U.S. patent application number 15/772521 was filed with the patent office on 2018-11-08 for preparation method for tedizolid, tedizolid intermedicate, and preparation method therefor.
The applicant listed for this patent is Shanghai Syncores Technologies Inc. Ltd., Zhejiang Huahai Pharmaceutical Co., Ltd. Invention is credited to Hong Gu, Shaoxiao Gui, Luning Huang, Siyuan Li, Anping Tao, Jicheng Zhang.
Application Number | 20180319828 15/772521 |
Document ID | / |
Family ID | 58661614 |
Filed Date | 2018-11-08 |
United States Patent
Application |
20180319828 |
Kind Code |
A1 |
Li; Siyuan ; et al. |
November 8, 2018 |
PREPARATION METHOD FOR TEDIZOLID, TEDIZOLID INTERMEDICATE, AND
PREPARATION METHOD THEREFOR
Abstract
The present invention relates to a preparation method for a
tedizolid compound in Formula I. In Formula I, R is selected from
hydrogen, formula A, formula B, benzyl or benzyl substituted by a
substituent, the substituent is selected from a group consisting of
halogen, nitryl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy,
and R.sub.1 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl
substituted by halogen. The method comprises: generating a compound
having a structure as shown in Formula C and a compound having a
structure as shown in Formula D by a coupled reaction under the
catalysis of a metal catalyst, a substituent of R being defined as
above, where X is a leaving group, the leaving group comprising
chlorine, bromine, iodine, and sulfonyl oxy such as
trifluoromethane sulfonic oxy, methylsulfonyl oxy and
benzenesulfonyl oxy, or benzenesulfonyl oxy substituted by one or
more substituents, the substituent being selected from a group
consisting of halogen, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
alkoxy. ##STR00001##
Inventors: |
Li; Siyuan; (Shanghai,
CN) ; Gui; Shaoxiao; (Shanghai, CN) ; Zhang;
Jicheng; (Shanghai, CN) ; Huang; Luning;
(Shanghai, CN) ; Tao; Anping; (Shanghai, CN)
; Gu; Hong; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zhejiang Huahai Pharmaceutical Co., Ltd
Shanghai Syncores Technologies Inc. Ltd. |
Linhai
Shanghai |
|
CN
CN |
|
|
Family ID: |
58661614 |
Appl. No.: |
15/772521 |
Filed: |
November 2, 2016 |
PCT Filed: |
November 2, 2016 |
PCT NO: |
PCT/CN2016/104311 |
371 Date: |
April 30, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 213/00 20130101;
C07C 235/78 20130101; B01J 31/2295 20130101; C07F 9/65583 20130101;
B01J 27/055 20130101; B01J 31/28 20130101; B01J 2231/44 20130101;
C07D 401/04 20130101; B01J 31/30 20130101; C07D 413/14 20130101;
B01J 31/0212 20130101; B01J 31/0238 20130101; C07C 217/40 20130101;
C07D 263/20 20130101; C07C 231/10 20130101; B01J 2531/824 20130101;
C07C 217/48 20130101; C07D 263/24 20130101; B01J 27/122
20130101 |
International
Class: |
C07F 9/6558 20060101
C07F009/6558; C07D 413/14 20060101 C07D413/14; C07D 401/04 20060101
C07D401/04; B01J 27/122 20060101 B01J027/122; B01J 27/055 20060101
B01J027/055; B01J 31/02 20060101 B01J031/02; B01J 31/30 20060101
B01J031/30; B01J 31/28 20060101 B01J031/28; B01J 31/22 20060101
B01J031/22 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2015 |
CN |
201510739910.6 |
Claims
1. A preparation method for tedizolid compound of the formula below
##STR00050## wherein R is selected from the group consisting of
hydrogen ##STR00051## benzyl or benzyl substituted by a substituent
which is selected from the group consisting of halogen, nitro,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, and R.sub.1 is
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl substituted by
halogen; wherein the preparation method comprises reacting the
compound having a structure of the formula below ##STR00052##
wherein X is a leaving group, which includes chlorine, bromine,
iodine, and sulfonyloxy; with the compound having a structure of
the formula below ##STR00053## under the catalysis of metal
catalyst to produce the tedizolid compound by a coupled reaction,
and wherein substituent R is as defined above.
2. The preparation method according to claim 1, wherein the metal
catalyst is a copper catalyst or a palladium catalyst.
3. The preparation method according to claim 1, wherein the coupled
reaction is performed in the presence of an alkaline substance as a
promoter.
4. The preparation method according to claim 1, wherein the
reaction solvent for the coupled reaction is toluene,
chlorobenzene, tetrahydrofuran, N,N-dimethylformamide, dimethyl
sulfoxide, dioxane, isopropanol, ethanol or acetonitrile; and the
reaction temperature is 60-110.degree. C.
5. The preparation method according to claim 1, wherein when the
metal catalyst is a copper catalyst, the copper catalyst acts
together with ligands which are selected from the group consisting
of a diamine ligand, a diketone ligand, a phenanthroline ligand, an
amino acid ligand, and a Phos ligand.
6. A preparation method for the compound of the formula below
##STR00054## wherein X is a leaving group, which includes chlorine,
bromine, iodine, and sulfonyloxy; wherein the preparation method
comprises reacting the compound having a structure of the formula
below ##STR00055## wherein, C is hydroxyl or amino; 1) with
sulfonyl chloride compounds, when C is hydroxyl, to produce the
compound having a structure of the formula below ##STR00056##
wherein X is a leaving group which is sulfonyloxy; or 2) when C is
amino, to produce diazonium salt compounds in the presence of
sodium nitrite, then being substituted with halogen ion to produce
the compound having a structure of the formula below ##STR00057##
wherein X is a leaving group including chlorine, bromine, and
iodine.
7. A preparation method for the compound of the formula below,
##STR00058## comprising reacting the compound having a structure of
the formula below ##STR00059## with the compound having a structure
of the formula below ##STR00060## under the catalysis of palladium
catalysts by a coupled reaction; wherein C is hydroxyl or amino;
one of A and B is a leaving group, and the other one is BF.sub.3 or
BR.sub.2R.sub.3, wherein R.sub.2 and R.sub.3 are independently
selected from the group consisting of OH, and C.sub.1-C.sub.6
monohydric alcohol and C.sub.1-C.sub.6 diol or C.sub.1-C.sub.6
monohydric alcohol and C.sub.1-C.sub.6 diol which are substituted
by halogen, and wherein R.sub.2 and R.sub.3 can form a ring;
wherein the leaving group includes halogens, and sulfonyloxy.
8. The preparation method according to claim 7, wherein the
palladium catalyst is palladium chloride, palladium acetate,
bis(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine)
palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium,
dichlorobis(tricyclohexylphosphine) palladium or
dichlorobis(triphenylphosphine) palladium.
9. The preparation method according to claim 7, wherein the
reaction solvent for the coupled reaction is any one of water,
toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl
sulfoxide, dioxane, isopropanol, ethanol, or acetonitrile or any
combination thereof; and the reaction temperature is 50-120.degree.
C.
10. A compound of the chemical formula below: ##STR00061## or the
chemical formula below: ##STR00062## wherein X is a leaving group
which includes chlorine, bromine, iodine, and sulfonyloxy.
11. The preparation method according to claim 1, wherein the
sulfonyloxy is selected from the group consisting of
trifluoromethane sulfonyloxy, methanesulfonyloxy,
benzenesulfonyloxy, or benzenesulfonyloxy substituted by one or
more substituent(s) which is selected from the group consisting of
halogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy.
12. The preparation method according to claim 2, wherein the copper
catalyst is selected from the group consisting of CuI, CuBr, CuCl,
CuO, Cu.sub.2O, CuSO.sub.4, Cu(OAc).sub.2, Cu(OTf).sub.2 or Cu
powder; and/or the palladium catalyst is selected from the group
consisting of palladium chloride, palladium acetate,
bis(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine)
palladium, tris(dibenzylideneacetone) dipalladium,
dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium,
dichlorobis(tricyclohexylphosphine) palladium or
dichlorobis(triphenylphosphine) palladium.
13. The preparation method according to claim 3, wherein the
alkaline substance is selected from the group consisting of
potassium carbonate, sodium carbonate, cesium carbonate, cesium
fluoride, potassium acetate, sodium hydroxide, potassium hydroxide,
potassium phosphate or sodium phosphate.
14. The preparation method according to claim 4, wherein the
reaction temperature is 90-110.degree. C.
15. The preparation method according to claim 5, wherein the
diamine ligand is selected from the group consisting of:
##STR00063## the diketone ligand is selected from the group
consisting of: ##STR00064## the phenanthroline ligand is selected
from the group consisting of: ##STR00065## the amino acid ligand is
selected from the group consisting of: ##STR00066## and the Phos
ligand is selected from the group consisting of X-Phos, XantPhos,
RuPhos, BrettPhos, SPhos, DavePhos, JohnPhos or tBuXPhos.
16. The preparation method according to claim 6, wherein the
sulfonyloxy is selected from the group consisting of
trifluoromethane sulfonyloxy, methanesulfonyloxy,
benzenesulfonyloxy, or benzenesulfonyloxy substituted by one or
more substituent(s), and wherein the substituent is selected from
the group consisting of halogen, C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy.
17. The preparation method according to claim 7, wherein B is a
leaving group, and A is BF.sub.3 or BR.sub.2R.sub.3, wherein
R.sub.2 and R.sub.3 can be independently selected from OH, and
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol or
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol which
are substituted by halogen, and wherein R.sub.2 and R.sub.3 can
form a ring; or A is a leaving group, and B is BF.sub.3 or
BR.sub.2R.sub.3, wherein R.sub.2 and R.sub.3 can be independently
selected from OH, and C.sub.1-C.sub.6 monohydric alcohol and
C.sub.1-C.sub.6 diol or C.sub.1-C.sub.6 monohydric alcohol and
C.sub.1-C.sub.6 diol which are substituted by halo en, and wherein
R.sub.2 and R.sub.3 can form a ring.
18. The preparation method according to claim 7, wherein the
halogens are selected from the group consisting of chlorine,
bromine and iodine; and/or the sulfonyloxy is selected from the
group consisting of trifluoromethane sulfonyloxy,
methanesulfonyloxy, benzenesulfonyloxy, or benzenesulfonyloxy which
is substituted by one or more substituents, and the substituent is
selected from the group consisting of halogen, C.sub.1-C.sub.6
alkyl and C.sub.1-C.sub.6 alkoxy; and/or BR.sub.2R.sub.3 is
B(OH).sub.2 or ##STR00067##
19. The preparation method according to claim 9, wherein the
reaction solvent for the coupled reaction is toluene, water and
dioxane, or isopropanol; and/or the reaction temperature is
70-100.degree. C.
20. The compound of claim 10, wherein the sulfonyloxy is selected
from the group consisting of trifluoromethane sulfonyloxy,
methanesulfonyloxy, benzenesulfonyloxy, or benzenesulfonyloxy
substituted by one or more substituent(s) which is selected from
the group consisting of halogen, C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy; or the leaving group is bromine or iodine,
i.e. the compound of the formula below: ##STR00068##
Description
[0001] This application claims priority to Chinese patent
application No. 201510739910.6 filed with SIPO on Nov. 3, 2015,
entitled "PREPARATION METHOD FOR TEDIZOLID AND INTERMEDIATE
THEREOF", the content of which is incorporated herein by reference
in its entirety.
TECHNICAL FIELD
[0002] The invention relates to a preparation method for a novel
oxazolidinone antibiotic tedizolid or its phosphates, and its
intermediate compounds and the preparation method thereof.
BACKGROUND ART
[0003] Tadizolid phosphate has a strong antibacterial activity to
pathogens of human and animal, including gram-positive bacteria
such as Staphylococcus, Enterococcus and Streptococcus, anaerobic
microorganisms such as bacteroid and Clostridium, and acidotolerant
microorganisms such as Mycobacterium tuberculosis and Mycobacterium
avium complex. Tadizolid (formerly called torezolid) was jointly
developed by the Cubist Pharmaceuticals company (a subsidiary of
Merck Corporation) and Bayer. It was originally found as an
antibacterial drug precursor by Dong-A Pharmaceutical (Dong-A ST)
and used for the treatment of gram-positive bacterial infections.
Tedizolid is rapidly transformed into its active form TR 700 (DA
7157) in plasma.
[0004] WO2005058886A1 discloses the synthesis of
3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydro-
xymethyl)-2-oxazolidinone, wherein 3-fluoroaniline is used as raw
material and reacts with glycidyl butyrate after being protected by
Cbz to obtain compound 3. Compound 3 is then iodinated and
converted into tin reagent 5, which is Suzuki coupled with
5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine to produce the key
intermediate K. The reaction scheme is depicted as follows:
##STR00002##
[0005] The reaction procedure of the original drug of Dong-A
Pharmaceutical is long, and the total yield is not high. In terms
of cost, relatively expensive reagents such as CF.sub.3COOAg are
needed, and Pd catalyst are needed twice for respectively preparing
intermediates 5 and K in the scheme. The reaction conditions are
harsh, which is not easy for a large scale production.
[0006] Later, the synthetic scheme of the original compound was
improved by an licensee Trius Therapeutics company, in whose patent
WO2010042887, 4-bromo-3-fluoroaniline is employed as the starting
material, first to synthesize boric acid ester 10, which is then
Suzuki coupled with 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine
to generate intermediate 11. Intermediate 11 then reacts with
glycidyl butyrate to obtain the oxazolidinone intermediate K. The
reaction scheme is depicted as follows:
##STR00003##
[0007] Compared with the patented method of Dong-A Pharmaceutical,
this scheme is short in reaction procedure with an improved total
yield. However, the reaction conditions are still rather harsh.
Butyl lithium is needed, and the reaction needs to be carried out
at ultra-low temperature (-65.degree. C.). The use of n-BuLi and
LiHMDS requires strict anhydrous condition.
[0008] In addition, CN104496979A discloses a method for preparing
tedizolid, which is as depicted in the reaction scheme below:
##STR00004##
wherein R is hydrogen or a hydroxyl protective group; one of L and
R.sub.1 is a leaving group, while the other one is BF.sub.3 or
BR.sub.2R.sub.3, wherein R.sub.2 and R.sub.3 are independently
selected from a group consisting of OH, and optionally substituted
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol, and
wherein R.sub.2 and R.sub.3 can form a ring. Pd is employed in this
scheme to catalyze the synthesis of borate intermediate II. After
separation and purification, the intermediate II is Suzuki coupled
with compound I under catalysis of Pd to obtain the compound of
formula H. In this scheme, the reaction operations are complicated,
since the intermediate II needs to be separated out before Suzuki
coupling.
[0009] The methods of prior art for preparing tedizolid
intermediates all suffer from complex operation, long reaction
time, low total yield and low purity.
SUMMARY OF THE INVENTION
[0010] One purpose of the invention is to provide a preparation
method of tedizolid, which has low production cost, simple
operation, relatively high yield and high purity, and is suitable
for industrial production. In particular, the invention relates to
a novel method for preparing tedizolid by using novel
intermediates.
[0011] To achieve the above purpose, the invention provides a
method for preparing a tedizolid compound of the formula below
##STR00005## [0012] wherein R is selected from a group consisting
of hydrogen,
[0012] ##STR00006## benzyl or benzyl substituted by a substituent
(the substituent is selected from a group consisting of halogen,
nitro, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy), and
R.sub.1 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl
substituted by halogen; wherein the method comprises reacting the
compound of the formula below
##STR00007## [0013] wherein X is a leaving group (the leaving group
includes chlorine, bromine, iodine, and sulfonyloxy such as
trifluoromethane sulfonyloxy, methane sulfonyloxy,
benzenesulfonyloxy, or benzene sulfonyloxy substituted by one or
more substituents, and the substituents are selected from the group
consisting of halogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkoxy; preferably, the leaving group is chlorine, bromine or
iodine; and more preferably, the leaving group is bromine or
iodine), with the compound of the formula below
##STR00008##
[0013] by catalysis of a metal catalyst by a coupled reaction,
wherein the substituent R is as defined above.
[0014] In a preferred embodiment of the present invention, the
metal catalyst is a copper catalyst. The copper catalyst is
preferably selected from a group consisting of Cu powder, CuI,
CuBr, Cu.sub.2O, CuO, Cu.sub.2O, CuSO.sub.4, Cu(OAc).sub.2 or
Cu(OTf).sub.2, and more preferably CuI and Cu(OAc).sub.2.
[0015] In addition to using a copper catalyst alone, in some
instances, ligands are also required for the reaction. Diamine
ligands, diketone ligands, phenanthroline ligands, amino acid
ligands, or Phos ligands can be used. The diamine ligands are
preferably selected from a group consisting of:
##STR00009##
[0016] The diketone ligands are preferably selected from a group
consisting of:
##STR00010##
[0017] The phenanthroline ligands are preferably selected from a
group consisting of:
##STR00011##
[0018] The amino acid ligands are preferably selected from a group
consisting of:
##STR00012##
[0019] The Phos ligands are preferably selected from a group
consisting of: X-Phos, XantPhos, RuPhos, BrettPhos, SPhos,
DavePhos, JohnPhos and tBuXPhos.
[0020] In other embodiments of the present invention, the metal
catalyst is a palladium catalyst, such as palladium chloride,
palladium acetate, tris(dibenzylideneacetone)dipalladium,
bis(dibenzylideneacetone)palladium,
tetrakis(triphenylphosphine)palladium, dichloro
[1,1'-Bis(diphenylphosphino)-ferrocene] palladium,
dichlorobis(tricyclohexylphosphine)palladium or
dichlorobis(triphenylphosphine)palladium, and preferably,
tris-(dibenzylideneacetone)dipalladium, palladium chloride or
palladium acetate.
[0021] Generally, the reaction can be promoted in alkaline
environment (such as potassium acetate, sodium carbonate, potassium
carbonate, cesium carbonate, cesium fluoride, sodium hydroxide,
potassium hydroxide, potassium phosphate or sodium phosphate, or
the like). The solvent is selected from a group consisting of
aromatic hydrocarbons, ethers, alcohols, ethers, nitriles, amides
and the like, preferably toluene, chlorobenzene, tetrahydrofuran
(THF), N,N-dimethyl-formamide (DMF), dimethyl sulfoxide (DMSO),
dioxane, isopropanol, ethanol or acetonitrile; more preferably
N,N-dimethylformamide (DMF) and dioxane. The reaction temperature
is preferably 60-110.degree. C., and more preferably 90-110.degree.
C.
[0022] When being not
##STR00013##
the protective group R can be optionally removed (where R is as
defined above, excluding hydrogen), to obtain the compound of the
formula below:
##STR00014##
[0023] The compound of the formula above can be further
phosphorylated to obtain tedizolid phosphate of the formula
below:
##STR00015##
[0024] The invention also provides a preparation method of a novel
tedizolid intermediate of the formula below:
##STR00016## [0025] wherein X is a leaving group as defined above;
wherein the method includes reacting the compound of the formula
below
[0025] ##STR00017## [0026] wherein C is hydroxyl group or amino
group; 1) with sulfochloride compounds (such as trifluoroformic
anhydride, methanesulfonyl chloride or benzenesulfonyl chloride, or
the like), when C is hydroxyl, to obtain the compound of the
formula below:
[0026] ##STR00018## [0027] wherein X is a leaving group (the
leaving group is sulfonyloxy such as trifluoromethane sulfonyloxy,
methanesulfonyloxy, benzenesulfonyloxy, or benzenesulfonyloxy
substituted by one or more substituents, and the substituents are
selected from a group consisting of halogen, C.sub.1-C.sub.6 alkyl
and C.sub.1-C.sub.6 alkoxy); [0028] in this circumstance, addition
of alkaline substances, such as potassium carbonate, sodium
carbonate, cesium carbonate, cesium fluoride, potassium acetate,
sodium hydroxide, potassium hydroxide, potassium phosphate, sodium
phosphate, or the like, can promote the reaction. 2) to obtain
diazonium compounds in the presence of sodium nitrite, when C is
amino group, and the diazonium compounds are then substituted by
halogen ions to form the compound with of a structure of the
formula below:
[0028] ##STR00019## [0029] wherein X is a leaving group, which is
selected from a group consisting of chlorine, bromine and iodine;
[0030] in this circumstance, under acidic conditions such as in the
presence of acetic acid, methanesulfonic acid, hydrochloric acid,
sulfuric acid or camphosulfonic acid, it is reacted with sodium
nitrite to form diazonium. Diazonium is then substituted by halogen
ions to obtain the compound of the formula above. Donors of the
halogen ions can be chlorine, bromine or iodine. Taking iodine as
an example, the donors may include iodine element or Iodide salt
such as sodium iodide, potassium iodide, or the like.
[0031] The invention also provides a method for preparing a novel
tedizolid intermediate, i.e. the compound of the formula below:
##STR00020##
wherein the method includes reacting the compound of the formula
below
##STR00021##
with the compound of the formula below
##STR00022##
by catalysis of palladium catalyst by a coupled reaction, wherein C
is a hydroxyl or amino group; one of A and B is a leaving group,
and the other one is BF.sub.3 or BR.sub.2R.sub.3, wherein R.sub.2
and R.sub.3 are independently selected from a group consisting of
OH and C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol
or C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol
substituted by halogen, and wherein R.sub.2 and R.sub.3 can form a
ring.
[0032] In one embodiment, preferably A is a leaving group, B is
BF.sub.3 or BR.sub.2R.sub.3, wherein R.sub.2 and R.sub.3 can be
independently selected from a group consisting of OH and
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol or
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol
substituted by halogen, and wherein R.sub.2 and R.sub.3 can form a
ring.
[0033] In another embodiment, preferably B is a leaving group, A is
BF.sub.3 or BR.sub.2R.sub.3, wherein R.sub.2 and R.sub.3 can be
independently selected from a group consisting of OH and
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol or
C.sub.1-C.sub.6 monohydric alcohol and C.sub.1-C.sub.6 diol
substituted by halogen, and wherein R.sub.2 and R.sub.3 can form a
ring.
[0034] The leaving groups include halogens such as chlorine,
bromine, or iodine, and sulfonyloxy such as trifluoromethane
sulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, or
benzenesulfonyloxy substituted by one or more substituents, and the
substituents are selected from a group consisting of halogen,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy; preferably the
leaving group is chlorine, bromine or iodine; and more preferably
the leaving group is bromine or iodine.
[0035] Preferably, BR.sub.2R.sub.3 is B(OH).sub.2 or
##STR00023##
[0036] In one embodiment, C is a hydroxyl or amino group;
preferably B is bromine or iodine, and A is BF.sub.3, B(OH).sub.2
or
##STR00024##
[0037] In an embodiment, the catalyst for reaction is palladium
catalyst. The palladium catalyst is palladium chloride, palladium
acetate, bis(dibenzylideneacetone) palladium,
tetrakis(triphenylphosphine) palladium,
dichloro[1,1'-bis-(diphenylphosphino)ferrocene] palladium,
dichlorobis(tricyclohexylphosphine) palladium or
dichlorobis(triphenylphosphine) palladium, or the like.
[0038] The reaction can be promoted in the presence of alkaline
substances, such as potassium carbonate, sodium carbonate, cesium
carbonate, cesium fluoride, potassium acetate, sodium hydroxide,
potassium hydroxide, potassium phosphate or sodium phosphate. The
solvent can be a combination of one or more selected from the group
consisting of water, toluene, tetrahydrofuran (THF),
N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
1,4-dioxane, isopropanol, ethanol, acetonitrile, or the like, and
preferably toluene, water and dioxane, or isopropanol. The reaction
temperature is preferably 50-120.degree. C., and more preferably
70-100.degree. C.
[0039] In another embodiment, C is a hydroxyl or amino group; and
preferably A is bromine or iodine, and B is BF.sub.3, B(OH).sub.2
or
##STR00025##
[0040] In one embodiment, the reaction is carried out preferably in
the presence of palladium catalyst. The solvent is preferably water
and dioxane, and the reaction temperature is about 60-80.degree. C.
Then the tedizolid intermediate compound below is prepared:
##STR00026##
[0041] The invention also provides a novel tedizolid intermediate,
i.e. the compound of the chemical formula below:
##STR00027##
or the compound of the chemical formula below:
##STR00028##
wherein X is a leaving group (the leaving group includes chlorine,
bromine, iodine, and sulfonyloxy such as trifluoromethane
sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, or benzene
sulfonyloxy substituted by one or more substituents selected from
the group consisting of halogen, C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy); preferably the leaving group is bromine or
iodine. The compound is preferably as follows:
##STR00029##
[0042] The invention achieves the following technical effects: by
comparison with the prior art, the present invention provides a
novel method for preparing tedizolid, having the advantages of
material availability, low cost, a high yield for each step, simple
process, easy operation and environmental friendliness, economical
efficiency and being conducive to industrial production. The
preparation method of the present invention involves the use of a
key intermediate 5-(4-substituent
group-2-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine which
allows the preparation scheme of tedizolid being carried out.
DETAILED DESCRIPTION OF THE INVENTION
Examples
[0043] In order to make the technical problems solved by the
invention, the technical solutions and the beneficial effects more
clearly, the invention will be further illustrated in combination
with specific examples. The specific examples given are preferred
examples of the invention.
[0044] Experiments and Data Analysis
[0045] Reagents are purchased from commercial sources and they are
directly used without treatment. .sup.1H-NMR spectra were measured
on a Bruker AVANCE 400 spectrometer operating at 400 MHz. MS data
were recorded by Agilent HPLC 1260 Infinity and 6120 Duadrupole
LC/MS.
Example 1: Preparation of
2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridine
##STR00030##
[0046] 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 1
eq), bis(pinacolato)-diboron (42.3 g, 2.0 eq), potassium acetate
(24.5 g, 3.0 eq) and toluene (400 mL) were added into a
three-necked flask equipped with agitator and thermometer. After
purging with N.sub.2, Pd(dppf)Cl.sub.2 (0.6 g, 3% w/w) was added,
followed by purging with N.sub.2 again, and the mixture was reacted
under stirring at 80-85.degree. C. for 12 h. The completion of the
reaction was monitored by HPLC. The reaction liquid was cooled to
40-50.degree. C., suction filtered at this temperature. 5 g
activated carbon was added to the filtrate. The mixture was then
heated to 70-80.degree. C. under stirring for 1-2 h for
decoloration, cooled to 40-50.degree. C., and suction filtered at
this temperature. The obtained filtrate was distillated under
reduced pressure to 40-60 mL, cooled to 10-15.degree. C. to
separate out white solid. The white solid was filtered and the
filter cake was oven dried at 50.degree. C. to obtain 19.5 g white
solid product with a yield of 81.5% and an HPLC purity of 98.5%.
LCMS[M+H]=288.1, NMR(CDCl.sub.3, 400 MHz): 9.15 (t, 1H), 8.22 (m,
2H), 4.44 (s, 3H), 1.25 (s, 12H).
Example 2: Preparation of
3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)-aniline
##STR00031##
[0047]
2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)pyridine (50 g, 1 eq), 4-bromo-3-fluoroaniline (36.4 g,
1.1 eq), Na.sub.2CO.sub.3 (36.9 g, 2.0 eq), water (300 mL) and
dioxane (1000 mL) were added into a three-necked flask equipped
with agitator and thermometer. After purging with N.sub.2,
Pd(dppf)Cl.sub.2 (1.5 g, 3% w/w) was added, followed by purging
with N.sub.2 again, and the mixture was reacted under stirring at
70-80.degree. C. for 12 h. The completion of the reaction was
monitored by HPLC. The mixture obtained was distilled under reduced
pressure to remove most of the dioxane, added with 500 mL water,
stirred at room temperature for 2-3 h; and then filtered. The
filter cake was pulped with ethanol (100 mL), and then filtered.
The obtained filter cake was oven dried at 50.degree. C. to obtain
42.3 g offwhite solid products with a yield of 90% and an HPLC
purity of 99.1%. LCMS[M+H]=271.0, NMR (DMSO-d6, 400 MHz): 9.01 (t,
1H), 8.54 (s, 2H), 8.18 (m, 2H), 7.75 (t, 1H), 7.59 (d, 1H), 7.29
(d, 1H), 4.41 (s, 3H).
Example 3: Preparation of
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
##STR00032##
[0048] 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)
pyridin-3-yl)aniline (30.0 g, 1 eq) and acetic acid (600 mL) were
added into a three-necked flask equipped with agitator and
thermometer, and dissolved under stirring at room temperature.
Then, camphorsulfonic acid (30.9 g, 1.2 eq), potassium iodide (36.9
g, 2.0 eq) and sodium nitrite (9.2 g, 1.2 eq) were successively
added. The mixture obtained was stirred for 16 h at room
temperature. The completion of the reaction was monitored by HPLC.
The mixture obtained was distilled under reduced pressure to remove
most of the acetic acid, then added with 300 mL water and 500 mL
dichloromethane, stirred and separated. The dichloromethane layer
was washed with water, and then distilled under reduced pressure to
remove solvent. 20.8 g brown solid product was obtained with a
yield of 49% and an HPLC purity of 96.7%. LCMS[M+H]=381.9, NMR
(DMSO-d6, 400 MHz): 8.85 (s, 1H), 8.28 (d, 1H), 8.01 (d, 1H), 7.65
(t, 1H), 7.56 (dd, 1H), 7.19 (d, 1H), 4.42 (s, 3H).
Example 4: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00033##
[0049]
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
(50.0 g, 1 eq), (R)-5-(hydroxymethyl)oxazolidin-2-one (23.0 g, 1.5
eq), cyclohexanediamine (1.5 g, 0.1 eq), cuprous iodide (1.3 g,
0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL)
were added into a three-necked flask equipped with agitator and
thermometer. After purging with N.sub.2, the mixture obtained was
reacted under stirring at 100-110.degree. C. for 16 h. The
completion of the reaction was monitored by HPLC. The mixture
obtained was distilled under reduced pressure to remove most of the
solvent. 1000 mL water was added into the residues, heated to
reflux for 1-2 h, then cooled to 70.degree. C., and suction
filtered. The filter cake was pulped with DMF (150 mL) for 2 h, and
then filtered. The filter cake was pulped again with water (300 mL)
and then filtered. The filter cake was oven dried at 65.degree. C.
to obtain offwhite solid products with a yield of 79.2% and an HPLC
purity of 97.9%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s,
1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10
(d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m,
2H), 3.01 (m, 1H).
Example 5: Preparation of
3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenol
##STR00034##
[0050]
2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)pyridine (25 g, 1 eq), 4-bromo-3-fluorophenol (19.9 g,
1.2 eq), Na.sub.2CO.sub.3 (18.5 g, 2.0 eq), water (120 mL) and
dioxane (600 mL) were added into a three-necked flask equipped with
agitator and thermometer. After purging with N.sub.2,
Pd(dppf)Cl.sub.2 (0.75 g, 3% w/w) was added, followed by purging
with N.sub.2 again, and the mixture was reacted under stirring at
70-80.degree. C. for 12 h. The completion of the reaction was
monitored by HPLC. The mixture was distilled under reduced pressure
to remove most of the dioxane. 500 mL water was added, stirred at
room temperature for 2-3 h, and then filtered. The filter cake was
pulped with isopropanol (70 mL). The mixture obtained was filtered,
and the filter cake was oven dried at 50.degree. C. to obtain 18.2
g white solid product with a yield of 77% and an HPLC purity of
99.5%. LCMS[M+H]=272.0, NMR (DMSO-d6, 400 MHz): 10.20 (s, 1H), 9.11
(s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.75 (t, 1H), 7.59 (d, 1H),
7.29 (d, 1H), 4.39 (s, 3H).
Example 6: Preparation of
3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl
trifluoromethanesulfonate
##STR00035##
[0051] 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenol
(15 g, 1 eq), trifluoromethanesulfonic anhydride (23.4 g, 1.5 eq),
pyridine (6.6 g, 1.5 eq), and tetrahydrofuran (150 mL) were added
into a three-necked flask equipped with agitator and thermometer.
After purging with N.sub.2, the mixture obtained was heated to
reflux and react for 5 h under stirring. The completion of the
reaction was monitored by HPLC. The mixture obtained was distilled
under reduced pressure to remove most of the tetrahydrofuran. Then,
100 mL ethyl acetate and 100 mL water were added, and stirred at
room temperature. Liquids were separated. The organic phase was
dried and distilled to remove solvent. 20.0 g white solid product
was obtained with a yield of 90% and an HPLC purity of 96.3%.
LCMS[M+H]=403.9, NMR (DMSO-d6, 400 MHz): 9.12 (s, 1H), 8.44 (d,
1H), 8.08 (d, 1H), 7.85 (t, 1H), 7.67 (d, 1H), 7.28 (d, 1H), 4.33
(s, 3H).
Example 7: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00036##
[0052] 3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl
trifluoromethanesulfonate (10.0 g, 1 eq),
(R)-5-(hydroxymethyl)oxazolidin-2-one (3.8 g, 1.3 eq),
Pd(dppf)Cl.sub.2 (300 mg, 3% w/w), XantPhos (300 mg, 3% w/w),
potassium carbonate (6.9 g, 2.0 eq) and dioxane (80 mL) were added
into a three-necked flask equipped with agitator and thermometer.
After purging with N.sub.2, the mixture obtained was reacted under
stirring at 100-110.degree. C. for 16 h. The completion of the
reaction was monitored by HPLC. The mixture obtained was distilled
under reduced pressure to remove most of the solvent. The residue
was added with 100 mL water, heated to reflux for 1-2 h, cooled to
70.degree. C., and filtered under reduced pressure. the filter cake
was pulped with DMF (150 mL) for 2 h. The obtained mixture was
filtered, and the filter cake was pulped with water (150 mL) again.
The obtained mixture was filtered, and the filter cake was oven
dried at 65.degree. C. to obtain 6.1 g offwhite solid product with
a yield of 66% and an HPLC purity of 96.9%. LCMS[M+H]=371.1, NMR
(DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78
(t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H),
3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).
Example 8: Preparation of Tedizolid Phosphate
##STR00037##
[0053]
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl-
)-5-(hydroxy methyl)-oxazolidin-2-one (10.0 g, 1 eq) and
tetrahydrofuran (200 mL) were added into a three-necked flask
equipped with agitator and thermometer. After purging with N.sub.2,
the mixture obtained was cooled to 0.degree. C. Triethylamine (8.2
g, 3 eq) was added dropwise. Phosphorus oxychloride was added
dropwise at 0-10.degree. C. under stirring. After the addition was
completed, the reaction mixture was warmed to room temperature
slowly and reacted for 20 h. The completion of the reaction was
monitored by HPLC. The reaction liquid was added into 100 mL ice
water dropwise slowly, stirred overnight, and filtered. The solid
product was washed with 50 mL to obtain filter cake. The filter
cake was oven dried at 65.degree. C. for 20 h and obtained crude
white solid, which was then pulped with 40 mL methanol, and
filtered. The filter cake was oven dried at 65.degree. C. to obtain
6.8 g pure product of white solid with a yield of 56% and an HPLC
purity of 99.7%. LCMS[M+H]=451.1, NMR (DMSO-d6, 400 MHz): 8.95 (s,
1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10
(d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m,
2H), 3.01 (m, 1H).
Example 9: Preparation of
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
##STR00038##
[0054] 4-bromo-3-fluoroaniline (50.0 g, 1 eq),
bis(pinacolato)diboron (100.2 g, 1.5 eq), potassium acetate (77.5
g, 3.0 eq) and toluene (500 mL) were added into a three-necked
flask equipped with agitator and thermometer. After purging with
N.sub.2, Pd(dppf)Cl.sub.2 (1.5 g, 3% w/w) was added, followed by
purging with N.sub.2 again, and the mixture was reacted under
stirring at 80-85.degree. C. for 8 h. The completion of the
reaction was monitored by HPLC. The reaction liquid was cooled to
40-50.degree. C., and filtered under reduced pressure at this
temperature. 10 g activated carbon was added to the filtrate. The
filtrate was heated to 70-80.degree. C. under stirring for 1-2 h
for decoloration, then cooled to 40-50.degree. C., and filtered
under reduced pressure at this temperature. The filtrate was
distilled under reduced pressure to 80-100 mL, cooled to
10-15.degree. C. to separate out white solid, and filtered. The
filter cake was oven dried at 50.degree. C. to obtain 54 g white
solid product with a yield of 87% and an HPLC purity of 98.9%.
LCMS[M+H]=238.1, NMR (DMSO-d6, 400 MHz): 7.51 (d, 1H), 7.02 (s,
1H), 6.87 (d, 1H), 6.51 (s, 2H), 1.25 (s, 12H).
Example 10: Preparation of
3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)aniline
##STR00039##
[0055]
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)aniline (15
g, 1 eq), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (18.2 g,
1.2 eq), Na.sub.2CO.sub.3 (13.4 g, 2.0 eq), water (60 mL) and
dioxane (300 mL) were added into a three-necked flask equipped with
agitator and thermometer. After purging with N.sub.2,
Pd(dppf)Cl.sub.2 (450 mg, 3% w/w) was added, followed by purging
with N.sub.2 again. The mixture was reacted under stirring at
70-80.degree. C. for 12 h. The completion of the reaction was
monitored by HPLC. The obtained mixture was distilled under reduced
pressure to remove most of the dioxane, added with 150 mL water,
stirred at room temperature for 2-3 h, and filtered. The filter
cake was pulped with ethanol (80 mL). The mixture obtained was
filtered, and the filter cake was oven dried at 50.degree. C. to
obtain 14.8 g offwhite solid product with a yield of 87% and an
HPLC purity of 98.3%. LCMS[M+H]=271.0, NMR (DMSO-d6, 400 MHz): 9.01
(t, 1H), 8.54 (s, 2H), 8.18 (m, 2H), 7.75 (t, 1H), 7.59 (d, 1H),
7.29 (d, 1H), 4.41 (s, 3H).
Example 11: Preparation of
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
##STR00040##
[0056] 4-Bromo-3-fluorophenol (30.0 g, 1 eq),
bis(pinacolato)diboron (59.8 g, 1.5 eq), potassium acetate (46.3 g,
3.0 eq) and toluene (300 mL) were added into a three-necked flask
equipped with agitator and thermometer. After purging with N.sub.2,
Pd(dppf)Cl.sub.2 (0.9 g, 3% w/w) was added, followed by purging
with N.sub.2 again, and the mixture was reacted under stirring at
80-85.degree. C. for 8 h. The completion of the reaction was
monitored by HPLC. The reaction liquid was cooled to 40-50.degree.
C., filtered under reduced pressure at this temperature. 10 g
activated carbon was added to the filtrate. The filtrate was heated
to at 70-80.degree. C. under stirring for 1-2 h for decoloration,
then cooled to 40-50.degree. C., and filtered under reduced
pressure at this temperature. The filtrate was distilled under
reduced pressure to 60-80 mL, cooled to 0-10.degree. C. to separate
out white solid, and filtered. The filter cake was oven dried at
50.degree. C. to obtain 29.8 g white solid product with a yield of
80% and an HPLC purity of 99.5%. LCMS[M+H]=239.0, NMR (DMSO-d6, 400
MHz): 10.50 (s, 1H), 7.65 (d, 1H), 7.42 (s, 1H), 7.01 (d, 1H), 1.26
(s, 12H).
Example 12: Preparation of
3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenol
##STR00041##
[0057] 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenol
(18.0 g, 1 eq), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (21.8
g, 1.2 eq), Na.sub.2CO.sub.3 (16.0 g, 2.0 eq), water (54 mL) and
dioxane (270 mL), were added into a three-necked flask equipped
with agitator and thermometer. After purging with N.sub.2,
Pd(dppf)Cl.sub.2 (540 mg, 3% w/w) was added, followed by purging
with N.sub.2 again, and the mixture was reacted under stirring at
70-80.degree. C. for 12 h. The completion of the reaction was
monitored by HPLC. The obtained mixture was distilled under reduced
pressure to remove most of the dioxane, added with 300 mL water,
stirred at room temperature for 2-3 h, and filtered. The filter
cake was pulped with isopropanol (90 mL). The obtained mixture was
filtered, and the filter cake was oven dried at 50.degree. C. to
obtain 16.0 g white solid product with a yield of 78% and an HPLC
purity of 98.9%. LCMS[M+H]=272.0, NMR (DMSO-d6, 400 MHz): 10.20 (s,
1H), 9.11 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.75 (t, 1H), 7.59
(d, 1H), 7.29 (d, 1H), 4.39 (s, 3H).
Example 13: Preparation of (R)-2-((benzyloxy)methyl)ethylene
oxide
##STR00042##
[0058] Benzyl alcohol (50 g, 1 eq), potassium hydroxide aqueous
solution 300 mL (50% w/w), TBAB (14.9 g, 0.1 eq) and
dichloromethane (300 mL) were added into a three-necked flask
equipped with agitator and thermometer, and cooled to 0-10.degree.
C. Epoxy chloropropane (64.2 g, 1.5 eq) was added dropwise slowly.
After the addition was completed, the mixture obtained was warmed
to room temperature and reacted for 16 h. The completion of the
reaction was monitored by HPLC. The stir was stopped and the
liquids were separated. The aqueous phase was extracted once with
300 mL dichloromethane; and the organic phases were combined and
directly used in the next step without purification.
Example 14: Preparation of (R)-1-amino-3-(benzyloxy)isopropanol
##STR00043##
[0060] A solution of (R)-2-((benzyloxy)methyl)oxirane in
dichloromethane and 100 mL aqueous ammonia were added into a
hydrogenated bottle equipped with agitator, heated to 35.degree. C.
after sealing, stirred and reacted for 16 h. The completion of the
reaction was monitored by HPLC. The stir was stopped, and 300 mL
water was added, and stirred. The liquids were separated. The
organic phase was washed with 0.1M HCl solution (100 mL), and
dichloromethane was separated and discarded. The aqueous phase was
adjusted with NaOH to pH 9-10, extracted with (300 mL)
dichloromethane and concentrated to obtain 55.0 g colorless liquid
product, with a two-step yield of 66% and an HPLC purity of 98.4%.
LCMS[M+H]=182.0, NMR (DMSO-d6, 400 MHz): 7.42-7.25 (m, 5H), 5.11
(s, 2H), 4.54 (s, 2H), 3.68 (m, 1H), 3.50-3.34 (m, 2H), 3.12-3.06
(br, 1H), 3.00-2.89 (m, 2H).
Example 15: Preparation of
(R)-5-((benzyloxy)methyl)oxazolidin-2-one
##STR00044##
[0061] (R)-1-amino-3-(benzyloxy)isopropanol (20 g, 1 eq) and
tetrahydrofuran (200 mL) were added into a three-necked flask
equipped with agitator, heated to 35.degree. C., added with CDI
(26.8 g, 1.5 eq). The obtained mixture was stirred and reacted for
16 h while keeping the temperature. The completion of the reaction
was monitored by HPLC. The stir was stopped and the
tetrahydrofuran-containing solution was concentrated. 200 mL ethyl
acetate and 100 mL 1M hydrochloric acid were added, and stirred.
The liquids were separated. The organic phase was washed with water
and the ethyl acetate-containing phase was concentrated to obtain a
colorless liquid product 21.0 g with yield of 92% and HPLC purity
of 99.0%. LCMS[M+H]=208.0, NMR (DMSO-d6, 400 MHz): 8.05 (s, 1H),
7.44-7.22 (m, 5H), 4.56 (s, 2H), 4.28-4.20 (m, 1H), 3.77-3.69 (m,
1H), 3.42-3.29 (m, 2H), 3.11-3.06 (m, 1H).
Example 16: Preparation of
(R)-5-(hydroxymethyl)oxazolidin-2-one
##STR00045##
[0062] (R)-5-((benzyloxy)methyl)oxazolidin-2-one (15 g, 1 eq),
tetrahydrofuran (150 mL) and Pd/C (1.5 g, 10% w/w) were added into
a three-necked flask equipped with agitator. After purging with
H.sub.2, the mixture obtained was heated to 45.degree. C., stirred
and reacted for 3 h by keeping this temperature. The completion of
the reaction was monitored by HPLC. The mixture obtained was
filtered without stir to remove Pd/C. The
tetrahydrofuran-containing phase was concentrated to obtain 8.4 g
colorless oil product with a yield of 99% and an HPLC purity of
98.6%. LCMS[M+H]=117.9, NMR (DMSO-d6, 400 MHz): 7.92 (s, 1H),
4.68-4.60 (m, 1H), 3.97-3.90 (m, 1H), 3.70 (br, 1H), 3.62-3.55 (m,
2H), 3.11-3.06 (m, 1H).
Example 17: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00046##
[0063]
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
(50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5
eq), cyclohexanediamine (1.5 g, 0.1 eq), copper sulfate (1.05 g,
0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL)
were added into a three-necked flask equipped with agitator and
thermometer. The mixture obtained was stirred and reacted at
100-110.degree. C. for 16 h. The completion of the reaction was
monitored by HPLC. The mixture obtained was distilled under reduced
pressure to remove most of the solvent. 1000 mL water was added
into the residue, heated to reflux for 1-2 h, then cooled to
70.degree. C., and filtered under reduced pressure. The filter cake
was pulped with DMF (150 mL) for 2 h. The mixture obtained was
filtered, and the filter cake was pulped with water (300 mL) again.
The mixture obtained was filtered; the filter cake was oven dried
at 65.degree. C. to obtain 36.3 g offwhite solid product with a
yield of 74.7% and an HPLC purity of 98.3%. LCMS[M+H]=371.1, NMR
(DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78
(t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H),
3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m, 1H).
Example 18: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00047##
[0064]
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
(50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5
eq), cyclohexanediamine (1.5 g, 0.1 eq), Cu(OAc).sub.2 (1.19 g,
0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and dioxane (500 mL)
were added into a three-necked flask equipped with agitator and
thermometer. After purging with N.sub.2, the mixture obtained was
stirred and reacted at 100-110.degree. C. for 16 h. The completion
of the reaction was monitored by HPLC. The mixture obtained was
distilled under reduced pressure to remove most of the solvent.
1000 mL water was added into the residue, heated to reflux for 1-2
h, cooled to 70.degree. C., and filtered under reduced pressure.
The filter cake was pulped with DMF (150 mL) for 2 h. The mixture
obtained was filtered; and the filter cake was pulped with water
(300 mL) again. The mixture obtained was filtered; and the filter
cake was oven dried at 65.degree. C. to obtain 39.9 g offwhite
solid products with a yield of 82.1% and an HPLC purity of 97.8%.
LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d,
1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62
(m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m,
1H).
Example 19: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00048##
[0065]
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
(50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5
eq), cyclohexanediamine (1.5 g, 0.1 eq),
tris(dibenzylideneacetone)dipalladium (1.5 g, 3% w/w), potassium
carbonate (36.3 g, 2.0 eq) and dioxane (500 mL) were added into a
three-necked flask equipped with agitator and thermometer. The
mixture obtained was stirred and reacted at 100-110.degree. C. for
16 h. The completion of the reaction was monitored by HPLC. The
mixture obtained was distilled under reduced pressure to remove
most of the solvent. 1000 mL water was added into the residue,
heated to reflux for 1-2 h, cooled to 70.degree. C., and filtered
under reduced pressure. The filter cake was pulped with DMF (150
mL) for 2 h. The mixture obtained was filtered; and the filter cake
was pulped with water (300 mL) again. The mixture obtained was
filtered; and the filter cake was oven dried at 65.degree. C. to
obtain 36.7 g offwhite solid product with a yield of 75.5% and an
HPLC purity of 98.0%. LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95
(s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H),
7.10 (d, 1H), 4.62 (m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35
(m, 2H), 3.01 (m, 1H).
Example 20: Preparation of
(R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridyl-3-yl)phenyl)-5-(h-
ydroxymethyl)oxazolidin-2-one
##STR00049##
[0066]
5-(2-fluoro-4-iodophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine
(50.0 g, 1 eq), (R)-5-(hydroxymethyl) oxazolidin-2-one (23.0 g, 1.5
eq), cyclohexanediamine (1.5 g, 0.1 eq), cuprous iodide (1.3 g,
0.05 eq), potassium carbonate (36.3 g, 2.0 eq) and DMF (500 mL)
were added into a three-necked flask equipped with agitator and
thermometer. After purging with N.sub.2, the mixture obtained was
stirred and reacted at 100-110.degree. C. for 16 h. The completion
of the reaction was monitored by HPLC. The mixture obtained was
distilled under reduced pressure to remove most of solvent. 1000 mL
water was added into the residue, heated to reflux for 1-2 h,
cooled to 70.degree. C., and filtered under reduced pressure. The
filter cake was pulped with DMF (150 mL) for 2 h. The mixture
obtained was filtered; and the filter cake was pulped with water
(300 mL) again. The mixture obtained was filtered; and the filter
cake was oven dried at 65.degree. C. to obtain 36.9 g offwhite
solid product with a yield of 76.0% and an HPLC purity of 99.5%.
LCMS[M+H]=371.1, NMR (DMSO-d6, 400 MHz): 8.95 (s, 1H), 8.24 (d,
1H), 8.10 (d, 1H), 7.78 (t, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 4.62
(m, 1H), 4.42 (s, 3H), 3.84 (m, 1H), 3.42-3.35 (m, 2H), 3.01 (m,
1H).
[0067] The description above was only preferred embodiments of the
present invention, which is not limited thereto. Any modification,
substitution and improvement made within the spirit and scope of
the present invention should fall into the scope claimed by the
present invention.
* * * * *