CN101341150A - Nitroimidazole compounds - Google Patents

Nitroimidazole compounds Download PDF

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Publication number
CN101341150A
CN101341150A CNA2006800480549A CN200680048054A CN101341150A CN 101341150 A CN101341150 A CN 101341150A CN A2006800480549 A CNA2006800480549 A CN A2006800480549A CN 200680048054 A CN200680048054 A CN 200680048054A CN 101341150 A CN101341150 A CN 101341150A
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group
halogen
low
compound
replaced
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J·基里塞克
S·帕特尔
T·H·凯勒
C·E·巴里三世
C·S·多德
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Novartis AG
US Department of Health and Human Services
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Novartis AG
US Department of Health and Human Services
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Abstract

The present invention relates to certain nitroimidazole compounds, which have interesting pharmaceutical properties. In particular, the compounds are useful in the treatment and/or prevention of infections such as those caused by Mycobacterium tuberculosis, Trypanosoma cruzi or Leishmania donovani. The invention also relates to pharmaceutical compositions containing the compounds, as well as processes for their preparation.

Description

Nitroimidazole compound
Technical field
The present invention relates to nitroimidazole compound, they the preparation method, they are as the purposes of medicine and the pharmaceutical composition that comprises them.
Background technology
Tuberculosis (TB), one of the most ancient disease known to the mankind, (Mycobacterium tuberculosis) (MTB) causes by the bacterium mycobacterium tuberculosis.This disease is communicable, as common influenza, and can be easily because of coughing and sneezing and pass through airborne transmission.At present, MTB has infected 1/3rd of world population, and it occupies AIDS (AIDS) afterwards, is the second largest reason of grownup because of communicate illness death, and tubercular's death is just arranged per 15 seconds.Recent two decades, TB disease are active once again, particularly in picture South East Asia and the area, Africa on the south the Sahara.
First kind of effective antitubercular agent, Streptomycin sulphate is to find nineteen forty-six.Yet because of the development of bacterial drug resistance, it is invalid that monotherapy becomes very soon.Along with more antimycobacterial drugs are found, can suppress chemical sproof appearance with the combination therapy of two or more medicines.Up-to-date anti-TB medicine, Rifampin is to find the sixties in 19th century.Nearest 30 years, there is not discovery to have the tuberculosis medicine of new binding mode.Present treatment to TB is effectively but relates to multiple medicine.Here it is begins to treat two months with Rimactazid, pyrazinoic acid amide and Tibutol, then treats 4 months with Rifampin and vazadrine again.The main drawback of this treatment plan is that treatment time is long, the challenge that this makes the patient face compliance and thoroughly implement this treatment plan.TB patient above 2/3rds can not obtain fully and TB treatment completely, and this just causes high recurrence rate and drug-fast appearance.At present, about 4% TB case is multidrug resistance (MDR) in the world wide, promptly to vazadrine and Rifampin tolerance.MDR-TB is difficult to cure, and its treatment time reaches 2 years, and the mortality height.Need new TB medicine badly, to shorten treatment time and to treat the TB of multidrug resistance in more effective mode.
Leishmaniasis is caused that by one of more than 20 kinds of parasitic protozoas these protozoons belong to Leishmania (Leishmania) and belong to, and leishmaniasis can be propagated by female Phlebotomus bite.Leishmaniasis is the endemy that comprises about 88 countries of many torrid zones and subtropical zone.
The leishmaniasis that four principal foum is arranged.Visceral leishmaniasis also is called kala-azar, is the most serious a kind of form, and (leishmania donovani) causes by the parasite Leishmania donovani.Suffer from the patient of visceral leishmaniasis, unless treated, otherwise can be dead in some months.Two kinds of main methods of treatment of visceral leishmaniasis are antimony derivative sodium stibogluconate (Pentostam
Figure A20068004805400091
) and meglumine antimonate (Glucantim ).Sodium stibogluconate has been used about 70 years, and the resistance of this medicine is become serious day by day problem.In addition, this treatment needs the long relatively time and is painful, can cause undesirable side effect.
Cha Jiasi (Chagas) sick (being also referred to as American trypanosomiasis) is another kind of human parasitosis, and it is the endemy in the poor population of American continent.This disease causes that by protozoon parasite Oswaldocruzia (Trypanosoma cruzi) it is propagated to the mankind by hematophagous bug.There are two kinds of periods in this human diseases: acute phase, infect the back and take place at once; And chronic phase, it is through slowly development for many years.Chronic infection cause various neurological disorders comprise dementia, to the infringement of cardiac muscle, digestive tube expansion and weight saving occur sometimes.Do not treat, this chronic disease is normally fatal.
The medicine that is currently available for the treatment chagas disease is nifurtimox and Rochagan.Yet the problem that these current treatments exist needs medical supervision during comprising their disadvantageous side effects, treatment phase length and treatment.In addition, treat at acute phase of disease, treatment is only really effectively.Opposing to these two kinds of front medicines has appearred.Suggestion with anti-mycotic agent amphotericin b as the two wires medicine, but this drug price is expensive and be deleterious relatively.
Therefore, also need to improve the new drug of the current treatment of leishmaniasis and chagas disease.
WO 97/01562 discloses many nitroimidazole compounds, PA-824 especially, and it can be used for treating TB.Yet PA-824 has the tablet formulation (because its solubleness is low) of expensive synthetic route, complexity, and needs further to improve effectiveness.
The purpose of this invention is to provide improved compound, it is suitable for pharmaceutical use, preferably has simple synthetic route, and has improved performance for effectiveness, solvability and stability.
Be surprisingly found out that nitroimidazole compound of the present invention has the advantageous feature for pharmaceutical use.
Summary of the invention
On the one hand, the invention provides formula (I) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400101
Wherein:
(a) m is 0;
W is that O and V do not exist;
One of R1 and R3 are halogenated aryls, and another is H; And
R2 and R4 are H;
Or:
(b) m is 1;
W is N, and V is alkylaryl, and it is optional to be replaced by one or more alkoxy substituents;
R1 and R3 are H; And
One of R2 and R4 are alkoxyl groups, and another is H;
Or:
(c) m is 1;
W is that O and V do not exist;
One of R1 and R3 are alkyl or aryls, and another is H; And
R2 and R4 are H;
Or:
(d) m is 1;
W is O, and V does not exist;
One of R2 and R4 are-L (B) n-(Z) p,-(L-B) q-(Z) pOr-Y-(B) q-Z, and another is H;
And
R1 and R3 are H;
Wherein, L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; N is 1 or 2; And Z is halogen, the low alkyl group that is replaced by halogen at least, the lower alkoxy that is replaced by a halogen at least or the rudimentary sulfane base that is replaced by a halogen at least;
And Y is-NHC (O)-;
N is 1 or 2; P is 0,1 or 2; Q is 1 or 2;
Prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 be-(L-B) q-(Z) p, wherein q is that 2, two B groups all are that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then Z is not 4-trifluoromethoxy, 4-fluoro, 4-trifluoro ethoxy, 4-five fluorine propoxy-, 4-tetrafluoro propoxy-, 4-trifluoromethyl, 2,4-difluoromethyl or 2,4-two fluoro.
Compound is preferably as above-mentioned (d) defined formula (I) compound.
When compound is during as above-mentioned (a) defined formula (I) compound, one of preferred R1 and R3 are the 4-fluorophenyls.
When compound is during as above-mentioned (b) defined formula (I) compound, preferred V is the optional benzyl that is replaced by one or more methoxy group.One of also preferred R2 and R4 are methoxy group.
When compound is during as above-mentioned (c) defined formula (I) compound, one of preferred R1 and R3 are ethyl, amyl group or phenyl group.
When compound is as above-mentioned (d) defined formula (I) compound, and wherein one of R2 and R4 are-Y-(B) qDuring-Z, preferred B is piperidines, pyrimidine or phenyl group.Further preferred p is 1.
When compound is as above-mentioned (d) defined formula (I) compound, and wherein one of R2 and R4 be-(L-B) q-(Z) pThe time, preferred B is phenyl or cyclohexyl.Further preferred L is-O-low-grade alkylidene, more preferably-O-CH 2-.
When compound is as above-mentioned (d) defined formula (I) compound, and wherein one of R2 and R4 are-L-(B) n-(Z) pThe time, preferred L is-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) N-,-OCH 2C (O) NHCH 2-,-OCH 2-or-OCH 2CH 2-.More preferably L is-OCH 2C (O)-.Further preferred B is 4 to 12, preferred 5 or 6 yuan cycloalkyl, heterocycle, aryl or heteroaryl ring.Described ring can be chosen wantonly and be replaced by one or more substituting groups, and described substituting group is preferably selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, B is a cyclic rings, it is selected from cyclopentyl, cyclohexyl, phenyl, morpholinyl, piperazinyl, piperidyl, pyridyl, pyrrolidyl, pyrazinyl, pyrimidyl, purine radicals, pyranyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, naphthyl, indyl, indolinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group, thiazolyl, imidazolyl, benzotriazole base, indanyl, oxadiazole base, pyrazolyl, triazolyl or tetrazyl.In a more preferred embodiment, B is a cyclic rings, and it is selected from piperazinyl, phenyl, pyridyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, thiazolyl.Z is halogen, the low alkyl group or the lower alkoxy that is replaced by at least one halogen, for example halogenated methyl, dihalo methyl, trihalomethyl group, five halogenated ethyls, halogenated methoxy, dihalo methoxyl group, three halogenated methoxies, five halogenated ethyls or the five halo oxyethyl groups that are replaced by at least one halogen preferably.
When compound is as above-mentioned (d) defined formula (I) compound, and wherein one of R2 and R4 are-L-(B) n-(Z) pThe time, preferred B is piperazine, pyridine, phenyl or benzoglyoxaline group, or person's oxazole or thiazolyl group, it preferably condenses with benzyl ring.Also preferred p is 1.
When compound is during as above-mentioned (d) defined formula (I) compound, preferred Z be F, Br, trifluoromethyl, trifluoromethoxy or-SCF 3
When compound is during as above-mentioned (d) defined formula (I) compound, preferred p is 1.
Compound is formula II compound or its pharmacy acceptable salt, ester or prodrug preferably:
Figure A20068004805400121
Wherein:
L is the atomic radical with formula-OR5-, wherein the R5 low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) N-,-OCH 2C (O) NHCH 2-,-OCH 2-and-OCH 2CH 2-;
B is 4 to 12, preferred 5 or 6 yuan cycloalkyl, heterocycle, aryl or heteroaryl ring.Described ring can be chosen wantonly and be replaced by one or more substituting groups, and described substituting group is preferably selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, B is a cyclic rings, it is selected from cyclopentyl, cyclohexyl, phenyl, morpholinyl, piperazinyl, piperidyl, pyridyl, pyrrolidyl, pyrazinyl, pyrimidyl, purine radicals, pyranyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, naphthyl, indyl, indolinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group, thiazolyl, imidazolyl, benzotriazole base, indanyl, oxadiazole base, pyrazolyl, triazolyl or tetrazyl.In a preferred embodiment, B is the cyclic rings that is selected from piperazinyl, phenyl, pyridyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, thiazolyl;
Low alkyl group or the lower alkoxy that is replaced by at least one halogen, for example halogenated methyl, dihalo methyl, trihalomethyl group, five halogenated ethyls, halogenated methoxy, dihalo methoxyl group, three halogenated methoxies, five halogenated ethyls or five halo oxyethyl groups that Z is halogen, replaced by at least one halogen.Halogen is fluorine or chlorine preferably, and fluorine is most preferred halogen.Z can be connected any position of ring structure B, but preferably be connected ring structure between the position, more preferably be connected the contraposition of ring structure.If n=2, then Z preferably is connected the cyclic rings place in the outside, promptly is not directly connected to the cyclic rings of L, and n is 1 or 2, preferred 2;
Prerequisite is, if n is 1, then B is not a phenyl; If or n be 1 and B be phenyl, then L is-OCH 2C (O) NH-or-OCH 2C (O) NHCH 2-.
Specifically, the present invention includes the 6-replacement-2-nitro-6 of formula (i), 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine and formula 6-replacement-2-nitro-6 (ii), 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine
Figure A20068004805400131
In a preferred embodiment, the present invention relates to formula (Ia) compound or its pharmacologically acceptable salts, ester or prodrug:
Figure A20068004805400141
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein X is C or N independently; Wherein 0,1,2,3 or 4 X is N, and prerequisite is that ring structure is chemically stable; And wherein each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, two adjacent X not all are N, and the X that is connected on the N of other ring texture is C, and L is selected from-OCH 2C (O)-,-OCH 2C (O) NHCH 2-,-OCH 2-,-OCH 2CH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
In a further preferred embodiment, the present invention relates to formula (Ib) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400142
Wherein, L and Z in above-mentioned formula (II) compound definition; And wherein X is C or N independently; Wherein each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NHCH 2-,-OCH 2-,-OCH 2CH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
In a further preferred embodiment, the present invention relates to formula (Ic) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400143
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NHCH 2-,-OCH 2CH 2-and-OCH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably at 4 or 7, more preferably at 5 and 6.
In a further preferred embodiment, the present invention relates to formula (Id) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400151
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, Y is O or N; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-,-OCH 2CH 2-and-OCH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably at 4 or 7, more preferably at 5 and 6.
In a further preferred embodiment, the present invention relates to formula (Ie) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400152
Wherein, L and Z in above-mentioned formula (II) compound definition; And wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-,-OCH 2CH 2-and-OCH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
In a further preferred embodiment, the present invention relates to formula (If) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400153
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-,-OCH 2CH 2-and-OCH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
In a further preferred embodiment, the present invention relates to formula (Ig) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A20068004805400161
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, Y is S or N; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-,-OCH 2CH 2-and-OCH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably at 4 or 7, more preferably at 5 and 6.
On the other hand, the present invention relates to formula (Ih) compound or its pharmacy acceptable salt, ester or prodrug:
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-and-OCH 2CH 2-, and Z be selected from-F ,-CF 3Or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
On the other hand, the present invention relates to formula (Ii) compound or its pharmacy acceptable salt, ester or prodrug:
Any aromatic yl group in preferred formula (I) compound is a phenyl group.Aromatic yl group can be chosen wantonly by one or more substituting groups and replace, and described substituting group is preferably selected from low-grade halogenated alkyl (more preferably trifluoromethyl), elementary halogenated alkoxy (more preferably trifluoromethoxy) or halogen (preferred Br, Cl or F, most preferably F).
On the other hand, the present invention relates to the formula V compound or its salt:
Figure A20068004805400172
Wherein, L and Z in above-mentioned formula (II) compound definition; Wherein, each ring can be independently again by 1,2,3 or more multi-substituent replace, described substituting group for example is selected from low alkyl group, halogen, hydroxyl, amino or lower alkoxy.In a preferred embodiment, L is selected from-OCH 2C (O)-,-OCH 2C (O) NH-,-OCH 2C (O) NHCH 2-and-OCH 2CH 2-, and Z be selected from-F ,-CF 3, or-OCF 3Z is preferably in the 3-position, more preferably in the 4-position.
On the other hand, the invention provides pharmaceutical composition, this pharmaceutical composition comprises formula (I), (II) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or its pharmacy acceptable salt, ester or prodrug, and pharmaceutically acceptable vehicle, diluent or carrier.
On the other hand, the invention provides as medicine: formula (I), (II) or (V) compound, perhaps any compound in the formula (Ia) to (Ii) as defined above, or its pharmacy acceptable salt, ester or prodrug.
On the other hand, the invention provides and treat and/or prevent by pathogenic micro-organism or the parasite method of the disease that causes of mycobacterium tuberculosis, Oswaldocruzia or Leishmania donovani for example, this method comprise will the treatment significant quantity formula (I), (II) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or their pharmacy acceptable salt, ester or prodrug are administered to human or animal's individuality that it needs.
On the other hand, the invention provides and comprise formula (I), (II) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or the pharmaceutical composition of their pharmacy acceptable salt, ester or prodrug, it is used to prepare and treats and/or prevents by the pathogenic micro-organism medicine of the disease that causes of mycobacterium tuberculosis for example.
On the other hand, the invention provides formula (I), (II) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or their pharmacy acceptable salt, ester or prodrug treat and/or prevent by the pathogenic micro-organism purposes in the medicine of the disease that causes of mycobacterium tuberculosis for example in preparation.
Described disease is to be preferably TB, more preferably the TB of multidrug resistance.
On the other hand, the invention provides the disease that caused by Oswaldocruzia or infection by Leishmania donovani or the method for illness for the treatment of and/or preventing, this method comprises the human or animal's individuality that the formula of significant quantity (III) compound or its pharmacy acceptable salt, ester or prodrug is administered to its needs:
Figure A20068004805400181
Wherein:
(a) m is 0;
W is that O and V do not exist;
One of R1 and R3 are halogenated aryl or alkyl, and another is H, and perhaps R1 and R3 are low-grade alkyl groups; And
R2 and R4 are H;
Or:
(b) m is 1
W is that N and V are kiki fang alkyl groups, and it is chosen wantonly and is replaced by one or more alkoxy substituents;
R1 and R3 are H; And
One of R2 and R4 are alkoxyl groups, and another is H;
Or:
(c) m is 1;
W is that O and V do not exist;
One of R1 and R3 are alkyl or aryls, and another is H; And
R2 and R4 are H;
Or:
(d) m is 1;
W is that O and V do not exist;
One of R2 and R4 are-L (B) n-(Z) p,-(L-B) q-(Z) pOr-Y-(B) q-Z, and another is H;
And
R1 and R3 are H;
Wherein, L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; And Z is halogen, the low alkyl group that is replaced by halogen at least, the lower alkoxy that is replaced by a halogen at least or the rudimentary sulfane base that is replaced by a halogen at least;
And Y is-NHC (O)-;
N is 1 or 2; P is 0,1 or 2; And q is 1 or 2.
On the other hand, the invention provides and comprise formula (I), (II), (III) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or the pharmaceutical composition of its pharmacy acceptable salt, ester or prodrug, it is used to prepare and treats and/or prevents by the parasite medicine of the disease that causes of Oswaldocruzia or Leishmania donovani for example.
On the other hand, the invention provides formula (I), (II), (III) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or its pharmacy acceptable salt, ester or prodrug treat and/or prevent by the parasite purposes in the medicine of the disease that causes of Oswaldocruzia or Leishmania donovani for example in preparation.
Described disease is chagas disease or leishmaniasis preferably.
On the other hand, the invention provides formula (I), (II), (III) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or its pharmacy acceptable salt, ester or prodrug, itself and a line or the medication combined application of two wires TB.On the other hand, the invention provides a kind of combined prod, this combination Wen Pin comprises a) formula (I), (II), (III) or (V) compound, or any compound in the formula (Ia) to (Ii) as defined above, or its pharmacy acceptable salt, ester or prodrug, and b) at least a TB medicine, it is selected from the vazadrine, Rifampin, pyrazinoic acid amide, Tibutol, Streptomycin sulphate, capromycin, kantlex, ethionamide (Ethioamide), para-aminosalicylic acid (PAS), seromycin, Ciprofloxacin, Ofloxacine USP 23, amikacin, clofazimine, Thioacetazone, Gatifloxacin, Moxifloxacin.
On the other hand, the invention provides the method for preparing nitrogen heterocyclic, wherein this method comprises: make the epoxide and the reaction of halo imidazolium compounds of non-sterically hindered replacement, generation has the adducts of alcohol functional group, and wherein the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is less than or equal to 1: 1;
Protect the alcohol functional group on the above-mentioned adducts, to form the adducts of alcohol-protection;
And
Adducts with cyclizing agent processing alcohol-protection forms nitrogen heterocyclic.
Nitrogen heterocyclic free or salt form is preferably represented by formula (IV) compound:
Figure A20068004805400201
Wherein, R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl.
The epoxide of non-sterically hindered replacement preferably also comprises the alcohol groups of sheltering.The epoxide of further preferred non-sterically hindered replacement is suc as formula shown in (Ij) compound:
Figure A20068004805400211
Wherein, R 4=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 5=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6=trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the phenylbenzene tertiary butyl is silica-based.
Further preferred halo imidazolium compounds is suc as formula shown in (Ik) compound:
Figure A20068004805400212
Wherein, X=Cl, Br or I; Y=H, Li, Na, K, CO 2H, CO 2 -, tertbutyloxycarbonyl, N, N-dimethylamino alkylsulfonyl, p-toluenesulfonyl or triisopropylsilyl; R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl.
Further the adducts of preferred alcohols-protection is suc as formula shown in (Im) compound:
Figure A20068004805400213
Wherein, R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 4=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 5=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6=H, trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the phenylbenzene tertiary butyl is silica-based; X=Cl, Br or I.
The mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.55-0.95 preferably: 1, more preferably 0.6-0.9: 1, further more preferably 0.65-0.85: 1, and further more preferably 0.65-0.8: 1, further more preferably 0.7-0.85: 1, further more preferably 0.7 to 0.8: 1.
The epoxide of non-sterically hindered replacement preferably with the halo imidazolium compounds 45 to 105 ℃, more preferably 55 to 95 ℃, further more preferably 65 to 85 ℃, further more preferably 60 to 80 ℃ of reactions, form the adducts have alcohol functional group.
The halo imidazolium compounds preferably comprises the halogenic substituent that is selected from chlorine or bromine.
Further preferred, the alcohol functional group in the adducts is handled in the presence of catalyzer, form the adducts of alcohol-protection.
Catalyzer is the tosic acid pyridinium salt preferably.Preferred cyclizing agent is selected from anhydrous tetrabutylammonium (TBAF), anhydrous Tetrabutylammonium bromide (TBABr) or NaH.
Preferably under microwave condition, handle the adducts of alcohol-protection, to form nitrogen heterocyclic with cyclizing agent.
Preferably under microwave condition, handle unprotected primary alconol adducts, to form nitrogen heterocyclic with cyclizing agent.
Preferably under vacuum, handle the adducts of alcohol-protection, to form nitrogen heterocyclic with cyclizing agent.
R 2THP trtrahydropyranyl preferably.Preferred R 3=H.Preferred R 4And R 5Be independently selected from halogen and alkyl.R 6Tertiary butyl dimethyl silica-based (TBDMS) preferably.
More preferably R 3, R 4And R 5All be H.
Nitrogen heterocyclic is 3-alkoxyl group-6-nitro-2H-3 preferably, 4-dihydro-[2-1b] imidazo pyrans or 3-aryloxy-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.3-alkoxyl group-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans or 3-aryloxy-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans are more preferably (S)-or (R)-isomer.
In a preferred embodiment, nitrogen heterocyclic is 3 (S)-THP trtrahydropyranyl oxygen base-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.
In a further preferred embodiment, nitrogen heterocyclic is 3 (R)-THP trtrahydropyranyl oxygen base-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.
The present invention provides the method for preparing nitrogen heterocyclic in addition, wherein, and will be suc as formula the adducts of the alcohol shown in (In) compound protection,
Figure A20068004805400231
Wherein, R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 4=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 5=H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6=trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the silica-based and R of the phenylbenzene tertiary butyl 6=H;
Handle under microwave condition with cyclizing agent, form suc as formula the nitrogen heterocyclic shown in (IV)
Figure A20068004805400232
Cyclizing agent is preferably selected from anhydrous TBAF, anhydrous TBABr or NaH.Also preferably the adducts of alcohol-protection is handled under microwave and pressurized conditions.
Also preferably unprotected primary alconol adducts is handled under microwave and pressurized conditions.
Nitrogen heterocyclic is (R)-or (S)-isomer preferably.
The present invention also provides aforesaid method, and it comprises in addition makes the compound shown in the formula (IV)
Wherein, R 1=nitro; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H;
With 4-(trifluoro methoxy) benzyl halide reaction,
Formation is suc as formula the nitrogen heterocyclic shown in (Io)
Figure A20068004805400241
Wherein, R 1=nitro; R 2=trifluoro-methoxybenzyl; R 3=H.
4-(trifluoromethoxy) benzyl halogenide is preferably selected from 4-(trifluoromethoxy) bromotoluene, 4-(trifluoromethoxy) benzyl chloride and 4-(trifluoromethoxy) benzyl iodide.
Preferably with the compound (IV) shown in the formula (IV)
Figure A20068004805400242
Wherein, R 1=nitro; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H;
Handle with alcohol-deprotection agent in addition, react with 4-(trifluoromethoxy) benzyl chloride then.Alcohol-deprotection agent is preferably selected from acetate, TBAF, TBABr.
Nitrogen heterocyclic is (R)-or (S)-isomer further preferably.
Detailed Description Of The Invention
Definition
Term " alkyl " comprises the alkyl group of straight chain and side chain as used herein.Alkyl preferably comprises 1 to 8 carbon atom.Unless otherwise indicated, any alkyl, alkoxyl group, alkenyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl can be unsubstituted or be replaced by one or more substituting groups that described substituting group is selected from for example low alkyl group, halogen, hydroxyl, amino.Term " alkylidene group " refers to by alkyl deutero-divalent radical.
Term " low alkyl group " refers to the alkyl of straight chain and side chain as used herein, and it comprises 1 to 5 carbon atom, preferred 1 to 3 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, n-propyl, normal-butyl, sec-butyl, the tertiary butyl.Term " lower alkoxy " used in the literary composition refers to-OR, and wherein R is a low alkyl group as defined above.The example of lower alkoxy groups comprises for example methoxyl group, oxyethyl group, tert.-butoxy.
Term " alkenyl " comprises the alkenyl of straight chain and side chain as used herein, and described alkenyl can be the C of all isomeric form for example 2-C 12Alkenyl.
Term " alkoxy carbonyl " refers to radicals R CO, and wherein R is an alkoxy base, for example, and the C of all isomeric form 1-C 12-alkoxy base.
" halo " or " halogen " refers to F, Cl, Br or I, preferred F or Cl.
Term " alkyl halide " or " haloalkyl " refer at least one halogen binding alkyl as defined above thereon as defined above.Example for example is methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group.Term " low alkyl group halogen " or " low-grade halogenated alkyl " have corresponding implication with " low alkyl group " as defined above.
Term " lower alkoxy halogen " or " elementary halogenated alkoxy " refer at least one halogen binding lower alkoxy groups as defined above thereon as defined above.Example for example is fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups.
Term " cycloalkyl " refers to (non-fragrance) saturated or fractional saturation ring, and this ring is optional further by for example low alkyl group, halogen, hydroxyl, the amino replacement.Example comprises for example cyclopentyl, cyclohexyl, methylcyclohexyl.Described cycloalkyl ring is 5 or 6 yuan of rings preferably.
Term " aryl " refers to fragrant monocycle or condensed twin nuclei, and it can comprise 4 to 12 carbon atoms, preferred 5 or 6 carbon atoms for monocycle, preferred 8,9 or 10 carbon atoms for condensed-bicyclic.Aromatic yl group is optional further by for example low alkyl group, halogen, hydroxyl, the amino replacement.Aromatic yl group can be a phenyl or naphthyl for example, preferred phenyl.Term " halogenated aryl " refers to by the aromatic yl group of one or more halogens as defined above, preferred one or more fluorin radicals replacements.Term " alkylaryl " refers to-the R-aryl, and wherein, R is an alkyl group as defined above, and aryl as defined above.Example is a benzyl.
Term " heterocycle " refers to (non-fragrance) saturated or fractional saturation ring, this ring comprises 1,2 or 3 heteroatoms in addition, described heteroatoms is selected from N, O and S, and described ring can be chosen heterocyclic fused with 1 or 2 phenyl ring and/or other wantonly, and described ring is optional is further replaced on ring C or ring hetero atom by for example low alkyl group, halogen, hydroxyl, amino group.
Term " heteroaryl " refers to aromatic heterocycle, 5 or 6 membered aromatic heterocycles for example, and it is optional heterocyclic fused with 1 or 2 phenyl ring and/or other, and it is optionally further replaced on ring C or ring hetero atom by for example low alkyl group, halogen, hydroxyl, amino group.The example of heterocycle or heteroaryl groups comprises for example morpholinyl, piperazinyl, piperidyl, pyridyl, pyrrolidyl, pyrazinyl, pyrimidyl, purine radicals, pyranyl, benzimidazoles base, benzoxazolyl, benzothiazolyl, indyl, indolinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group, thiazolyl, imidazolyl, benzotriazole base, indanyl, oxadiazole base, pyrazolyl, triazolyl or tetrazyl.
Term " nitrogen heterocyclic " refers to comprise sp in the ring of this structure as used herein 2The ring texture of the nitrogen of-hydridization.
As used herein, term " replacement " expection comprises the admissible substituting group of all organic compound, comprises the formation of positively charged ion or anion salt.In broad aspect, admissible substituting group comprises the substituting group of the organic compound of acyclic and cyclic, side chain and unbranched, carbocyclic ring and heterocyclic, fragrance and non-fragrance.Be not intended to use by any way admissible substituting group restriction the present invention of organic compound.
" epoxide of non-sterically hindered replacement " refers to the epoxide that replaces, and wherein substituting group does not have sterically hinderedly to following reaction, and comprises the hint condition, promptly replace with substituted atom allow that valency is consistent.
Term " nitroimidazole of replacement " refers to be loaded with nitro substituent and other substituent imidazoles parent nucleus on the imidazoles parent nucleus as used herein, and described substituting group is usually at imidazole ring carbon location place or in imidazole ring nitrogen position.
Term " protecting group " refers to temporary transient or permanent chemical group as used herein, and it protects potential reactive functionality to avoid the chemical conversion that takes place not expect.The example of this class protecting group comprises the ester of carboxylic acid, the silica-based ether of alcohol and the acetal and the ketal of aldehyde and ketone respectively.The field of protecting group chemistry is known in the field; The example of protecting group comprises the conventional protecting group of using; it for example is found in " protecting group in the organic synthesis (Protective Groups in Organic Synthesis) " T.W.Greene, P.M.Wuts, John Wiley and sons; 1991, the 10-142 page or leaf.
Term " alcohol groups of sheltering " refers to be generally used for any group of the temporary protection of hydroxy functional group as used herein, and it causes sheltering the reactive behavior of free alcohol group.The example of suitable alcohol functional group protecting group includes but not limited to following example: silica-based group of alkoxy carbonyl, acyl group, alkyl silyl or alkylaryl and alkoxy-alkyl group.
Term " deprotection " is known in the organic synthesis field as used herein, refers to remove protecting group or the chemical group of sheltering functional group's potential reaction, stays the situation of unprotected functional group.The example of suitable deprotection agent or condition " protecting group in the organic synthesis " T.W.Greene as seen for example for various functional groups, P.M.Wuts, John Wiley and sons, 1991.
Term " free form " refers to the salt-independent shape of compound as used herein.In addition, The compounds of this invention can exist with non-solvent compound and solvate, comprises hydrate forms, crystalline form and polymorphic form.
Term " salt " or " salt form " refer to and metal or the amine base addition salt that forms of basic metal and alkaline-earth metal or organic amine for example as used herein.Example as cationic metal comprises sodium, potassium, magnesium, calcium etc.The example of suitable amine comprises N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, dicyclohexylamine, quadrol, N-methylglucosamine and PROCAINE HCL, PHARMA GRADE (are seen for example people such as BergeS.M., " pharmaceutical salts (Pharmaceutical Salts) ", pharmaceutical society's magazine (J.of Pharma.Sci.), 66:1,1977.
Term " electron-withdrawing group " is art-recognized, refers to that substituting group trends towards attracting valence electron from adjacent atom, and promptly for adjacent atom, substituting group is electronegative.The example of electron-withdrawing group comprises nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen etc.
Term " microwave condition " refers to be used for produce or simulated microwave radiating technology as used herein.Applied microwave radiating example can see for example tetrahedron (Tetrahedron) in organic synthesis, 57:9225-9283, and (2001) and chemistry can be commented (Acc.Chem.Soc), 82:14-19, (2004).
The present invention also comprises enantiomer, racemoid, diastereomer and the mixture of The compounds of this invention.For a person skilled in the art, apparent, The compounds of this invention comprises unsymmetrical carbon.Therefore, should be appreciated that expection is included in independent steric isomer in the scope of the invention.Represent as used herein the term " R " of chemical structure and " S " with IUPAC in the " suggestion of E part; basic stereoscopic chemistry (Recommendations for Section E; FundamentalStereochemistry) " definition, unadulterated application chemistry (Pure Appl.Chem.), 45:13-30, (1976).
The reagent by generic name and trade(brand)name sign in the literary composition and the structure of compound for example can derive from for example international monopoly (PatentsInternational) (for example IMS world publication (IMS World Publications)) of " the Merck index (The Merck Index) " or database, therefore, can learn any technician in this area.
The compounds of this invention
The compounds of this invention can be used for the treatment of and/or prevent pathogenic infection.Pathogenic agent is preferably bacterium or protozoon, particularly, mycobacterium (Mycobacterium), fusobacterium (Clostriduim), Cryptosporidium (Cryptosporidium), Helicobacterium (Helicobacter), trypanosoma (Trypanosoma), Leishmania (Leishmania) or plasmodium (Plasmodium).Described bacterium or protozoon be mycobacterium tuberculosis (the particularly mycobacterium tuberculosis of multidrug resistance) more particularly, clostridium difficile (Clostridium difficile), Cryptosporidium parvum (Cryptosporidiumparvum), Hp (Helicobacter pylori), Bu Shi trypanosoma rhodesiense (T.bruceirhodesiense), Bu Shi castellanella gambiense (T.brucei gambience), Oswaldocruzia (Trypanosoma cruzi), Leishmania donovani (Leishmania donovani), leishmania major (L.major), plasmodium falciparum (Plasmodium falciparum), bird mycobacterium (Mycobacterium avium), mycobacterium ulcerans (Mycobacterium ulcerans).Specifically, pathogenic agent is mycobacterium tuberculosis, Oswaldocruzia or Leishmania donovani.
The The compounds of this invention that exists with free form or pharmacy acceptable salt form has demonstrated valuable pharmacological character, as antiseptic-germicide, for example shown in the embodiment test, therefore is applicable to treatment.
The compounds of this invention shows the IC of its anti-Leishmania donovani 50Value is lower than 5 μ M, preferably is lower than 4 μ M, and more preferably less than 3 μ M, the utmost point is more preferably less than 2 μ M, and the utmost point is more preferably less than 1 μ M, the utmost point more preferably less than 0.5 μ M and the utmost point more preferably less than 0.1 μ M.
The compounds of this invention shows the IC of its anti-Oswaldocruzia 50Value is lower than 5 μ M, preferably is lower than 4 μ M, and more preferably less than 3 μ M, the utmost point is more preferably less than 2 μ M, the utmost point more preferably less than 1 μ M and the utmost point more preferably less than 0.5 μ M.
Its against mycobacterium tuberculosis minimal inhibitory concentration (MIC) of described compound exhibits is preferably less than 0.8 μ M, be more preferably less than 0.5 μ M, be more preferably less than 0.1 μ M, be more preferably less than 0.05 μ M, be more preferably less than 0.01 μ M, be more preferably less than 0.005 μ M, be more preferably less than 0.001 μ M, be more preferably less than 0.0005 μ M.
The compounds of this invention can exist with free form or salt form, for example with the additive salt of organic or inorganic acid as trifluoroacetic acid or hydrochloric acid, perhaps when they comprise carboxylic group for example with the obtainable salt of alkali, for example basic salt such as sodium, sylvite or replacement or do not have the ammonium salt of replacement.
The compounds of this invention can be used as the single-activity composition or as a kind of delivery of active ingredients that comprises in the composite tablet of several activeconstituentss (for example microbiotic).
Certainly change according to concrete illness and the desired effects that administering mode, quilt are treated for medicinal needed dosage.As a rule, the per daily dose expection of about 0.03 to 2.5mg/kg body weight can obtain the satisfactory result of whole body.Recommended in bigger Mammals (for example people) is about 0.5 to about 100mg, for example with one day maximum four times divided dose or slow release formulation administration easily.The suitable unit dosage form of oral administration comprises about 1 to 100mg activeconstituents.
The compounds of this invention can be with any conventional route administration, particularly enterally administering, and is for example oral, as with tablet or capsule form; Perhaps administered parenterally is for example with Injectable solution or suspensoid form; Topical is for example with lotion, gelifying agent, ointment or ointment form; Perhaps intranasal administration or suppository form.The pharmaceutical composition that comprises the formula 1-8 compound that exists with free form or pharmacy acceptable salt form and at least a pharmaceutically acceptable carrier or thinner can be by preparing with pharmaceutically acceptable carrier or mixing diluents in a usual manner.
The compounds of this invention can be with free form or pharmacy acceptable salt form administration, for example as mentioned above.Described salt can prepare with usual manner, and has the active rank identical with free cpds.
Formula (i) and (ii) compound can be according to the preparation of following reaction process:
Figure A20068004805400301
Wherein, R 2Be nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 3It is protecting group, for example 2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based, triethyl is silica-based; R 4Be H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 5Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 7Be protecting group, for example trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the phenylbenzene tertiary butyl is silica-based; X is Cl, Br or I; W is H, Li, Na, K, CO 2H, CO 2 -, tertbutyloxycarbonyl, N, N-dimethylamino alkylsulfonyl, p-toluenesulfonyl or triisopropylsilyl.
The invention provides the method for preparing nitrogen heterocyclic.In one embodiment, this method comprises epoxide and the reaction of halo imidazolium compounds that makes non-sterically hindered replacement, formation has the adducts of alcohol functional group, and wherein the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is less than or equal to 1: 1; The alcohol functional group of protection adducts, the adducts of formation alcohol-protection; Make the adducts and the cyclizing agent reaction of alcohol-protection, form nitrogen heterocyclic.In addition, the invention provides the method that the alcohol adducts that makes two protections is converted into the primary alconol adducts of single protection, the primary alconol adducts of described single protection and cyclizing agent reaction form nitrogen heterocyclic.
According to method provided by the invention, the halogenated-imidazole that comprises two electron-withdrawing substituents by use has been avoided the use of volatile dinitrobenzene imidazoles fully.Also for advantageously, method of the present invention provides the effective ways of preparation imidazo pyrans, and this method needs more a spot of labor-intensive purification step.Entire method ratio such as US 6,087,358 disclosed methods are more effective and be more suitable for extensive synthetic.
By adopting the starting raw material of appropriate molar ratios, per step productive rate and synthetic overall yield can be improved in a step of synthesis step.In addition, use the starting raw material of appropriate molar ratios, the labour that the product that purifying forms needs is alleviated.The inventive method can further improve combined coefficient by introducing cyclisation step, forms nitroimidazole and pyrans product with high yield.Cyclisation can be in preferred embodiments carried out under microwave condition, pressurization or microwave and both combination condition of pressurizeing.
Cyclisation can be in preferred embodiments carried out under microwave condition, pressurization or microwave and both combination condition of pressurizeing.Term " microwave condition " refers to use and is used to produce or the technology of simulated microwave condition as used herein.Applied microwave radiating example can see for example tetrahedron in organic synthesis, 57:9225-9283, and (2001) and chemistry can be commented 82:14-19, (2004).
Therefore, in a preferred embodiment, the invention provides the method that formula (Ir) compound is transformed an accepted way of doing sth (IV) compound with microwave radiation.
In a preferred embodiment, the halo imidazolium compounds is suc as formula shown in (Ip) compound:
Figure A20068004805400311
Wherein, X is Cl, Br or I; W is H, Li, Na, K, CO 2H, CO 2 -, blocking group for example tertbutyloxycarbonyl, N, N-dimethylamino alkylsulfonyl, p-toluenesulfonyl or triisopropylsilyl; R 2Be nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 4Be H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl.
The halo imidazolium compounds can by with sprotic weak base for example pre-treatment such as Anhydrous potassium carbonate, proton sponge, DBU obtain the activation, be used for the reaction.The epoxide that makes halo imidazolium compounds and non--sterically hindered replacement is at anhydrous solvent for example dehydrated alcohol, anhydrous methanol, anhydrous tetrahydro furan, anhydrous N, and there are reaction down in N-dimethyl sulfoxide (DMSO), anhydrous methylene chloride etc.Halo imidazolium compounds free or salt form adopts the epoxide of suitable mol ratio nucleophilic addition(Adn) to non-sterically hindered replacement, obtains having the adducts of alcohol functional group.
The halo imidazolium compounds is the nitrogen heterocyclic that comprises the imidazoles parent nucleus, and this imidazoles parent nucleus has halogenic substituent for example chlorine, bromine, iodine etc.This imidazoles parent nucleus can further be substituted, usually at carbon or azo-cycle atom place.The substituting group that can use representative types is acyl group, formyl radical, alkylsulfonyl, silica-based, trifluoromethyl, cyano group, halogen, nitro or alkoxy carbonyl for example.
In one aspect of the invention, the substituting group at the carboatomic ring atom place comprises electron-withdrawing group for example acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen, nitro or alkoxy carbonyl.In a preferred embodiment, the substituting group at imidazole ring carbon atom place is a nitryl group.In a preferred embodiment, substituting group is the nitro on 4 of imidazoles parent nucleus.
The present invention replaces on imidazoles parent nucleus theheterocyclic nitrogen atom on the other hand.The imidazoles nitrogen-atoms can be unsubstituted, and is promptly protonated, or derivatize, so nitrogen-atoms taken off proton or temporary protection, to allow and epoxide generation nucleophilic reaction.Substituent example on imidazoles parent nucleus nitrogen-atoms includes, but are not limited to Li, Na, K, CO 2H, CO 2 -, tertbutyloxycarbonyl, N, N-dimethylamino alkylsulfonyl, p-toluenesulfonyl and triisopropylsilyl.
The epoxide of non-sterically hindered replacement is to comprise epoxide and the reaction of halo imidazolium compounds are not had sterically hindered substituent epoxide.Substituent example on the epoxide includes but not limited to alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl, heteroaryl, comprises isometry and stereomeric substituting group.Substituting group on the epoxide can be any configuration, produces the epoxide of symmetry or asymmetric replacement.
One aspect of the present invention provides and has for example substituting group of hydroxyl, silica-based, alkoxyl group, alkenyl, aryl, aryloxy, amino, cyano group, acyl group etc. of functional group, and described functional group is pair sterically hindered with instead would not producing of halo imidazolium compounds.Can be with the protection of the reactive functional groups on the substituting group, so that the masking reaction activity.In one embodiment, the epoxide of non-sterically hindered replacement comprises the alcohol groups of sheltering in addition.Representational hydroxy-protective group comprises carboxyl groups, benzyl and trityl ether, THP trtrahydropyranyl ether, trialkyl silyl ether and allyl ethers.
In one embodiment of the invention, the substituting group on the epoxide can comprise that silica-based-blocking group is for example trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based, the phenylbenzene tertiary butyl is silica-based and similar alkylating silica-based.In another embodiment, the epoxide of non-sterically hindered replacement comprises the amino group of sheltering in addition.Representational amido protecting group comprise formyl radical, ethanoyl, trifluoroacetyl group, benzyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, trimethyl silicon based, 2-is trimethyl silicon based-trityl group of ethylsulfonyl, trityl and replacement, allyloxy carbonyl, 9-fluorenylmethyloxycarbonyl, nitro-veratryl oxygen base carbonyl etc.
In a preferred embodiment, the epoxide of non-sterically hindered replacement is suc as formula shown in (Iq) compound:
Figure A20068004805400331
Wherein, R 5Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 7Be trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the phenylbenzene tertiary butyl is silica-based.
On the one hand, the present invention relates to the application of mol ratio of the amount of the epoxide of non-sterically hindered replacement and halo imidazolium compounds.In one embodiment, the mol ratio of the epoxide of non-sterically hindered replacement is less than or equal to 1: 1.In another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.55 to 0.95: 1.In another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.6 to 0.9: 1.In another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.65 to 0.85: 1.In another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.65 to 0.8: 1.In another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.7 to 0.85: 1.Still in another embodiment, the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is 0.7 to 0.8: 1.
On the other hand, the present invention relates to the reaction under 45-105 ℃ of temperature, carried out.In a preferred embodiment, the epoxide of non-sterically hindered replacement and halo imidazolium compounds form the adducts that has alcohol functional group in about 55-95 ℃ of thermotonus.In a further preferred embodiment, the epoxide of non-sterically hindered replacement and halo imidazolium compounds form the adducts that has alcohol functional group in about 65-85 ℃ of thermotonus.Still in a further preferred embodiment, the epoxide of non-sterically hindered replacement and halo imidazolium compounds form the adducts that has alcohol functional group in about 60-80 ℃ of thermotonus.
The epoxide reaction of halo imidazolium compounds and non-sterically hindered replacement obtains reaction product, by separating with the method that well known to a person skilled in the art, obtains the adducts that has alcohol functional group as final product.The example that forms post-treatment of final products is comprised filtration, remove and desolvate, extraction (using conventional organic solvent for example ethyl acetate, ether, chloroform, methylene dichloride etc.) between water and organic phase, use the dry organic phase of conventional drying agent then, after removing solvent, obtain having the adducts of alcohol functional group.
Comprise the alcohol functional group of deriving and obtaining by the epoxide of non-sterically hindered replacement and the adducts of halo imidazolium compounds reaction formation by the nucleophilic ring opening of epoxide.The adducts that comprises alcohol functional group that obtains obtains so that its protonated form is separated, and purity is calculated productive rate according to epoxide and is equal to or greater than 90% greater than 90%.Advantage is, can mass preparation have the adducts of alcohol functional group, and it need not be further purified the following step that promptly can be used for present method.The responseless halo imidazolium compounds that is used as starting raw material in reaction can reclaim from aqueous phase, and circulation is used for reaction, make entire method more economically, efficient and be suitable for extensive synthetic.
In one embodiment, the adducts of alcohol-protection is suc as formula shown in (Ir) compound:
Figure A20068004805400341
Wherein, R 2Be nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 3It is protecting group, for example 2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based, triethyl is silica-based, carbobenzoxy-(Cbz), allyloxy carbonyl; R 4Be H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 5Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 6Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl; R 7H is a protecting group, and is for example trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, dibutylmethyl is silica-based, diphenyl methyl is silica-based, the phenyl dimethyl is silica-based or the phenylbenzene tertiary butyl is silica-based; X is Cl, Br or I.
The stereochemistry of the inventive method is to be determined by the selected enantiomer of epoxide of the non-sterically hindered replacement of using.Therefore, the enantiomer that provides by the inventive method or be (S)-enantiomorph, or be (R)-enantiomorph, this depends on the selection of enantiomorph used in the epoxide parent material.
It is another aspect of the present invention that the selectivity of regional isomer forms.According to the direction of nucleophilic addition(Adn), separate obtaining one or another kind of regional isomer.The method according to this invention, having only a kind of regional isomer is advantage, can separate to obtain from reaction.Another kind of regional isomer by adopt LC-MS and LC-UV wave spectrum detection method be detect less than.The other step of the inventive method comprises the protection alcohol adducts, preferably in the presence of catalyzer, to form the adducts of alcohol-protection.The method that alcohol is changed into the adducts of alcohol-protection is this area, and especially the protecting group field is known, for example, and in " protecting group in the organic synthesis ", chapter 2, T.W.Greene and P.G.M.Wuts, the third edition, 1999.Therefore, the inventive method comprises with protecting group handles alcohol adducts, with the step of the adducts that alcohol adducts changed into corresponding alcohol-protection.The example of these pure protecting groups includes but not limited to dihydro pyranyl, 2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2; 2; 2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl and (2,3-dimethyl-2-butyl)-dimethyl is silica-based.In one embodiment, use 3,4-dihydro-2H-pyrans is converted into alcohol adducts the alcohol adducts of corresponding dihydro pyranyl-protection.The new distillatory 3 that obtains by the Kugelrohr water distilling apparatus for example, 4-dihydro-2H-pyrans is preferred.
Be converted in the process of adducts of corresponding alcohol-protection at the adducts that will have alcohol functional group, use gentle reaction conditions, to avoid any reactive group or derived from the cracking of the temporary transient masking reaction group of non-sterically hindered epoxide.Gentle reaction conditions is included in 15 ℃ to 35 ℃ room temperature and will reacts stir about 20-30 hour.Carry out for the ease of reaction, especially under lower temperature, can add catalyzer.Described catalyzer is well known in the art, comprises acyl group, benzyl and trityl ether, THP trtrahydropyranyl ether, trialkyl silyl ether and allyl ethers.But, find catalyzer for example the application of tosic acid can cause the cracking of tertiary butyl dimethyl silica-based (TBDMS) protecting group.In a preferred embodiment, catalyzer is the tosic acid pyridinium salt.
In the latter stage of alcohol adducts and protecting group reaction, for example by reacting with cancellation such as saturated sodium bicarbonate aqueous solutions, can stopped reaction.In case remove organic layer, for example methylene dichloride, ether and ethyl acetate extraction be for several times with volatile organic solvent with water layer.Merge the organic layer that extraction obtains, water, salt water washing, and conventional drying agent dried over mgso for example.Vacuum is removed solvent and is obtained residue, and residue is removed the catalyzer of any remnants with filtered through silica gel, and catalyzer will stick on the pillar.With the cyclohexane solution wash-out of 50%EtOAc, solvent removed in vacuo obtains the adducts of alcohol-protection, and it need not be further purified and can then use.The adducts that the present invention relates to cyclisation alcohol-protection on the other hand forms nitrogen heterocyclic.In one embodiment, make adducts cyclisation in the presence of cyclizing agent of alcohol-protection, wherein cyclizing agent is selected from anhydrous TBAF and anhydrous TBABr.
In another embodiment, the adducts of alcohol-protection is handled under microwave condition with cyclizing agent, formed nitrogen heterocyclic.In another embodiment, the adducts of alcohol-protection is handled under pressurized conditions with cyclizing agent, formed nitrogen heterocyclic.In a preferred embodiment of the present invention, the adducts of alcohol-protection is handled under microwave and pressurized conditions with cyclizing agent, form nitrogen heterocyclic.Be used for this reaction, cyclizing agent can extend further to and comprise for example N of alkali, N-diisopropylethylamine, triethylamine etc. and NaH.
In another embodiment, unprotected primary alconol adducts is handled under microwave condition with cyclizing agent, formed nitrogen heterocyclic.In another embodiment, unprotected primary alconol adducts is handled under pressurized conditions with cyclizing agent, formed nitrogen heterocyclic.In a preferred embodiment of the present invention, unprotected primary alconol adducts and cyclizing agent are handled under microwave and pressurized conditions, form nitrogen heterocyclic.
In cyclization, before adding cyclizing agent, the adducts of alcohol-protection is dissolved in anhydrous aprotic solvent for example in the tetrahydrofuran (THF).Be used to prepare to contain for several parts 20 to 30mL the use of self-actuated sampler of the reactor of anhydrous tetrahydro furan, can quicken and enlarge the method that preparation is used to the anhydrous tetrahydro furan that uses in a large number in proportion.In a preferred embodiment, cyclizing agent is anhydrous TBAF.The commercial TBAF (Aldrich, 1M, THF solution) that can buy provides with anhydrous form.In other embodiments, before using anhydrous TBAF is outgased, preferably with nitrogen or argon-degassed.
To contain the reactor sealing of ether in anhydrous solvent and cyclizing agent, and be exposed under microwave and the pressurized conditions then, under 100 ℃ to 160 ℃ temperature, kept 10-30 minute.In one embodiment, microwave condition can use Biotage system (http://www.biotagedcg.com/) to produce.In above-mentioned time end, the solvent of removing in the reactor obtains residue, and residue is obtained required nitrogen heterocyclic by purification by silica gel column chromatography, and productive rate is equal to or greater than 70%.Compare with it, as be disclosed in that synthetic N-among the WO2004/035547 replaces-other synthetic route of 4-nitro-halogenated-imidazole and nitroimidazole and pyrans class, the productive rate of its report is approximately 50%.
The nitrogen heterocyclic that forms is the imidazo pyrans that is connected with alcohol functional group in the 3-position of pyranoid ring.In one embodiment, the nitrogen heterocyclic of free or salt form is suc as formula shown in (IV) compound:
Figure A20068004805400371
Wherein, R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl.
In one embodiment, nitrogen heterocyclic is included in the nitro substituent of 6-position.In another embodiment, the nitrogen heterocyclic of formation is (S)-isomer.In a preferred embodiment, the nitrogen heterocyclic of formation has nitro substituent (S)-isomer at the 6-bit strip.
On the other hand, the invention provides the method for preparing nitrogen heterocyclic, wherein, nitrogen heterocyclic is alkoxyl group-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans or aryloxy-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.In one embodiment of the invention, the method of preparation formula (I) nitrogen heterocyclic is provided, and wherein, nitrogen heterocyclic is 3-alkoxyl group-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans or 3-aryloxy-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.In another embodiment, nitrogen heterocyclic can be (S)-or (R)-isomer.In one embodiment of the invention, provide the method for preparation formula (I) nitrogen heterocyclic, wherein, nitrogen heterocyclic is 3 (R)-THP trtrahydropyranyl oxygen base-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.In a preferred embodiment of the present invention, the method for preparation formula (I) nitrogen heterocyclic is provided, wherein, nitrogen heterocyclic is 3 (S)-THP trtrahydropyranyl oxygen base-6-nitro-2H-3,4-dihydro-[2-1b] imidazo pyrans.
On the other hand, the present invention comprises in addition: with the compound shown in the formula (IV)
Figure A20068004805400381
Wherein, R 1=nitro; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl;
Be converted into following formula: compound:
Figure A20068004805400382
R wherein 1=nitro; R 2=trifluoro-methoxybenzyl; R 3=H.
On the other hand, the invention provides the method for preparing The compounds of this invention, this method comprises:
A) make formula (Is) compound
Figure A20068004805400383
R wherein 2Such as in the above-mentioned compound (Ip)-(Ir) definition; R 4Such as in the above-mentioned compound (Ip)-(Ir) definition; R 8Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl or heteroaryl, and, wherein X be Cl, Br, I ,-OCOO-isobutenyl, low alkyl group, phenyl;
With the reaction of formula (It) compound,
Figure A20068004805400384
Wherein, Y is N or CH; R 9Be H, alkyl, alkenyl, aryl, assorted alkyl, heterochain thiazolinyl, heteroaryl, neighbour, or three fluoro-of para-orientation, trifluoromethoxy-, fluoro-phenyl, xenyl, heteroaryl, benzyl;
Perhaps react with formula (Iw) compound,
Figure A20068004805400391
Wherein Z as defined above, and n=0,1,2 or 3;
Perhaps react with formula (Ix) compound,
Figure A20068004805400392
Wherein Y and Z are as defined above;
Perhaps react with formula (Iy) compound,
Figure A20068004805400393
Wherein Z as defined above;
B) make formula (Iz) compound
Figure A20068004805400394
R wherein 2Such as in the above-mentioned compound (Ip)-(Ir) definition; R 4Such as in the above-mentioned compound (Ip)-(Ir) definition; And R 3Be hydrogen or counter ion such as Li, Na, K, Mg, Zn, Ca;
With formula (Iaa) reaction,
Figure A20068004805400395
Wherein X is a halogen, Cl, Br, I;
Or with formula (Iab) reaction,
Figure A20068004805400396
Wherein, R 10Be H, alkyl, alkenyl, aryl, assorted alkyl, fluoroalkyl, fluorine alkenyl, fluoroalkyl, trifluoroalkyl, pentafluoroethyl group, seven fluoropropyls, nine fluorine butyl, heterochain thiazolinyl, heteroaryl, neighbour, or to three fluoro-that replace, trifluoromethoxy-, fluoro-phenyl, xenyl, heteroaryl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, benzyl, and wherein X is a halogen, Cl, Br, I.
The universal method of preparation The compounds of this invention
Flow process 1 has been illustrated two important intermediates 6 and 7.Flow process 2 has been illustrated the preparation of formula (If) compound, flow process 3 has been illustrated the preparation of formula (Ig) compound, flow process 4 illustrated formula (i), (ii), the preparation of (Ia), (Ic), (Ie) compound, flow process 5 and flow process 6 have been illustrated the preparation of formula (Id) compound.
Flow process 1.1
Figure A20068004805400401
Flow process 1.2
Figure A20068004805400402
Flow process 2
Figure A20068004805400403
Flow process 3
Figure A20068004805400411
Flow process 4
Figure A20068004805400412
Flow process 5
Figure A20068004805400413
Flow process 6
Figure A20068004805400414
Embodiment
Present invention is described with reference to the following examples.Should be appreciated that the present invention is not limited to these embodiment.
Embodiment 1
(S)-1-(tertiary butyl dimethylsilyl oxygen base)-3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol (3)
Figure A20068004805400421
(20.0g, 0.14mol 100mol%) are dissolved among the anhydrous EtOH (200mL), add anhydrous K in room temperature with 2-chloro-4-nitro-imidazoles 2CO 3(2.82g, 0.020mol, 15mol%), then add the tertiary butyl-dimethyl-((S)-1-oxyethane ylmethoxy)-silane (22.2mL, 0.11mol, 0.78mol%).Reaction mixture is heated to 70 ℃ keeps 6-10h.Then solvent is removed in vacuum, reaction mixture is dissolved in the ethyl acetate.Organic layer water, 0.5 N HCI, water, salt water washing are removed solvent the pure crude product that obtains little yellow solid shape for several times in a vacuum.This solid suspension in ether, is filtered, obtain the end product of colourless powder shape.Remaining filtrate is concentrated, will repeat twice with the process of ether sedimentation products.
MS：M +336.3.
Fusing point: 116-118 ℃.
[α] 21 D＝-29.43(C＝0.003，MeOH).
Embodiment 2
1-[(S)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2- Chloro-4-nitro-1H-imidazoles (4)
Figure A20068004805400422
With (S)-1-(tertiary butyl-dimethyl-silanyloxy base)-3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol (3.0g, 8.9mmol, 100mol%) be dissolved in the methylene dichloride (100mL), with new distillatory 3,4-dihydro-2H-pyrans (1.5g, 17.8mmol, 200mol%) add in this solution, then add the tosic acid pyridinium salt (3.4g, 13.4mmol, 150mol%).With reaction mixture at stirring at room 24h.With saturated sodium bicarbonate aqueous solution cancellation reaction mixture.Organic layer is separated the water section dichloromethane extraction.To merge organic layer water, salt water washing, through MgSO 4Drying is removed solvent in a vacuum, obtains the 1-[(S of colorless oil)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2-chloro-4-nitro-1H-imidazoles.
MS：M +420.6.
Embodiment 3
(S)-and 2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6,7-dihydro-5H-imidazo [2,1-b]-[1,3]-Evil Piperazine (5)
Figure A20068004805400431
With 1-[(S)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2-chloro-4-nitro-1H-imidazoles (0.74g, 1.76mmol, 100mol%) be dissolved in the anhydrous tetrahydro furan (180mL), with TBAF (1M THF solution, 1.76mL, 100mol%) add in the above-mentioned solution.With the reaction tubes sealing, and be exposed in the microwave at 140 ℃ of maintenance 7min.Solvent is removed under vacuum,, obtained (S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6 of little yellow oily, 7-dihydro-5H-imidazo [2,1-b]-[1,3] oxazine the residue silica gel purification.
With (S)-3-(2-chloro-4-nitro-imidazoles-1-yl)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-third-1-alcohol (0.053g, 0.172mmol, 100mol%) be dissolved in the anhydrous tetrahydro furan (17mL), TBAF (1MTHF solution, 0.17mL, 100mol%) add in this solution.With the reaction tubes sealing, and be exposed in the microwave at 140 ℃ of maintenance 7min.Solvent is removed under vacuum, and the residue silica gel purification obtains (S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6 of little yellow oily, 7-dihydro-5H-imidazo [2,1-b]-[1,3] oxazine.
MS：M +270。
Embodiment 4
(S)-and 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6)
With (S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6,7-dihydro-5H-imidazo [2,1-b]-[1,3] (4.35g, 16.1mmol 100mol%) were dissolved in HOAc/THF/ water 4: 2: 1 (72: 36: 18ml) to-oxazines, reaction mixture is heated to 60 ℃, and stirs 18h.Reaction mixture is cooled to room temperature, and drip dichloromethane grinds it, and sedimentation obtains product.After the filtration, filtrate volume is reduced, repeat process of lapping for several times, obtain (S)-2-nitro-6 of little yellow solid shape, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol.
MS：M +186.4
1H?NMR(CD 3SOCD 3，400MHz)：δ8.07(s，1H)，5.65(s，1H)，4.4(dd，J＝11.3，0.9Hz，1H)，4.3(dt，J＝11.3，2.4Hz，1H)，5.25(m，1H)，4.19(dd，J＝12.9，3.3Hz，1H)，3.95(dt，J＝12.9，2.4Hz，1H)。
Fusing point: 212-214 ℃.
[α] 21 D＝-68.46(c＝0.0027，MeOH).
Embodiment 5
(S)-and 2-nitro-6-[2-(4-trifluoromethoxy-phenyl)-thiazole-4-ylmethoxy]-6,7-dihydro-5H- Imidazo [2,1-b] [1,3] oxazine (11)
Figure A20068004805400441
4-trifluoromethoxy-benzamide (2.5g, 12.2mmol, 100%) is dissolved in the 25ml glycol dimethyl ether (DME), adds Lawesson reagent (2.5g, 6.1mmol, 50%), with reactant in stirred overnight at room temperature.Reactant is concentrated,, obtain 4-trifluoromethoxy-thiobenzamide (M of yellow solid shape by the silica gel column chromatography purifying +222.2).
With 4-trifluoromethoxy-thiobenzamide (3.7g, 16.6mmol, 100mol%) and saleratus (13.3g, 132.7mmol 800mol%) are dissolved in the tetrahydrofuran (THF) (26mL) ultrasonic 5min.Then, (6.2mL, 49.7mmol 300mol%) add, and reactant is stirred 2h with ethyl bromide acetone.Make reaction be cooled to 0 ℃, add 2, and the 6-lutidine (16.4mL, 141.0mmol, 850mol%) and trifluoroacetic anhydride (9.20mL, 66.3mmol, 400mol%) mixture in tetrahydrofuran (THF).Sluggish is risen to room temperature, restir 1h.Reactant is concentrated in a vacuum, add ethyl acetate.Organic layer washes twice with water, uses MgSO 4Drying is removed solvent in a vacuum.Crude product silica gel column chromatography purifying obtains white solid 2-(4-trifluoromethoxy-phenyl)-thiazole-4-ethyl formate (M +318.1).
With 2-(4-trifluoromethoxy-phenyl)-thiazole-4-ethyl formate (3.0g, 9.5mmol, 100mol%) and LiAlH 4(1.0g, 26.7mmol 280mol%) are dissolved in the exsiccant tetrahydrofuran (THF) (20mL) at 0 ℃, and reactant is stirred 30min.Use 2mL water, then react with the sodium hydroxide solution cancellation of 1mL 15%.Solid is filtered, several times with the ethyl acetate washing.At vacuum concentrated filtrate, obtain [2-(4-trifluoromethoxy-phenyl)-thiazole-4-yl]-methyl alcohol.
(2.5g, 9.1mmol 100mol%) join in the acetic acid solution (access) of 33%HBR, and are heated to 100 ℃ with [2-(4-trifluoromethoxy-phenyl)-thiazole-4-yl]-methyl alcohol.Reaction is cooled to 0 ℃, with flaky sodium hydrate cancellation reaction, is 8.0 until the pH value.The product ethyl acetate extraction is through MgSO 4Drying concentrates under vacuum and obtains the oily crude product, and it is obtained 4-brooethyl-2-(4-trifluoromethoxy-phenyl)-thiazole with the silica gel column chromatography purifying.
Under 0 ℃, argon gas atmosphere, (60% in mineral oil, 0.16g with NaH, 3.9mmol, 150mol%) be added to (S)-2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (0.49g, 2.64mmol, 100mol%), 4-brooethyl-2-(4-trifluoromethoxy-phenyl)-thiazole (1.05g, 3.17mmol, 120mol%) and tetrabutylammonium iodide (0.05g, 0.13mmol is in dry DMF 5mol%) (10.0mL) solution.Making mixture be warmed to room temperature and stir spends the night.Make reaction be cooled to 0 ℃, use the frozen water cancellation.Product is with 250mL EtOAc extracting twice, through MgSO 4Drying concentrates under vacuum and obtains brown oily crude product, and it with anti-phase preparation type LC purifying, is obtained (S)-2-nitro-6-[2-(4-trifluoromethoxy-phenyl)-thiazole-4-ylmethoxy]-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine.
MS：M +443.1.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.03(m，3H)，7.67(s，1H)，7.48(d，J＝8.06Hz，2H)，4.78(abq，J＝12.93，1.69Hz，2H)，4.70(dt，J＝11.96，2.45Hz，1H)，4.48(d，J＝11.82Hz，1H)，4.26(m，3H)。
Fusing point: 140-141 ℃.
Ultimate analysis: C 17H 13F 3N 4O 5S calculated value: C, 46.15; H, 2.97; N, 12.66, measured value: C, 45.68; H, 2.71; N, 12.40.
Embodiment 6
((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-acetate (7)
Figure A20068004805400461
Under 0 ℃, argon gas atmosphere, (60% in mineral oil, 0.13g with NaH, 3.24mmol, 120mol%) be added to (S)-2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (0.50g, 2.70mmol, 100mol%), bromo-acetic acid tert-butyl (0.48mL, 3.20mmol, 120mol%) and tetrabutylammonium iodide (0.05g, 0.14mmol is in dry DMF 5mol%) (10.0mL) solution.Make mixture be warming up to room temperature, and stir and spend the night.Make reaction be cooled to 0 ℃, use the icy water cancellation.Throw out is filtered, vacuum-drying, obtain ((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-tert.-butyl acetate.The dichloromethane solution of trifluoroacetic acid (100mL) with 50% join above-mentioned ester (1.40g, 4.71mmol, 100mol%) in, at stirring at room 0.5h.Solvent is removed under vacuum, and by adding toluene, then the trifluoroacetic acid of trace is removed in evaporation.Repeat this step until ((the S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base) that obtain free-pouring shallow white solid-acetate.
MS：M -242.2；
1H?NMR(CD 3SOCD 3，400MHz)：δ8.04(s，1H)，4.59(dt，J＝11.92，2.47Hz，2H)，4.43(d，J＝11.83Hz，2H)，4.20(m，3H).
Fusing point: 178-179 ℃.
Synthetic 12 and 13 universal method
Figure A20068004805400462
In inert atmosphere, ((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-acetate (100mol%) is dissolved in (0.20M) in the anhydrous methylene chloride, adds HATU (120mol%) and DIEA (120mol%).Reactant behind stirring at room 5min, is added 1, the benzene (120mol%) of 2-diamino-replacement.With the reaction mixture that obtains in stirred overnight at room temperature.Reactant is concentrated, and be dissolved in the ethyl acetate, wash with water three times.The organic layer anhydrous Na 2SO 4Drying concentrates, and obtains the light brown solids with anti-phase preparation type LC purifying.This solid is dissolved in the Glacial acetic acid (0.33M), is heated to 95 ℃ of reaction 30min.Crude product mixture is concentrated, and the residue of gained obtains white solid with the anti-phase LC purifying of preparation type.
Embodiment 7
(S)-and 2-nitro-6-(6-Trifluoromethyl-1 H-benzimidazolyl-2 radicals-ylmethoxy)-6,7-dihydro-5H-imidazoles And [2,1-b] [1,3] oxazine (12)
Figure A20068004805400471
MS：M +383.9.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.50(s，1H)，8.05(s，1H)，7.86(s，1H)，7.71(d，J＝8.43Hz，1H)，7.49(dd，J＝8.48，1.45Hz，1H)，4.92(s，2H)，4.70(dt，J＝12.04，2.50Hz，1H)，4.48(d，J＝11.99Hz，1H)，4.34(dd，J＝13.31，1.89Hz，2H)，4.24(dd，J＝13.25，2.97Hz，1H).
Fusing point: 120-121 ℃.
Ultimate analysis: C 19H 20F 3N 5O 6 *HCO 2H calculated value: C, 44.76; H, 3.29; N, 16.30, measured value: C, 45.26; H, 3.32; N, 16.65.
Embodiment 8
(S)-and 2-nitro-6-(6-trifluoromethoxy-1H-benzimidazolyl-2 radicals-ylmethoxy)-6,7-dihydro-5H-miaow Azoles is [2,1-b] [1,3] oxazine (13) also
MS：M +399.8.
1H?NMR(CD 3SOCD 3，400MHz)：δ12.73(d，J＝13.72Hz，1H)，8.05(s，1H)，7.55(m，2H)，7.17(m，1H)，4.89(S，2H)，4.70(dt，J＝11.98，2.39Hz，1H)，4.48(d，J＝11.98Hz，1H)，4.32(m，2H)，4.24(dd，J＝13.86，3.57Hz，1H).
Fusing point: 99-100 ℃.
[α] 21 D＝-42.844(c＝0.0031.MeOH)。
The universal method of synthetic 14-21
In inert atmosphere, ((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-acetate (100mol%) is dissolved in (0.20 M) in the anhydrous methylene chloride, adds HATU (120mol%) and DIEA (120mol%).Reactant behind stirring at room 5min, is added amine (120mol%).With the reaction mixture that obtains in stirred overnight at room temperature.Reactant is concentrated, be dissolved in the ethyl acetate, wash with water three times.The organic layer anhydrous Na 2SO 4Drying concentrates, and with anti-phase preparation type LC purifying, obtains required product.
Embodiment 9
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-N-(4-trifluoro Methoxyl group-phenyl)-ethanamide (14)
Figure A20068004805400482
MS：M +403.4.
1H?NMR(CD 3SOCD 3，400MHz)：δ9.98(s，1H)，8.08(s，1H)，7.70(d，J＝9.09Hz，1H)，7.31(d，J＝8.48Hz，1H)，4.69(dt，J＝11.97，2.49Hz，1H)，4.46(d，J＝11.86Hz，1H)，4.31(m，2H)，4.27(s，2H)，4.23(dd，J＝13.13，3.02Hz，1H).
Fusing point: 157-158 ℃,
[α] 21 D＝-50.01(c＝0.005，MeOH).
Ultimate analysis: C 15H 13F 3N 4O 6Calculated value: C, 44.78; H, 3.26; N, 13.92, measured value: C, 43.67; H, 2.87; N, 13.36.
Embodiment 10
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-N-(4-trifluoro Methoxyl group-benzyl)-ethanamide (15)
Figure A20068004805400491
MS：M +417.4
1H?NMR(MeOD，400MHz)：δ7.73(s，1H)，7.35(d，J＝8.70Hz，2H)，7.19(d，J＝8.70Hz，2H)，4.72(dt，J＝12.25，2.50Hz，1H)，4.45(d，J＝12.5Hz，1H)，4.40(s，2H)，4.35(dt，J＝11.7，2.5Hz，1H)，4.22-4.3(m，2H)，4.2(d，J＝3.7Hz，2H).
Fusing point: 110-111 ℃.
[α] 21 D＝-46.69(c＝0.0027，MeOH).
Ultimate analysis: C 16H 15F 3N 4O 6Calculated value: C, 46.16; H, 3.64; N, 13.45, measured value: C, 46.06; H, 3.67; N, 13.05.
Embodiment 11
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-N-[4-(4- Trifluoromethoxy-phenyl)-thiazol-2-yl]-ethanamide (16)
Figure A20068004805400492
MS：M +486.4.
1H?NMR(CD 3SOCD 3，400MHz)：δ12.31(s，1H)，8.09(s，1H)，8.00(ad，J＝8.80Hz，2H)，7.73(s，1H)，7.42(d，J＝8.65Hz，2H)，4.68(dt，J＝11.95，2.46Hz，1H)，4.46(d，J＝11.86Hz，1H)，4.42(s，2H)，4.35(m，2H)，4.23(dd，J＝14.09，3.88Hz，1H).
Fusing point: 120-121 ℃.
[α] 21 D＝-30.67(c＝0.0028，MeOH).
Ultimate analysis: C 19H 20F 3N 5O 6 *H 2O calculated value: C, 42.94; H, 3.21; N1 13.90, measured value: C, 42.65; H, 3.31; N, 13.48.
Embodiment 12
2-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-N-(6-fluoroform Oxygen base-benzothiazole-2-yl)-ethanamide (17)
Figure A20068004805400501
MS：M +460.2.
1H?NMR(CD 3SOCD 3，400MHz)：δ12.45(s，1H)，8.12(m，1H)，8.09(s，1H)，7.82(d，J＝8.82Hz，1H)，7.42(m，1H)，4.69(dt，J＝11.99，2.53Hz，1H)，4.46(d，J＝11.54Hz，2H)，4.35(m，2H)，4.23(dd，J＝13.72，3.61Hz，1H).
Fusing point: 89-90 ℃.
Ultimate analysis: C 16H 12F 3N 5O 6S *CH 3CO 2H calculated value: C, 41.62; H, 3.11; N, 13.48, measured value: C, 41.53; H, 2.66; N, 13.85.
Embodiment 13
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-(4-three for 1-[4- Fluorine methoxyl group-phenyl)-piperazine-1-yl]-ethyl ketone (18)
Figure A20068004805400511
MS：M +472.3.
1H?NMR(MeOD，400MHz)：δ7.79(s，1H)，7.12(d，J＝9.2Hz，2H)，6.9(d，J＝9.2Hz，2H)，4.7-4.8(m，1H)，4.45-4.55(m，2H)，4.32-4.42(m，2H)，4.2-4.3(m，2H)，3.7-3.8(m，1H)，3.5-3.7(m，3H)，3.05-3.25(m，3H)，2.95-3.05(m，1H).
Fusing point: 77-79 ℃.
[α] 21 D＝-44.46(c＝0.006，MeOH).
Ultimate analysis: C 19H 20F 3N 5O 6Calculated value: C, 48.41; H, 4.29; N, 18.85, measured value: C, 48.28; H, 4.07; N, 14.85.
Embodiment 14
1-[4-(4-fluoro-phenyl)-piperazine-1-yl]-2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-ethyl ketone (19)
Figure A20068004805400512
MS：M +406.5.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.06(s，1H)，7.03(m.2H)，6.93(m，2H)，4.64(dt，J＝11.94，2.35Hz，1H)，4.39(m，3H)，4.23(m，3H)，3.50(m，4H)，2.93(m，4H).
Fusing point: 73-74 ℃.
Ultimate analysis: C 18H 2OFN 5O 5 *0.5HCO 2H calculated value: C, 51.86; H, 4.95; N, 16.34, measured value: C, 51.67; H, 4.83; N, 15.68.
Embodiment 15
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-(5-three for 1-[4- Methyl fluoride-pyridine-2-yl)-piperazine-1-yl]-ethyl ketone (20)
Figure A20068004805400521
MS：M +475.2.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.41(s，1H)，8.06(s，1H)，7.80(dd，J＝9.10，2.5Hz，1H)，6.93(d，J＝9.09Hz，1H)，4.64(dt，J＝11.94，2.35Hz，1H)，4.40(m，3H)，4.23(m，3H)，3.58(m，6H)，3.43(m，2H).
Fusing point: 189-190 ℃.
[α] 21 D＝-31.96(C＝0.0026，MeOH).
Ultimate analysis: C 18H 19F 3N 6O 5Calculated value: C, 47.37; H, 4.20; N, 18.40, measured value: C, 47.17; H, 3.77; N, 18.00.
Embodiment 16
2-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen base)-(5-three for 1-[4- Fluorine methoxyl group-1H-benzimidazolyl-2 radicals-yl)-piperidines-1-yl]-ethyl ketone (21)
Figure A20068004805400522
MS：M +511.5.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.05(s，1H)，7.56(d，J＝8.66Hz，1H)，7.48(s，1H)，7.13(d，J＝8.68Hz，1H)，4.64(bd，J＝11.87Hz，1H)，4.35(m，6H)，3.73(bd，J＝12.03Hz，1H)，3.15(m，3H)，2.81(t，J＝11.35Hz，1H)，2.06(m，2H)，1.72(m，2H).
Fusing point: 131-132 ℃.
Ultimate analysis: C 21H 21F 3N 6O 6 *H 2O *2 *HCO 2H calculated value: C, 44.52; H, 4.39; N, 13.54, measured value: C, 44.30; H, 3.79; N, 13.60.
Embodiment 17
4-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen ylmethyl)-the benzene first Acid (22)
Figure A20068004805400531
Under 0 ℃, argon gas atmosphere, (60% in mineral oil, 0.26g with NaH, 6.48mmol, 120mol%) be added to (S)-2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (1.0g, 5.40mmol, 100mol%), 4-bromomethyl-benzoic acid methyl ester (1.48g, 6.48mmol, 120mol%) and tetrabutylammonium iodide (0.10g, 0.27mmol is in dry DMF 5mol%) (20.0mL) solution.Make mixture be warming up to room temperature, stirring is spent the night.Make reaction be cooled to 0 ℃, with icy water cancellation reaction.Throw out is filtered, and dry under vacuum, obtain shallow white solid.
MS：M +333.9.
1H?NMR(CD 3SOCD 3，400MHz)：δ8.02(s，1H)，7.90(d，J＝6.69Hz，2H)，7.43(d，J＝8.23Hz，2H)，4.69(m，3H)，4.46(d，J＝11.91Hz，1H)，4.25(m，3H)，3.83(s，3H).
Fusing point: 169-170 ℃.
((0.60g, 1.80mmol in DMF 100mol%) (4.0mL) solution, are heated to 95 ℃ of reactions with the reaction mixture that obtains and spend the night 200mol%) to be added to above-mentioned solid ester for 3.60mL, 3.60mmol with the 1N sodium hydroxide solution.Solvent is removed under vacuum, then added 1.0mL water.Use the Glacial acetic acid acidifying to pH 2.0 reaction mixture then.(3 * 100mL) extractions with the organic layer anhydrous sodium sulfate drying that merges, concentrate, and obtain 4-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [the basic oxygen ylmethyl of 1,3] oxazine-6-)-phenylformic acid with EtOAc with product.
MS：M +319.9.
1H?NMR(CD 3SOCD 3，400MHz)：δ12.99(s，1H)，8.02(s，1H)，7.90(d，J＝8.28Hz，2H)，7.41(d，J＝8.39Hz，2H)，4.70(m，3H)，4.46(d，J＝11.89Hz，1H)，4.24(m，3H).
Fusing point: 212-213 ℃.
Embodiment 18
(S)-and 2-nitro-6-[4-(5-trifluoromethoxy-1H-benzimidazolyl-2 radicals-yl)-benzyloxy]-6, the 7-dihydro -5H-imidazo [2,1-b] [1,3] oxazine (23)
Figure A20068004805400541
In inert atmosphere, with 4-((S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen ylmethyl)-phenylformic acid (100mol%) is dissolved in (0.20 M) in the anhydrous methylene chloride, adds HATU (120mol%) and DIEA (120mol%).Reactant at stirring at room 5min, is added 1 then, the benzene (120mol%) of 2-diamino-replacement.With the reaction mixture that obtains in stirred overnight at room temperature.Reactant is concentrated, and be dissolved in the ethyl acetate, wash with water three times.The organic layer anhydrous Na 2SO 4Drying concentrates, and obtains the light brown solid, and it is dissolved in (0.36M) in the Glacial acetic acid.Reaction mixture is heated to 95 ℃ of reaction 30min.Crude product mixture is concentrated, the residue of gained with anti-phase preparation type LC purifying, is obtained final compound, be fluffy solid.
MS：M +476.4.
1H?NMR(CD 3OH，400MHz)：δ8.05(d.J＝8.18Hz，2H)，7.74(s，1H)，7.62(d，J＝8.76Hz，1H)，7.50(m，3H)，7.18(dd，J＝8.73，1.24Hz，1H)，4.87(s，2H)，4.73(m，2H)，4.48(d，J＝12.05Hz，1H)，4.30(m，2H).
Fusing point: 98-99 ℃.
[α] 21 D＝-37.81(C＝0.003，MeOH).
Embodiment 19
4-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen ylmethyl)-benzonitrile (24)
Under 0 ℃, argon gas atmosphere, (60% in mineral oil, 0.16g with NaH, 4.05mmol, 150mol%) be added to the 2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (0.50g, 2.70mmol, 100mol%), 4-brooethyl benzonitrile (0.63g, 3.20mmol, 120mol%) and tetrabutylammonium iodide (0.050g, 0.14mmol is in dry DMF 5mol%) (12ml) solution.Mixture is warming up to room temperature, and stirs 4h.With methyl alcohol cancellation reaction, removal of solvent under reduced pressure.Methylene dichloride is added in the residue, mixture is removed by filter inorganic salt.With the organic layer vacuum concentration,, obtain 4-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen ylmethyl)-benzonitrile with anti-phase LC purifying.
MS：M +301.2.
1H?NMR(CD 3SOCD 3.400MHz)：δ8.02(s，1H)，7.80(d，J＝8.30Hz，2H)，7.48(d，J＝8.34Hz，2H)，4.74(abq，J＝13.16，3.32Hz，2H)，4.67(dt，J＝12.02，2.37Hz，1H)，4.47(d，J＝11.91Hz，1H)，4.24(m，3H).
Fusing point: 166-167 ℃.
Embodiment 20
2-nitro-6-[4-(5-trifluoromethoxy-benzoxazoles-2-yl)-benzyloxy]-6,7-dihydro-5H-imidazoles And [2,1-b] [1,3] oxazine (25)
Figure A20068004805400552
Under 0 ℃, argon gas atmosphere, Acetyl Chloride 98Min. (3500mol%) is added in the ethanolic soln (0.16M) of 4-(2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-base oxygen ylmethyl)-benzonitrile (100mol%) of stirring.Mixture is warmed to room temperature, and stirs 5h.Reactant is concentrated under vacuum, and be used for the next step.Residue is dissolved in (0.30M) in the exsiccant ethanol once more, adds 1,2-amino-phenol (120mol%) and triethylamine (120mol%) spend the night the reaction mixture stirring that obtains.Reactant is concentrated, and end product obtains the final compound of brown ceramic powder shape with the anti-phase LC purifying of preparation type.
MS：M +477.0.
1H?NMR(CD 3Cl，400MHz)：δ8.22(d，J＝8.30Hz，2H)，7.62(s，1H)，7.57(d，J＝8.82Hz，1H)，7.47(d，J＝8.26Hz，2H)，7.40(s，1H)，7.22(m，1H)，4.75(abq，J＝44.57，12.4Hz，2H)，4.65(m，1H)，4.37(d，J＝12.16Hz，1H)，4.17(m，2H).
Fusing point: 187-188 ℃.
Ultimate analysis: C 21H 15F 3N 4O 6Calculated value: C, 52.94; H, 3.18; N, 11.75, measured value: C, 52.77; H, 3.22; N, 11.21.
Embodiment 21
(S)-1-(tertiary butyl-dimethyl-silanyloxy base)-3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol (26)
With mixture 2-chloro-4-nitroimidazole (20.0g, 0.14mol, 100mol%) be dissolved in the dehydrated alcohol (200mL), at room temperature add Anhydrous potassium carbonate (2.82g, 0.020mol, 15mol%), add the tertiary butyl-dimethyl-((S)-1-oxyethane ylmethoxy)-silane (22.2mL then, 0.11mol, 0.78mol%).Reaction mixture is heated to 70 ℃ of reaction 6-10h.Then solvent is removed in a vacuum, compound of reaction is dissolved in the ethyl acetate.Organic layer water, 0.5N hydrochloric acid, water, salt water washing remove in a vacuum and desolvate several times, obtain pure crude product (35.7g, 90.2%), are faint yellow solid.This solid suspension in ether, is filtered the final compound that obtains the colourless powder shape.Remaining filtrate is concentrated, will repeat twice with the process of ether sedimentation products.
MS：M +336.3.
Embodiment 22
1-[(S)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2- Chloro-4-nitro-1H-imidazoles (27)
With (S)-1-(tertiary butyl-dimethyl-silanyloxy base)-3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol (3.0g, 8.9mmol, 100mol%) be dissolved in the methylene dichloride (100mL), with fresh distillatory 3,4-dihydro-2H-pyrans (1.5g, 17.8mmol, 200mol%) be added in the above-mentioned solution, then add the tosic acid pyridinium salt (3.4g, 13.4mmol, 150mol%).With reaction mixture at stirring at room 24h.With saturated sodium bicarbonate aqueous solution with the reaction mixture cancellation.Separate organic layer, with the water section dichloromethane extraction.With organic phase water, the salt water washing that merges, use dried over mgso, under vacuum, remove and desolvate, obtain the 1-[(S of colorless oil)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2-chloro-4-nitro-1H-imidazoles.
MS：M +420.6.
Embodiment 23
(S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6,7-dihydro-5H-imidazo [2,1- Piperazine (28)
With 1-[(S)-3-(tertiary butyl-dimethyl-silanyloxy base)-2-(tetrahydrochysene-pyrans-2-base oxygen base)-propyl group]-2-chloro-4-nitro-1H-imidazoles (0.74g, 1.76mmol, 100mol%) be dissolved in the anhydrous tetrahydro furan (180ml), in this solution, add the TBAF (tetrahydrofuran solution of 1M, 1.76ml, 100mol%).With the reaction tubes sealing, be exposed under the microwave at 140 ℃ of reaction 7min.Solvent is removed under vacuum, and the residue silica gel purification obtains (S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6 of faint yellow oily, 7-dihydro-5H-imidazo [2,1-b]-[1,3] oxazine.
Embodiment 24
(S)-and 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (29)
With (S)-2-nitro-6-(tetrahydrochysene-pyrans-2-base oxygen base)-6,7-dihydro-5H-imidazo [2,1-b]-[1, (4.35g, 16.1mmol 100mol%) were dissolved in HOAc/THF/ water 4: 2: 1 (72: 36: 18ml) to 3] oxazines, reaction mixture is heated to 60 ℃, and stirs 18h.Reaction mixture is cooled to room temperature, and drip dichloromethane grinds, with sedimentation products.After the filtration, filtrate volume is reduced, process of lapping is repeated several times, obtain (S)-2-nitro-6 of faint yellow solid shape, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol.
MS：M +186.4
Embodiment 25
Alkylation (S)-2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (29) general Method
Under 0 ℃, argon gas atmosphere, (60% in mineral oil with NaH, 0.16g 3.9mmol 150mol%) is added to (S)-2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] and [1,3] oxazine-6-alcohol (2.64mmol, 100mol%), benzyl halogenide (120mol%) and tetrabutylammonium iodide (0.05g, 0.13mmol, in dry DMF 5mol%) (10.0ml) solution.Mixture is warming up to room temperature, and stirs and spend the night.Reaction is cooled to 0 ℃, uses the icy water cancellation.Product use dried over mgso with 250ml ethyl acetate extraction twice, and is concentrated under vacuum, obtains brown oily crude product, this its with anti-phase preparation LC purifying, obtain product.
Embodiment 26
Figure A20068004805400582
The method of describing among the compound 30 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and the preparation of 1-bromo-4-chloromethylbenzene.
MS：M +356.3
Embodiment 27
The method of describing among the compound 31 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and 1-chloromethyl-4-Trifluoromethyl phenyl ether preparation.
MS：M +360.3
Embodiment 28
Figure A20068004805400592
The method of describing among the compound 32 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and 1-chloromethyl-2-Trifluoromethyl phenyl ether preparation.
MS：M +360.3
Embodiment 29
Figure A20068004805400593
The method of describing among the compound 33 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and 1-brooethyl-3, the preparation of 5-di-trifluoromethyl benzene.
MS：M +412.3
Embodiment 30
Figure A20068004805400594
The method of describing among the compound 34 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and the preparation of 1-brooethyl benzene.
MS：M +275.7
Embodiment 31
Figure A20068004805400601
The method of describing among the compound 35 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (6) and 1-brooethyl-4-cyclohexyl anisole preparation.
MS：M +388.1
Embodiment 32
Figure A20068004805400602
With the 4-fluoro benzyl bromide (1.89g, 10.0mmol), the 4-hydroxy-benzyl alcohol (1.24g, 10.0mmol) and Cs 2CO 3(6.52g, anhydrous acetonitrile 20.0mmol) (30ml) mixture heating up backflow 18h.Mixture is cooled to room temperature, filters, removal of solvent under reduced pressure obtains the light brown solid, and it is ground with a spot of methylene dichloride, obtains 36, is light yellow crystalloid solid.
mp：132.0-133.4℃. 1H?NMR(CDCl 3)δ4.63(s，2H)，5.03(s，2H)，6.93-7.11(m，4H).
MS：M +388.1。
Embodiment 33
Figure A20068004805400603
The method of describing among the compound 37 usefulness embodiment 25, by 2-nitro-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (29) and 1-chloromethyl-4-(4-fluorine benzyloxy) benzene preparation.Obtain 37 of light yellow solid shape after the aftertreatment.
Mp：150.2-150.9℃. 1H?NMR(CDCl 3)δ4.09-4.22(m，3H)，4.36(d，12.0Hz，1H)，4.56-4.64(m，2H)，4.70(d，12.0Hz，1H)，5.06(s，2H)，6.96-7.15(m，4H)，7.25-7.46(m，5H). 13C?NMR(CDCl 3)δ48.0，67.6，68.9，69.8，70.9，115.6，116.0，117.4，130.4，130.6，131.1，134.5，148.3，159.5，161.7，164.9.
Embodiment 34
Figure A20068004805400611
At 0 ℃, with methylsulfonyl chloride (0.78mL, 10.0mmol) be added to stirring 29 (0.93g, 5.0mmol) and triethylamine (2.1mL is in DMF 15.0mmol) (40mL) solution.Then reaction mixture is stirred 1h at 0 ℃ again.Solvent and excessive reagent decompression are removed.(50mL) is added in the light brown residue with water.Then mixture is filtered,, obtain 38 of yellow/white solid solid water (50mL) washing.
Mp:213-214 ℃. 1H NMR (acetone-d 6) δ 3.30 (s, 1H), 4.58 (br d, 14.1Hz, 1H), 4.69 (dd, 3.3Hz, 14.1Hz, 1H), 4.77-4.78 (m, 2H), 5.56-5.60 (m, 1H), 7.86 (s, 1H). 13C NMR (DMSO-d 6) δ 37.9,47.6,68.6,69.1,117.9,142.2,146.5.
Embodiment 35
With compound 38 (1.68g, 6.3mmol), NaN 3(5g, DMF 76mmol) (20mL) mixture are in inert atmosphere, in 70 ℃ of heating 48h.The solvent decompression is removed.(100mL) is added in the residue with water.(3 * 80mL) extract with ethyl acetate with mixture.Organic extract is merged, with salt solution (200mL) washing, dried over mgso.Then, the solvent decompression is removed, obtain brown solid, get it, obtain 39, be yellow solid by column chromatography purification (silica gel, the dichloromethane solution of 0-5% methyl alcohol).
Mp:152.0-152.4 ℃. 1H NMR (acetone-d 6) δ 4.36 (dt, 2.4Hz, 13.5Hz, 1H), 4.58 (dd, 3.6Hz, 13.5Hz, 1H), 4.62-4.74 (m, 3H), 7.83 (s, 1H).
Embodiment 36
Under hydrogen atmosphere (balloon), with 39 (40mg, 0.19mmol) and Pd/C (10% palladium is on gac, and ethyl acetate 38mg) (8mL) mixture is at stirring at room 2h.TLC (5% methyl alcohol chloroformic solution) shows that starting raw material exhausts.Same TLC further launches with 25% methyl alcohol chloroformic solution, at R f=0.20 place shows a point.Mixture is filtered, and decompression obtains 40 with solution concentration, is light brown membranoid substance (17mg, 50%). 1H?NMR(CD 3OD)δ3.54-3.60(m，1H)，3.88(ddd，1.4Hz，5.5Hz，12.8Hz，1H)，4.23-4.30(m，2H)，4.47(ddd，1.6Hz，2.7Hz，12.8Hz，1H)，7.79(s，1H).
Embodiment 37
At room temperature, with 4-(trifluoromethoxy) phenoxyacetyl chloride (1.2g, 4.6mmol) be added to stirring amine 40 crude products (the amine crude product that trinitride reduction obtains ,～1.1mmol) and triethylamine (1.1mL is in DMF 8.0mmol) (20mL) solution.With reaction mixture again at stirring at room 18h.Solvent and excessive reagent decompression are removed.Add entry (50mL).(3 * 50mL) extract with methylene dichloride with mixture.Organic extract is merged, and (2 * 100mL) washings are through dried over mgso for water.Then, the solvent decompression is removed, obtain brown jelly, it with preparation TLC (with the dichloromethane solution wash-out of 5% methyl alcohol) purifying, is obtained 41 of yellow solid shape.
Mp:158.0-159.5 ℃. 1H NMR (CDCl 3) δ 4.18 (br d, 13.2Hz, 1H), 4.29 (dd, 4.7Hz, 13.2Hz, 1H), 4.43 (dd, 1.7Hz, 11.7Hz, 1H), and 4.53-4.62 (m, 3H), 4.78-4.88 (m, 1H), (6.82-7.14 m, 1,4-two substitute modes, 4H, fragrant H), 7.28 (s, 1H, imidazoles-H), 8.20 (br d, 7.8Hz, 1H, acid amides-H). calculated value: C44.78, H3.26, N13.93; Measured value: C44.89, H3.25, N13.75.
Embodiment 38
Figure A20068004805400631
In inert atmosphere, 40 (100mol%) are dissolved in (0.2M) in the dry DMF, add 1-(4-trifluoromethyl-pyrimidine-2-base)-piperidines-4-formyl chloride (120mol%) and triethylamine (200mol%).With the reaction mixture that obtains in stirred overnight at room temperature.Reactant is concentrated, and be dissolved in the ethyl acetate, wash with water three times.With the organic layer anhydrous sodium sulfate drying, concentrate, with anti-phase preparation type LC purifying, obtain 42.
MS：M +442.3
Embodiment 39
Figure A20068004805400632
2-chloro-4-nitroimidazole (2.6mmol) once is added in the ethanolic soln of 2-(4-the fluorophenyl)-oxyethane (2.17mmol) in sealed tube, at 70 ℃ of heating 16h.Reaction mixture is concentrated, residue is dissolved in the methylene dichloride, and filter.Filtrate concentrating obtained crude compound.With crude compound silica gel (60-120 order) column purification, the ethyl acetate with 10% to 25%: the sherwood oil gradient is made eluent, obtains 204mg alcohol 43.
MS：M +251.3
Embodiment 40
At room temperature, the tetrahydrofuran solution of alcohol 43 (0.7mmol) is added in NaH (using the exsiccant hexane wash before using) the tetrahydrofuran (THF) suspension (1.4.mmol) of suspension, stirs 2h at 80 ℃.Solvent is removed under vacuum, residue is dissolved in the methylene dichloride, water, salt water washing, dry (using sodium sulfate).With the concentrated crude product that obtains of organic layer.With crude compound with silica gel (60-120 order), adopt the ethyl acetate of 15% to 25% gradient: sherwood oil is made the eluent purifying, obtains 45mg target compound 44.
MS：M +250.2
Embodiment 41
In the dry methylene chloride solution of the 3-chloro-1-phenyl-1-propyl alcohol (1.1mmol) that stirs, add imidazoles (2.33.mmol), then add DMAP (0.11mmol), stir 1/2h.Add TBDMSCl (4.68mmol) then, stirring at room 12h uses the TLC monitoring reaction.With the reaction mixture dilute with water, (3 * 30mL) extractions with pure water, salt water washing, dry (using sodium sulfate), use Rotary Evaporators at concentrating under reduced pressure below 40 ℃ to methylene dichloride.
MS：M +284.9
Embodiment 42
Figure A20068004805400643
With K 2CO 3(1.4mmol) and NaI (0.066mmol) be added in the dry DMF solution of compound 45 (0.7mmol) of stirring stirring at room 30min.Then, add compound 2-chloro-4-nitro-imidazoles (0.84mmol), and spend the night, use the TLC monitoring reaction 80 ℃ of stirrings in room temperature.With the reaction mixture dilute with water, the usefulness methylene dichloride (3 * 25mL) extractions, water, salt water washing, dry (using sodium sulfate), and under vacuum, concentrate.It is the eluent purifying that crude compound adopts 30% ethyl acetate/petroleum ether with neutral alumina, obtains 46.
MS：M +396.3
Embodiment 43
Figure A20068004805400651
In room temperature, in the tetrahydrofuran solution of compound 46 (0.5mmol), add 1MTBAF-THF (1.5.mmol), and stir 12h at 60 ℃, use the TLC monitoring reaction.With reaction mixture cancellation in water, (3 * 25mL) extractions, dried over sodium sulfate is used in water, salt water washing, concentrates under vacuum at 40 ℃ with methylene dichloride.The TLC of crude compound analyzes and shows and have the product of institute's phase and by simple deprotection deutero-alcohol.These two kinds of compositions by silica gel (100-200 order) column chromatography for separation, are made eluent with 40% ethyl acetate/petroleum ether.Use TBAF-THF in 60 ℃ of processing, the cyclisation product of being measured in addition once more alcohol.
MS：M +246.3
Embodiment 44
Figure A20068004805400652
With 1 of 2-chloro-4-nitroimidazole (4.11mmol) and triethylamine (1.58mmol), 4-dioxane mixture stirs 30min.Then, 1-octene-3-ketone (3.16mmol) is added in the said mixture, in sealed tube, stirs 12h in 60 ℃.To react dilute with water, (3 * 30mL) extractions, water, salt water washing are with dried over sodium sulfate and concentrated with ethyl acetate.Crude samples need not be further purified, and promptly can be used for next step.
MS：M +274.2
Embodiment 45
Figure A20068004805400661
With Na 2BH 4(2.2mmol) be added in the dry methanol solution of compound 48 (2.2mmol) of precooling (0 ℃) in batches, and stir 2h at 0 ℃.To react and use the acetone cancellation, and stir 30min, evaporate organic solvent then.With the reactant dilute with water, and with ethyl acetate (3 * 30mL) extraction.Organic layer water, salt water washing through dried over sodium sulfate, and concentrate.Crude compound is filtered by short neutral alumina post, is eluent with ethyl acetate.Solvent evaporated obtains 49.
MS：M +276.2
Embodiment 46
Figure A20068004805400662
In room temperature, in the dry tetrahydrofuran solution of compound 49 (1.8mmol), add TBAF (5.4mmol) lentamente, and stir 12h at 60 ℃.With the reactant dilute with water, and with ethyl acetate (3 * 30mL) extraction.Organic layer water, salt water washing with dried over sodium sulfate and concentrated, obtain crude product 50.The compound that obtains is passed through silica gel (100-200 order) purifying, use 5% ethyl acetate: the chloroform give eluent.Solvent evaporated obtains pure 50.
MS：M +240.3[M] +
Embodiment 47
Figure A20068004805400671
With 2-azido methyl-oxyethane (6.5g, 65.6mmol), 2-chloro-4-nitro-1H-imidazoles (10.6g, 72.2mmol), (1.8g 13.1mmol) mixes in exsiccant ethanol (100ml) salt of wormwood, and at 70 ℃ of heating 18h.Under vacuum, remove and desolvate,, obtain 1-azido--3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol, be light yellow sticky solid the crude product purification by flash chromatography.
MS：246.61M +＝247.2M -＝245.1
1H?NMR(400MHz，CDCl 3)：δ7.92(s，1H)，4.35(bs，1H)，4.19-4.14(m，2H)，4.05-3.99(m，1H)，3.49-3.38(m，2H).
Sodium hydride (60% in mineral oil) and methyl iodide (120mol%) in-20 ℃ of dry DMF (25ml) solution that are added to 1-azido--3-(2-chloro-4-nitro-imidazoles-1-yl)-propan-2-ol (120mol%), and are stirred 4h.With reaction mixture icy water (100ml) cancellation, (3 * 100ml) extract water layer with ethyl acetate.With the organic layer anhydrous sodium sulfate drying that merges, concentrate in a vacuum,, obtain 1-(3-azido--2-methoxyl group-propyl group)-2-chloro-4-nitro-1H-imidazoles through purification by flash chromatography, be light yellow sticky solid, it be reduced to corresponding amine with the Staudinger reaction.1-(3-azido--2-methoxyl group-propyl group)-2-chloro-4-nitro-1H-imidazoles (100mol%) and triphenylphosphine (120mol%) are dissolved in the methylene dichloride, with reactant at stirring at room 6h.To react cancellation, obtain 3-(2-chloro-4-nitro-imidazoles-1-yl)-2-methoxyl group-propylamine with 1N HCl.
At room temperature, 4-(methoxyl group) phenyl aldehyde (150mol%) is added to 3-(2-chloro-4-nitro-imidazoles-1-yl)-2-methoxyl group-propylamine (amine crude product that obtains by trinitride reduction of stirring, in～100mol%) the DMF solution, then add Glacial acetic acid (100mol%).Behind the 30min, add NaBH 3CN (200mol%).With reaction mixture again at stirring at room 18h.The solvent decompression is removed.(50mL) is added in the residue with water.(3 * 50mL) extract with methylene dichloride with mixture.Organic extract is merged, and water (100mL) washing is through dried over mgso.Then, removal of solvent under reduced pressure obtains brown jelly, and it is dissolved among the DMF.Add DBU (150mol%), with reactant in microwave in 120 ℃ of radiation 10min, behind the preparation HPLC purifying, obtain 6-methoxyl group-8-(4-methoxyl group-benzyl)-2-nitro-5,6,7,8-tetrahydrochysene-imidazo [1,2a] pyrimidine.
MS：M +319.3
Embodiment 48
(S)-and 2-nitro-6-(4-trifluoromethyl sulfane base-benzyloxy)-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (52)
Figure A20068004805400681
In 0 ℃, argon gas atmosphere, (60% in mineral oil with NaH, 150mol%) be added to (S)-2-nitro-6 of stirring, 7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine-6-alcohol (100mol%), 1-brooethyl-4-trifluoromethyl sulfane base-benzene are (in the anhydrous DMF solution of 120mol% and tetrabutylammonium iodide (5mol%).Mixture is warming up to room temperature, and stirring is spent the night.Reactant is cooled to 0 ℃, and uses the icy water cancellation.Product, concentrates under the vacuum through dried over mgso with 250mL ethyl acetate extraction twice, obtains brown oily crude product, it with anti-phase preparation type LC purifying, is obtained (S)-2-nitro-6-(4-trifluoromethyl sulfane base-benzyloxy)-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazines, 52
MS：M +376.3
Embodiment 49
2-nitro-6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-ylmethyl]-6,7-dihydro-5H-imidazo [2,1-b] [1,3] oxazine (53)
Figure A20068004805400682
(10.54g 48.9mmol) is dissolved in the methylene dichloride (100ml), adds diatomite (10g), and suspension is stirred 30min with pyridinium chlorochromate.(5g, dry methylene chloride drips of solution 34.2mmol) is added in the reaction mixture, at stirring at room 2h with (2,2-dimethyl-1,3-diox-5-yl) methyl alcohol.Reaction mixture with ether (80ml) dilution, is stirred 10min, by diatomite filtration, with the ether washing several times, remove in a vacuum and desolvate, obtain 2,2-dimethyl-[1,3] diox-5-formaldehyde crude product need not be further purified, and uses it for next step.
With 2,2-dimethyl-[1,3] diox-5-formaldehyde (3.52g 24.4mmol) is dissolved in 1, in the 2-ethylene dichloride (250ml), adds 1-[4-(trifluoromethoxy)-phenyl]-piperazine (6.01g, 24.4mmol) 1,2-ethylene dichloride (50ml) solution.Reaction mixture is kept 1h in room temperature.(20.72g 97.7mmol) is added in the reaction mixture to gradation in a small amount with sodium triacetoxy borohydride.With reaction mixture at stirring at room 9h.Water is added in the reaction mixture, uses chloroform extraction.With the organic layer drying, concentrate, obtain 1-(2, the 2-dimethyl-[1,3] diox-5-ylmethyl)-4-(4-trifluoromethoxy-phenyl)-piperazine.
With this bridged piperazine derivatives (7.09g 18.9mmol) is dissolved in the methyl alcohol (80ml), adds entry (3ml), then add tosic acid (3.91g, 22.7mol), with reaction mixture at 60 ℃ of reflux 3h.Compound of reaction is concentrated,, then use chloroform extraction with the neutralization of 10% sodium bicarbonate aqueous solution.In a vacuum solvent is removed, is obtained 2-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-ylmethyl]-the third-1, the 3-glycol, it need not be further purified, and promptly can be used for next step.
(2.58g 64.6mmol) is cooled to-20 ℃ at exsiccant DMF (100ml) suspension, and (4.5g, DMF 16.1mmol) (25ml) solution is added in the reaction mixture, stirs 1h with above-mentioned glycol with sodium hydride.(2.92g, dry DMF drips of solution 19.3mmol) adds in the reaction mixture, and stirs 1 hour with TERT-BUTYL DIMETHYL CHLORO SILANE.With reaction mixture icy water cancellation, and use ethyl acetate extraction.With organic layer water, salt water washing, through dried over sodium sulfate, concentrate, by column chromatography purification, obtain 3-(tertiary butyl-dimethyl-silanyloxy base)-2-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-ylmethyl]-third-1-alcohol.
1H?NMR(400MHz，CDCl 3)：δ7.2(d，2H)，6.9(d，2H)，3.9(dd，1H)，3.7(dd，1H)，3.5(h，1H)，3.2(bs，4H)，3.2(m，2H)，2.8(bs，4H)，2.2(m，1H)，1.3(s，9H)，0.1(s，6H).
MS：M +449.6.
(100mol%) is dissolved among the DCM with above-mentioned alcohol, adds DMAP (0.07mol%), then adds triethylamine (157mol%) and NsCl (100mol%) at 0 ℃.Reaction mixture is risen to room temperature, stir 5h.Remove solution in a vacuum, residue is dissolved in the ethyl acetate, dried over mgso is used in water, 0.5N hydrochloric acid, water, salt water washing, filters and concentrates.Residue need not be further purified and be directly used in next step.
Thick m-nitrobenzene sulfonic acid ester (nosylate) is dissolved among the DMF, adds 2-chloro-nitroimidazole (150mol%) and salt of wormwood (120mol%), reaction mixture is heated to 150 ℃ of reaction 5min in microwave.Solvent is removed, and residue is dissolved in the ethyl acetate, with 0.5N hydrochloric acid, water, salt water washing for several times, use dried over mgso.Remove in a vacuum and desolvate.With the residue column chromatography purification, obtain 1-[3-(tertiary butyl-dimethyl-silanyloxy base)-2-(2-chloro-4-nitro-imidazoles-1-ylmethyl)-propyl group]-4-(4-trifluoromethoxy-phenyl)-piperazine.
MS：M +578.6.
With 1-[3-(tertiary butyl-dimethyl-silanyloxy base)-2-(2-chloro-4-nitro-imidazoles-1-ylmethyl)-propyl group]-4-(4-trifluoromethoxy-phenyl)-piperazine (100mol%) is dissolved in the anhydrous tetrahydro furan, (tetrahydrofuran solution of 1M 100mol%) is added in the above-mentioned solution with TBAF.With the reaction tubes sealing, be exposed under the microwave at 140 ℃ of reaction 8min.Under vacuum, remove and desolvate,, obtain the compound 53 of faint yellow solid shape residue silica gel and preparation HPLC purifying.
MS：M +428.6.
Embodiment 50
Figure A20068004805400701
Synthetic compound 54 shown in the following surface current journey.
Embodiment 51
Figure A20068004805400712
Compound 55 bases are described in European pharmaceutical chemistry magazine (Eur J Med Chem), and 24,1989, the method among the 631-633 is synthetic.
Embodiment 52: the Killing Mycobacterium Tuberculosis activity
Anti-two kinds of the MIC values of test-compound and control compound have been tested with reference to organism mycobacterium bovis bcg (BCG) pasteur (Pasteur) (ATCC 35745) and mycobacterium tuberculosis H37Rv (ATCC27294).Described bacterium is being added with 10% (v/v) albumin-glucose saline [ADS:0.81%NaCl, 5%BSA fraction V (Luo Shi (Roche), Mannheim, Germany) and 2% glucose], cultivate in the Middlebrook 7H9 meat soup (BectonDickinson) of 0.2% glycerine, 0.05% tween 80.
Some improved broth microdilution antifungal susceptibility test (NCCLS, national clinical experiment standard committee (2003 methods of the dilution antimicrobial susceptibility test of National Committee for Clinical Laboratory Standards. growth aerobic bacteria are adopted in drug susceptibility experiment; Approval standards (2003 Methodsfor Dilution Antimicrobial Susceptibility Tests for Bacteria that GrowAerobically; Approved Standard), sixth version) in flat 96-orifice plate, carry out.Streptomycin sulphate and PA-824 are used as control drug.The mycobacterium nutrient solution of active growth is diluted in completely in the 7H9 meat soup, with the optical density(OD) (about 106 CFU/ml) that obtains OD600-0.04.The dilution nutrient solution of equal volume (100 μ L) is added in the hole of the medicine (100 μ L) that contains serial dilution.MIC microwell plate sealing avoiding evaporating, and is cultivated them 4-7 days at 37 ℃.Redox dye Alamar blue is adopted in the growth of bacterium, and (Serotec Ltd., Oxford UK) or by measuring light density (OD600) are undertaken quantitatively.
For Alamar blue MIC analyzes, the Alamar Blue of 50 μ l prepared fresh and 1: 1 mixture of 10% tween 80 are added in each hole.Microwell plate is cultivated 24h again at 37 ℃.Bacterial growth fluorescence measurement standard measure, excite and the emission wavelength that the fluorescence measurement method is used are respectively 530nm and 590nm (SpectraMax M2, Molecular Devices), and relative intensity of fluorescence unit (RFU) is lower than 15000 and is considered to not growth.Therefore, MIC is defined as obtains≤the minimum drug level of 15000 RFU reading.
For nephelometric analysis MIC method, the OD600 value (SpectraMax M2, Molecular Devices) of record microwell plate after 7 days.With MIC be defined as value that generation obtains by the antibiotic-free growth control≤the minimum drug level of 1/10 light absorption ratio reading.Two kinds of MIC analyze and provide the repeatably result that makes peace; For the control drug Streptomycin sulphate, be respectively 06-0.13 and 0.25 μ g/mL to the MIC value of cow mycobacteria BCG and mycobacterium tuberculosis H37Rv.
Embodiment 53: anti-Oswaldocruzia activity
Use Oswaldocruzia Tulahuen C2C4 strain.With in infective amastigote and the trypomastigote stage L-6 cell (the bone sarcoplast system of rat) in RPMI 1640 substratum, at 12.5cm 2Tissue culture flasks in cultivate, described RPMI 1640 substratum are added the foetal calf serum of 2mM L-glutaminate and 10% heated and inactivated.Amastigote is divided into trypomastigote at Intracellular growth, and leaves host cell.These trypomastigotes infect new L-6 cell, and are the stages that is used to cause infection in analysis.All cultivations and analyzing all at 37 ℃ at an atmospheric 5%CO that contains 2Carry out under the air.
The compound stock solution is prepared into 10mg/mL with 100% dimethyl sulfoxide (DMSO) (DMSO), if necessary, can heat or ultrasonic with sample dissolution.After the use, storing solution is kept at-20 ℃.Analyze for this, adopt perfect medium further diluted chemical compound to be arrived suitable concentration.The DMSO concentration that contains in the hole of the highest drug level is no more than 1%.
Analysis is carried out on aseptic 96-hole microwell plate, and every hole comprises contains 2 * 10 3100 μ L substratum of L-6 cell.Behind the 24h, with 50 μ L comprise from substratum, obtain 5 * 10 3The trypanosome suspension of trypomastigote blood flow type is added in each hole.Behind the 48h, substratum is removed from each hole, replaced with the 100 μ L fresh cultures that contain or do not contain the series compound diluent.At this moment, the L-6 cell should be infected by amastigote, should not have the free trypomastigote in substratum.7 3-times of diluted chemical compound liquid have been used, from 90 μ g/mL to 0.123 μ g/mL.Each compound same form part is again tested.In order to prove conclusively, with twice of active compound test.After cultivating 96h, procuratorial work microwell plate under inverted microscope is guaranteed the growth and the asepsis growth that contrast.
Then, with substrate CPRG/Nonidet (dichlorophenol sulfonphthalein-D-galactopyranose (and CPRG, Luo Shi diagnoses company limited (Roche Diagnostics Ltd); 15.19mg) and 250 μ L Nonidet P-40 be dissolved in the aseptic phosphate buffer soln of 100mL (pH7.2), obtain 5 * CPRG in 0.25%Nonidet P-40/PBS of final desired concn), with 50 μ L add to institute porose in.As seen color reaction becomes in 2-6h, and can read at 540nm with spectrophotometer.Data conversion is become figure, and the inhibition curve of S shape obtains measuring, and calculates IC 50Value.
Embodiment 54: anti-Leishmania donovani activity
Use Leishmania donovani strain MHOM/ET/67/L82 (from Dr.S.Croft, London health and tropical medicine institute (London School of Hygiene and Tropical Medicine) locate to obtain).This strain system is kept in the Syria golden hamster (Syrian Golden hamster).From the spleen of the hamster that infects, collect amastigote.Amastigote in axenic culture, 37 ℃, at an atmospheric 5%CO that contains 2Air in, in pH value 5.4, adding (Cunningham I., protozoology magazine (J.Protozool.), 24:325-329,1977) growth in the SM substratum of foetal calf serum (FBS) of 10% heated and inactivated.
The compound stock solution is prepared into 10mg/mL with 100% dimethyl sulfoxide (DMSO) (DMSO), if necessary, can heat or ultrasonic with sample dissolution.After the use, storing solution is kept at-20 ℃.For this analysis, adopt perfect medium further diluted chemical compound to be arrived suitable concentration.The DMSO concentration that contains in the hole of the highest drug level is no more than 1%.
Analysis is carried out on the aseptic flat microwell plate in 96-hole (Costar, Corning Inc.), and every hole comprises 100 μ L and contains from 10 of axenic culture 5The substratum of amastigote, every hole contain or do not contain the series compound diluent.The concentration of amastigote is at the CASY cell analysis system
Figure A20068004805400741
System, Reutlingen, Germany) middle mensuration.To before the amastigote counting, with the parasite culture by No. 22 pins twice, so that make amastigote bunch separately.
The maximum concentration of test-compound is 90 μ g/mL.7 3-times of diluted chemical compound liquid have been used, from 30 μ g/mL to 0.041 μ g/mL.Each compound is tested in duplicate.In order to prove conclusively, with twice of active compound test.After cultivating 72h, procuratorial work microwell plate under inverted microscope guarantees to contrast the growth with aseptic condition.
Then, 10 I Alamar blue (the 12.5mg resazurin is dissolved in the 100ml distilled water) are added in each hole, microwell plate is cultivated 2h again.Then, (CA USA) adopts the excitation wavelength of 536nm and the emission wavelength of 588nm to carry out reading for Molecular Devices Cooperation, Sunnyvale with Spectramax GeminiXS microwell plate photofluorometer with microwell plate.
(CA USA) analyzes data for Molecular Devices Cooperation, Sunnyvale with microwell plate reading software Softmax Pro.Fluorescent weakening (promptly suppressing) is represented with the percentage ratio of the fluorescence of control cultures, and drug level is drawn.IC 50Value suppresses curve calculation by software program from S shape and obtains.
Commercial Application
Nitroimidazole compound of the present invention has useful pharmaceutical properties. Specifically, described chemical combination Thing for example can be used for the treatment of and/or prevent those by Much's bacillus, Oswaldocruzia or Du Shi profit The infection that assorted graceful protozoon causes.

Claims (10)

1. formula (I) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A2006800480540002C1
Wherein:
(a) m is 0;
W is that O and V do not exist;
One of R1 and R3 are halogenated aryls, and another is H; And
R2 and R4 are H;
Or:
(b) m is 1;
W is N, and V is kiki fang alkyl group, and it is optional to be replaced by one or more alkoxy substituents;
R1 and R3 are H; And
One of R2 and R4 are alkoxyl groups, and another is H;
Or:
(c) m is 1;
W is that O and V do not exist;
One of R1 and R3 are alkyl or aryls, and another is H; And
R2 and R4 are H;
Or:
(d) m is 1;
W is O, and V does not exist;
One of R2 and R4 are-L (B) n-(Z) p,-(L-B) q-(Z) pOr-Y-(B) q-Z, and another is H;
And
R1 and R3 are H;
Wherein, L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; And Z is halogen, the low alkyl group that is replaced by halogen at least, the lower alkoxy that is replaced by a halogen at least or the rudimentary sulfane base that is replaced by a halogen at least;
And Y is-NHC (O)-;
N is 1 or 2; P is 0,1 or 2; And q is 1 or 2;
Prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 be-(L-B) q-(Z) p, wherein q is that 2, two B groups all are that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then Z is not 4-trifluoromethoxy, 4-fluoro, 4-trifluoro ethoxy, 4-five fluorine propoxy-, 4-tetrafluoro propoxy-, 4-trifluoromethyl, 2,4-difluoromethyl or 2,4-two fluoro.
2. as claim 1 claimed compounds or its pharmacy acceptable salt, ester or prodrug, wherein,
M is 1;
W is O, and V does not exist;
One of R2 and R4 are-L (B) n-(Z) p,-(L-B) q-(Z) pOr-Y-(B) q-Z, and another is H;
And
R1 and R3 are H;
Wherein, L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; And Z is halogen, the low alkyl group that is replaced by halogen at least, the lower alkoxy that is replaced by a halogen at least or the rudimentary sulfane base that is replaced by a halogen at least;
And Y is-NHC (O)-;
N is 1 or 2; P is 0,1 or 2; And q is 1 or 2;
Prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 be-(L-B) q-(Z) p, wherein q is that 2, two B groups all are that phenyl and L are-O-CH 2In-time, then p is not 0;
And prerequisite is, when R2 or R4 are-L-(B) n-(Z) p, wherein n is 1, B is that phenyl and L are-O-CH 2In-time, then Z is not 4-trifluoromethoxy, 4-fluoro, 4-trifluoro ethoxy, 4-five fluorine propoxy-, 4-tetrafluoro propoxy-, 4-trifluoromethyl, 2,4-difluoromethyl or 2,4-two fluoro.
3. as claim 1 or claim 2 claimed compounds or its pharmacy acceptable salt, ester or prodrug, wherein, one of R2 and R4 are-L-(B) n-(Z) p, wherein B is piperazine, pyridine, phenyl or benzoglyoxaline group or person's oxazole or thiazolyl group, it is chosen wantonly with benzyl ring and condenses.
4. as any one claimed compounds in the claim 1 to 3 or its pharmacy acceptable salt, ester or prodrug, wherein L is-OCH 2C (O)-.
5. formula (II) compound or its pharmacy acceptable salt, ester or prodrug:
Figure A2006800480540004C1
Wherein:
L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-;
B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; N is 1 or 2; And Z is halogen, the low alkyl group that is replaced by halogen at least or the lower alkoxy that is replaced by a halogen at least; Prerequisite is, when n was 1, then B was not a phenyl, perhaps when n be 1 and B when being phenyl, then L is-OCH 2C (O) NH-or-OCH 2C (O) NHCH 2-.
6. pharmaceutical composition, this pharmaceutical composition comprises as any one claimed compounds in the claim 1 to 5 or its pharmacy acceptable salt, ester or prodrug, and pharmaceutically acceptable vehicle, diluent or carrier.
7. treat and/or prevent the disease that caused by mycobacterium tuberculosis, Oswaldocruzia or infection by Leishmania donovani or the method for illness, this method comprises significant quantity is administered to the individuality of its needs as any one claimed compounds in the claim 1 to 5 or its pharmacy acceptable salt, ester or prodrug.
8. treat and/or prevent the disease that caused by Oswaldocruzia or infection by Leishmania donovani or the method for illness, this method comprises the individuality that the formula of significant quantity (III) compound or its pharmacy acceptable salt, ester or prodrug is administered to its needs:
Figure A2006800480540005C1
Wherein:
(a) m is 0;
W is that O and V do not exist;
One of R1 and R3 are halogenated aryl or alkyl, and another is H, and perhaps R1 and R3 are low-grade alkyl groups; And
R2 and R4 are H;
Or:
(b) m is 1
W is that N and V are kiki fang alkyl groups, and it is chosen wantonly and is replaced by one or more alkoxy substituents;
R1 and R3 are H; And
One of R2 and R4 are alkoxyl groups, and another is H;
Or:
(c) m is 1;
W is that O and V do not exist;
One of R1 and R3 are alkyl or aryls, and another is H; And
R2 and R4 are H;
Or:
(d) m is 1;
W is that O and V do not exist;
One of R2 and R4 are-L (B) n-(Z) p,-(L-B) q-(Z) pOr-Y-(B) q-Z, and another is H;
And
R1 and R3 are H;
Wherein, L is the atomic radical with formula-O-R5-, wherein R5 be low-grade alkylidene ,-C (O)-, low-grade alkylidene-C (O)-,-C (O)-low-grade alkylidene, low-grade alkylidene-C (O)-NH-, low-grade alkylidene-NH-; B is cycloalkyl, heterocycle, aryl or heteroaryl ring, and it is chosen wantonly and is replaced by one or more substituting groups; And Z is halogen, the low alkyl group that is replaced by halogen at least, the lower alkoxy that is replaced by a halogen at least or the rudimentary sulfane base that is replaced by a halogen at least;
And Y is-NHC (O)-;
N is 1 or 2; P is 0,1 or 2; And q is 1 or 2;
Or its pharmacy acceptable salt, ester or prodrug.
9. the method for preparing nitrogen heterocyclic, this method comprises:
Make the epoxide and the reaction of halo imidazolium compounds of non-sterically hindered replacement, form the adducts that has alcohol functional group, wherein the mol ratio of the epoxide of non-sterically hindered replacement and halo imidazolium compounds is less than or equal to 1: 1;
Alcohol functional group on the protection adducts, the adducts of formation alcohol-protection; With
Adducts with cyclizing agent processing alcohol-protection forms nitrogen heterocyclic.
10. as claim 9 method required for protection, nitrogen heterocyclic wherein free or salt form is represented with formula (IV) compound:
Figure A2006800480540007C1
Wherein, R 1=nitro, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl; R 2=2-THP trtrahydropyranyl, 2-ethoxyethyl group, trityl, methyl, ethyl, allyl group, trimethyl silicon based ethoxyl methyl, 2,2,2-three chloroethyls, benzyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, the phenyl dimethyl is silica-based, triisopropylsilyl or (2,3-dimethyl-2-butyl)-dimethyl is silica-based; R 3=H, acyl group, formyl radical, alkylsulfonyl, trifluoromethyl, cyano group, halogen or alkoxy carbonyl.
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