelle loi 9 2007-07-02 200,00 $ 2007-06-07
Taxe de maintien en état - brevet - nouvelle loi 10 2008-07-02 250,00 $ 2008-06-23
Taxe de maintien en état - brevet - nouvelle loi 11 2009-07-02 250,00 $ 2009-06-19
Enregistrement de documents 100,00 $ 2010-02-09
Taxe de maintien en état - brevet - nouvelle loi 12 2010-07-02 250,00 $ 2010-06-18
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
MERCK SHARP & DOHME CORP.
Titulaires antérieures au dossier
ASHWOOD, MICHAEL S.
BRANDS, KAREL M. J.
CAMERON, MARK
COTTRELL, IAN F.
DAVIES, ANTONY J.
DOLLING, ULF H.
JOBSON, RONALD B.
MERCK & CO., INC.
WILLIAMS, JOHN M.
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Abrégé 1999-12-13 1 54
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