Process for preparing 2-chloro-4-nitroimidazole derivatives
阅读说明：本技术 制备2-氯-4-硝基咪唑衍生物的方法 (Process for preparing 2-chloro-4-nitroimidazole derivatives ) 是由 彼得·诺瓦克 彼得·扎赫拉德尼克 吉里·塔赫曼 扬·科奇 安东尼·斯图尔克 于 2018-01-29 设计创作，主要内容包括：本发明提供了一种制备2-氯-4-硝基咪唑衍生物的改进方法,所述2-氯-4-硝基咪唑衍生物是制备抗结核药有用的中间体。所述方法可以包括用氯化剂和活化剂使硝基咪唑氯化从而得到2-氯-4-硝基咪唑衍生物的步骤。(The present invention provides an improved process for the preparation of 2-chloro-4-nitroimidazole derivatives, which are useful intermediates for the preparation of antituberculotic drugs. The method may include the step of chlorinating nitroimidazole with a chlorinating agent and an activating agent to obtain a 2-chloro-4-nitroimidazole derivative.)
1. A process for the preparation of a compound of formula I,
[ chemical formula 1]
Wherein R is1Is selected from C1-6alkoxy-C1-6Alkyl radical, C1-6alkoxy-C1-6alkoxy-C1-6Alkyl radical, C1-6Alkanoyl radicalOxymethyl radical, C6-14Aralkyl radical, C6-10Aryloxy group-C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C6-10Aryl carbonyl group, C1-6Alkylsulfonyl radical, C1-6alkyl-C6-10Arylsulfonyl and tetrahydropyranyl, each of which may be optionally substituted by at least one halogen atom,
the process comprises chlorinating a compound of formula II with a chlorinating agent and an activating agent to obtain a compound of formula I:
[ chemical formula 2]
2. The method of claim 1, wherein R1Is selected from C1-6Alkoxymethyl group, C1-6Alkoxycarbonyl, benzyl, phenoxymethyl, and tetrahydropyranyl, each of which may be optionally substituted with at least one halogen atom.
3. The process according to claim 1 or 2, wherein the chlorinating agent is a 5-or 6-membered heteromonocyclic ring comprising one or more of the following chloroimine moieties in the ring:
[ chemical formula 3]
4. The process according to claim 1 or 2, wherein the chlorinating agent is a 5-or 6-membered heteromonocyclic ring comprising one or more of the following amide moieties in the ring:
[ chemical formula 4]
5. The process according to any one of claims 1 to 4, wherein the chlorinating agent is selected from: trichloroisocyanuric acid, N-chlorosuccinimide and 1, 3-dichloro-5, 5-dimethylhydantoin.
6. The method of any one of claims 1 to 5, wherein the activator is selected from compounds of formulae III, IV, and V:
[ chemical formula 5]
Wherein R is2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3May combine to form a 5-or 6-membered heteromonocyclic ring;
R4is selected from C1-6Alkyl and C6-14An aryl group;
R5is C1-6An alkoxy group; and is
X is O or S.
7. The method of claim 6, wherein R2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3Can be combined to form a saturated 5-or 6-membered heteromonocyclic ring containing two nitrogen atoms.
8. The method of claim 6 or 7, wherein the activator is selected from compounds of formula III or IV.
9. The process of claim 8, wherein the activator is selected from compounds of formula III or IV wherein X is S.
10. The method of claim 6, wherein the activator is selected from the group consisting of: urea, thiourea, thioacetamide, thiobenzamide, N-methylThiourea, 1, 3-dimethylthiourea, 2-imidazolidinethione, N-methylthioacetamide, benzamide and (iPrO)3B。
11. The method of claim 1, wherein R1Selected from: c1-6Alkoxymethyl group, C1-6Alkoxycarbonyl, benzyl, phenoxymethyl, which may be optionally substituted with at least one halogen atom, and tetrahydropyranyl;
the chlorinating agent is selected from: trichloroisocyanuric acid, N-chlorosuccinimide, and 1, 3-dichloro-5, 5-dimethylhydantoin; and is
The activator is selected from compounds of formulae III, IV and V:
[ chemical formula 6]
Wherein R is2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3Can combine to form a saturated 5-or 6-membered heteromonocyclic ring containing two nitrogen atoms;
R4is selected from C1-6Alkyl and C6-14An aryl group;
R5is C1-6An alkoxy group; and is
X is O or S.
12. The process according to any one of claims 1 to 11, wherein the chlorination is carried out in a solvent selected from the group consisting of esters, nitriles, halogenated hydrocarbons, and any mixtures thereof.
13. The process of any one of claims 1 to 12, wherein a dechlorinating agent is added after chlorination of the compound of formula II.
14. The process of any one of claims 1 to 13, further comprising the step of deprotecting the compound of formula I to give 2-chloro-4-nitroimidazole.
15. A compound of the formula (Ia),
[ chemical formula 7]
Wherein R is1aIs selected from C1-6Alkoxymethyl group, C1-6Alkoxycarbonyl, phenoxymethyl, and tetrahydropyranyl, each of which may be optionally substituted with at least one halogen atom.
16. The compound of claim 15, wherein R1aSelected from: ethoxymethyl, tert-butoxycarbonyl, 3-chloro-phenoxymethyl, and tetrahydropyranyl.
Technical Field
The present invention relates to an improved process for the preparation of 2-chloro-4-nitroimidazole derivatives, which are useful intermediates for the preparation of antituberculotic drugs.
Background
2-chloro-4-nitroimidazole (hereinafter also referred to as "2-CNI") was prepared by the following anti-tubercular drug Delamani (chemical name: (2R) -2-methyl-6-nitro-2- [ (4- {4- [4- (trifluoromethoxy) phenoxy ] N-oxyl)]-1-piperidinyl } phenoxy) methyl]-2, 3-dihydroimidazo [2,1-b][1,3]
[ chemical formula 1]
The diramanib can be used for treating multi-drug resistant tuberculosis.
Many methods of synthesizing 2-CNI have been reported, including various approaches. However, most of them have various disadvantages such as risk of explosion, toxicity and high overall production cost.
A method for preparing 2-CNI by nitration is disclosed in the Journal of Polish Chemistry 1982, 56, 1261-. However, the production method has a major problem in terms of safety, that is, some intermediates such as dinitroimidazole are unstable and cause explosion. WO 2010/021409 discloses several optimized processes for the preparation of 2-CNI by nitration as shown below. The process is economically advantageous, but there are still safety risks in the synthesis and the process.
[ chemical formula 2]
Another method for preparing 2-CNI by nitrating 2-chloroimidazole is disclosed in CN 103396369a, but it brings with it some disadvantages, such as the use of nitrating mixtures (e.g. fuming nitric acid and fuming sulfuric acid) as shown below, and higher costs associated with the special reaction materials.
[ chemical formula 3]
In another method, 2-chloro-4-nitroimidazole is prepared by N-protected 4-nitroimidazole (WO 2006/035960, shown below). 2-bromo-5-halo-4-nitroimidazole is protected under alkoxyalkyl action and then selectively reduced to form the corresponding 1-alkoxyalkyl-2-bromo-4-nitroimidazole. Then, the 1-alkoxyalkyl-2-bromo-4-nitroimidazole is treated with hydrochloric acid to obtain 2-chloro-4-nitroimidazole. But this is a lengthy process.
[ chemical formula 4]
In the above reaction scheme, R1Is lower alkyl, n is an integer of 1 to 3, X1Is halogen, X2Is halogen or lower alkoxy.
Another method disclosed in US 2007/0161802 a1 comprises iodinating a 4-nitroimidazole compound, and then reducing the obtained 5-iodo-4-nitroimidazole compound to prepare a 2-halogenated 4-nitroimidazole compound, as shown below.
[ chemical formula 5]
In the above reaction scheme, X1And X2Each independently is chlorine or bromine.
Efficient selective chlorination of 4-nitroimidazole is unknown, and further efficient methods for preparing 2-chloro-4-nitroimidazole derivatives are needed.
List of reference files
Patent document
[PTL 1]WO 2010/021409
[PTL 2]CN 103396369A
[PTL 3]WO 2006/035960
[PTL 4]US 2007/0161802
Non-patent document
[ NPL 1] Journal of Polish Journal of Chemistry 1982, 56, 1261-
Problem of operation
The present invention provides an improved process for the preparation of 2-chloro-4-nitroimidazole derivatives, which are useful intermediates for the preparation of the antituberculotic delamanit.
Technical scheme for solving problems
The present inventors have conducted extensive studies to improve a process for preparing 2-chloro-4-nitroimidazole derivatives, and then developed and realized an efficient process for preparing 2-chloro-4-nitroimidazole derivatives via selective chlorination by combining an appropriate chlorinating agent with an activator.
The methods disclosed herein include the following embodiments:
a process for preparing a compound of formula I:
[ chemical formula 6]
Wherein R is1Is selected from C1-6alkoxy-C1-6Alkyl radical, C1-6alkoxy-C1-6alkoxy-C1-6Alkyl radical, C1-6Alkanoyloxymethyl radical, C6-14Aralkyl radical, C6-10Aryloxy group-C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C6-10Aryl carbonyl group, C1-6Alkylsulfonyl radical, C1-6alkyl-C6-10Arylsulfonyl and tetrahydropyranyl, each of which may be optionally substituted with at least one halogen atom, the method comprising chlorinating a compound of formula II with a chlorinating agent and an activating agent to give a compound of formula I:
[ chemical formula 7]
Advantageous effects of the invention
The methods disclosed herein may have at least one of the following advantages:
selective chlorination can be achieved by selecting a suitable chlorinating agent in combination with a suitable activating agent;
such selective chlorination can reduce unreacted starting materials that can be difficult to separate or reduce the production of by-products;
the chlorinated products may not be very harmful;
the procedure in the process is also easy and feasible on an industrial scale; and
the low production costs make the process economically justifiable.
Detailed description of the preferred embodiments
One aspect of the invention includes the following embodiments:
(item 1)
A process for the preparation of a compound of formula I,
[ chemical formula 8]
Wherein R is1Is selected from C1-6alkoxy-C1-6Alkyl radical, C1-6alkoxy-C1-6alkoxy-C1-6Alkyl radical, C1-6Alkanoyloxymethyl radical, C6-14Aralkyl radical, C6-10Aryloxy group-C1-6Alkyl radical, C1-6Alkoxycarbonyl group, C6-10Aryl carbonyl group, C1-6Alkylsulfonyl radical, C1-6alkyl-C6-10Arylsulfonyl and tetrahydropyranyl, each of which may be optionally substituted by at least one halogen atom,
the process comprises chlorinating a compound of formula II with a chlorinating agent and an activating agent to obtain a compound of formula I:
[ chemical formula 9]
(item 2)
The method of claim 1, wherein R1Is selected from C1-6Alkoxymethyl group, C1-6Alkoxycarbonyl, benzyl, phenoxymethyl, and tetrahydropyranyl, each of which may be optionally substituted with at least one halogen atom.
(item 3)
The process according to item 1 or 2, wherein the chlorinating agent is a 5 or 6 membered heteromonocyclic ring comprising one or more of the following chloroimine moieties in the ring:
[ chemical formula 10]
(item 4)
The process according to item 1 or 2, wherein the chlorinating agent is a 5 or 6 membered heteromonocyclic ring comprising one or more of the following amide moieties in the ring:
[ chemical formula 11]
(item 5)
The process according to any one of items 1 to 4, wherein the chlorinating agent is selected from: trichloroisocyanuric acid, N-chlorosuccinimide and 1, 3-dichloro-5, 5-dimethylhydantoin.
(item 6)
The process according to any one of items 1 to 5, wherein the amount of the chlorinating agent is in the range of 0.3 to 3 equivalents with respect to the compound of formula II.
(item 7)
The method of any one of items 1 to 6, wherein the activator is selected from compounds of formulae III, IV, and V:
[ chemical formula 12]
Wherein R is2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3May combine to form a 5-or 6-membered heteromonocyclic ring;
R4is selected from C1-6Alkyl and C6-14An aryl group;
R5is C1-6An alkoxy group; and is
X is O or S.
(item 8)
The method of item 7, wherein R2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3Can be combined to form a saturated 5-or 6-membered heteromonocyclic ring containing two nitrogen atoms.
(item 9)
The method of item 7 or 8, wherein the activator is selected from compounds of formula III or IV.
(item 10)
The process according to item 9, wherein the activator is selected from compounds of formula III or IV wherein X is S.
(item 11)
The method of item 7, wherein the activator is selected from the group consisting of: urea, thiourea, thioacetamide, thiobenzamide, N-methylthiourea, 1, 3-dimethylthiourea, 2-imidazolidinethione, N-methylthioacetamide, benzamide and (iPrO)3B。
(item 12)
The method of any of items 7 to 11, wherein the amount of activator is in the range of 1 to 10 mol%.
(item 13)
The method of claim 1, wherein R1Is selected from C1-6Alkoxymethyl group, C1-6Alkoxycarbonyl, benzyl, phenoxymethyl, which may optionally be substituted by at least one halogen atom, and tetrahydroA pyranyl group;
the chlorinating agent is selected from trichloroisocyanuric acid, N-chlorosuccinimide and 1, 3-dichloro-5, 5-dimethylhydantoin; and is
The activator is selected from compounds of formulae III, IV and V:
[ chemical formula 13]
Wherein R is2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3Can combine to form a saturated 5-or 6-membered heteromonocyclic ring containing two nitrogen atoms;
R4is selected from C1-6Alkyl and C6-14An aryl group;
R5is C1-6An alkoxy group; and is
X is O or S.
(item 14)
The process of any one of items 1 to 13, wherein the chlorination is carried out in a solvent selected from the group consisting of esters, nitriles, halogenated hydrocarbons, and any mixtures thereof.
(item 15)
The process of any one of items 1 to 14, wherein a dechlorinating agent is added after chlorination of the compound of formula II.
(item 16)
The method of any one of items 1 to 15, further comprising the step of deprotecting the compound of formula I to give 2-chloro-4-nitroimidazole.
(item 17)
A compound of the formula (Ia),
[ chemical formula 14]
Wherein R is1aSelected from: c1-6Alkoxy radicalMethyl, C1-6Alkoxycarbonyl, phenoxymethyl, and tetrahydropyranyl, each of which may be optionally substituted with at least one halogen atom.
(item 18)
The compound of item 17, wherein R1aSelected from: ethoxymethyl, tert-butoxycarbonyl, 3-Cl-phenoxymethyl and tetrahydropyranyl.
Definition of
The term "halogen atom" as used herein includes, for example, fluorine, chlorine, bromine and iodine.
The term "C" as used herein1-6Alkyl "denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms and may form part of other groups. The term specifically includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylpropyl, 1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, and 2-ethylbutyl. In some embodiments, C1-6The alkyl group may be methyl, ethyl, n-propyl or t-butyl.
The term "C" as used herein1-6Alkoxy "denotes a straight or branched chain alkoxy group having 1 to 6 carbon atoms and may form part of other groups. The term specifically includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy and 3-methylpentoxy.
The term "C" as used herein1-6Alkanoyl "means" C "as defined above1-6Alkyl "substituted carbonyl, and may form part of other groups.
The term "C" as used herein6-14Aryl "denotes a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and may constitute a part of other groups. The term specifically includes, for example, phenyl, naphthyl, anthracenyl, fluorenyl and phenanthrenyl. In some embodiments, aryl may be C6-10And (4) an aryl group. In other embodiments, C6-14The aryl group may be phenyl.
The term "aralkyl" as used herein denotes a straight or branched chain alkyl group having at least one, preferably 1 to 3 carbon atoms, substituted by a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, and may form part of other groups. In some embodiments, the aralkyl group may be C6-14An aralkyl group. Exemplary aralkyl groups include benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, and 2-naphthylmethyl.
The term "chlorinating agent" as used herein denotes a 5-7 membered heterocyclic ring containing one or more of the following chloroimine or amide moieties in the ring:
[ chemical formula 15]
Which can chlorinate 4-nitroimidazole. Exemplary chlorinating agents include trichloroisocyanuric acid, N-chlorosuccinimide, and 1, 3-dichloro-5, 5-dimethylhydantoin, among others.
The term "heteromonocyclic" or "heteromonocyclic group" as used herein denotes a 5-7 membered heteromonocyclic or heteromonocyclic group which may be saturated or partially unsaturated, said ring or group containing at least one nitrogen atom and optionally further containing at least one heteroatom selected from oxygen or sulphur. Exemplary heteromonocyclic rings include pyrrolidine, piperidine, azepane, imidazoline, imidazolidine, dihydrotriazine, triazacyclohexane, and the like,Oxazolidines, morpholines, thiazolidines and dihydrothiazines. In some embodiments, the heteromonocyclic or heteromonocyclic group may be optionally substituted with at least one group selected from chloro or oxo. In other embodiments, the heteromonocyclic or heteromonocyclic group is a saturated 5-or 6-membered heteromonocyclic ring containing at least one, preferably two or three nitrogen atoms.
The term "alkali metal hydroxide" as used herein includes sodium hydroxide, potassium hydroxide and cesium hydroxide.
The term "alkali metal hydride" as used herein includes sodium hydride, potassium hydride and cesium hydride.
The term "alkali metal carboxylate" as used herein includes sodium acetate, potassium acetate and sodium butyrate.
The term "alkali metal carbonate" as used herein includes sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate.
The term "alkali metal bicarbonate" as used herein includes sodium bicarbonate, potassium bicarbonate and cesium bicarbonate.
The term "alkali metal phosphate" as used herein includes sodium phosphate and potassium phosphate.
The term "alkali metal hydrogen phosphate" as used herein includes sodium hydrogen phosphate, potassium hydrogen phosphate and cesium hydrogen phosphate.
The term "aromatic amine" as used herein includes pyridine and lutidine.
The term "tertiary amines" includes triethylamine, tripropylamine, tributylamine, diisopropylethylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, tetramethylethylenediamine, tetramethylpropylenediamine and 1, 8-diazabicyclo [5,4,0] undec-7-ene (diazabicycloundecene).
The term "metal amide" as used herein includes lithium diisopropylamide and lithium hexamethyldisilazide.
The term "metal alkoxide" as used herein includes sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium phenoxide.
The term "hydrocarbon" as used herein includes aliphatic hydrocarbons such as hexane and pentane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and aromatic hydrocarbons such as benzene and toluene.
The term "halogenated hydrocarbon" as used herein includes chloroform, dichloromethane, dichloroethane and tetrachloroethane.
The term "alcohol" as used herein includes methanol, ethanol, isopropanol, propanol and tert-butanol.
The term "ether" as used herein "Including chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether and diphenyl ether; and cyclic ethers, e.g. 1, 4-bisAlkanes and tetrahydrofuran.
The term "ester" as used herein includes ethyl acetate, n-propyl acetate and ethyl propionate.
The term "ketone" as used herein includes acetone, methyl ethyl ketone, and methyl isobutyl ketone.
The term "amide" as used herein includes N, N-dimethylformamide, N-dimethylacetamide and N-methyl-2-pyrrolidone.
The term "nitrile" as used herein includes acetonitrile and propionitrile.
The term "sulfoxide" as used herein includes dimethylsulfoxide.
The term "activator" as used herein denotes an additive that may be used in combination with a chlorinating agent in a chlorination step. Such activators may have any of the following structures III, IV and V:
[ chemical formula 16]
Wherein R is2And R3Each independently selected from hydrogen and C1-6Alkyl and C6-14Aryl, and R2Or R3Each independently is or one R2And one R3May combine to form a 5-or 6-membered heteromonocyclic ring;
R4is selected from C1-6Alkyl and C6-14An aryl group;
R5is C1-6An alkoxy group; and is
X is O or S.
The 5-or 6-membered heteromonocyclic ring includes, for example, a saturated or partially unsaturated 5-or 6-membered heteromonocyclic ring containing two or three nitrogen atoms in the ring. Exemplary 5-or 6-membered heteromonocyclic rings in the activator include imidazolidine, dihydrotriazine, or triazacyclohexane. Exemplary embodiments of the inventionActivators include urea, thiourea, thioacetamide, thiobenzamide, N-methylthiourea, 1, 3-dimethylthiourea, 2-imidazolidinethione, N-methylthioacetamide, benzamide and (iPrO)3B。
The term "dechlorination agent" as used herein refers to any agent that can reduce the production of by-products, particularly dichloro by-products, in the chlorination reaction and can increase the yield of mono-chlorinated products. Exemplary dechlorinating agents include sodium sulfite and sodium thiosulfate.
General procedure
The 2-chloro-4-nitroimidazole derivative represented by formula I may be prepared by chlorinating N-protected 4-nitroimidazole represented by formula II. N-protected 4-nitroimidazoles may be prepared by protecting 4-nitroimidazoles. The 2-chloro-4-nitroimidazole derivative may be deprotected to produce 2-chloro-4-nitroimidazole, which is a useful intermediate in the production of diramanib. In some embodiments, a series of reactions are illustrated in scheme 1. However, the method of the present invention is not limited thereto.
Scheme 1: preparation of 2-chloro-4-nitroimidazole
[ chemical formula 17]
In the above reaction scheme, R1Has the same meaning as defined in item 1.
In step (a), the reaction may be carried out by reacting 4-nitroimidazole with R in an inert solvent in the presence of a base1-X1(wherein X1Is a suitable leaving group, e.g. a halogen atom), by means of a protecting group R on the nitrogen atom in position 1 of 4-nitroimidazole1Protection to prepare the N-protected 4-nitroimidazole of formula II. Suitable N-protecting groups for 4-nitroimidazole can improve the selectivity of chlorination and yield of chlorinated and deprotected products in subsequent steps. In some embodiments, R1Including, for example, C1-6alkoxy-C1-6Alkyl radicals, e.g. C1-6An alkoxymethyl group; c1-6alkoxy-C1-6alkoxy-C1-6Alkyl groups such as 2-methoxyethoxymethyl (MEM); c1-6Alkanoyloxymethyl groups such as pivaloyloxymethyl; c6-14Aralkyl groups such as benzyl; c6-10Aryloxy group-C1-6Alkyl groups such as phenoxymethyl; c1-6Alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); c6-14Aralkoxycarbonyl, such as benzyloxycarbonyl (Cbz); c6-10Arylcarbonyl, such as benzoyl; c1-6Alkylsulfonyl such as methylsulfonyl; and C1-6alkyl-C6-10Arylsulfonyl, for example p-toluenesulfonyl, which may each be optionally substituted by at least one halogen atom, in particular by one to three halogen atoms. In some embodiments, X1Preferably selected from fluorine, chlorine, bromine and iodine.
In step (a), R may also be used in any alternative manner known in the art1Introducing into 4-nitroimidazole. For example, compounds wherein R may be prepared by reacting 4-nitroimidazole with dihydropyrane1A compound of formula II which is Tetrahydropyranyl (THP).
Alternatively, 4-nitroimidazole may be reacted with a dimer derivative R-X2-R (wherein R is C1-6Alkoxy or C1-6Alkoxycarbonyl, and X2is-CH2-or-O-), instead of with R1-X1And reacting to obtain the compound shown in the formula II. In some embodiments, R-X2-R is diethoxymethane or Boc2O。
The protecting agent R may be suitably selected in view of the stability of the protecting group during the chlorination step (b)1-X1Or R-X2R, since the chlorination reaction may take a relatively long time (e.g., 24 hours or more). In some embodiments, the protecting group R1Can be easily removed in the deprotection step (c).
The base used in step (a) includes, for example, alkali metal hydroxide, alkali metal hydride, alkali metal carbonate, alkali metal hydrogencarbonate, alkali metal hydrogenphosphate, aromatic amine, tertiary amine, metal amide, metal alkoxide, and may be a mixture in which any two or more thereof are present in an appropriate ratio. The amount of the base used may be generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 4-nitroimidazole. In some embodiments, sodium hydride, potassium carbonate, or triethylamine is used in this step.
The inert solvent used in this step includes, for example, hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, alcohols, water, amides, nitriles and sulfoxides, and may be a mixture in which any two or more thereof are present in an appropriate ratio. In some embodiments, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, or acetonitrile is used in this step.
The reaction temperature in this step may be, for example, in the range of 20 ℃ to 110 ℃. The reaction time in this step may be, for example, 0.5 to 16 hours.
In step (b), the compound of formula I may be prepared by chlorinating the compound of formula II with a chlorinating agent in an inert solvent in the presence of an activating agent. In some embodiments, compounds of formula II are used, wherein R is1Is selected from C1-6Alkoxymethyl, benzyl, THP, C1-6Alkoxycarbonyl and phenoxymethyl, which groups may optionally be substituted by at least one halogen atom, in particular by 1 to 3 halogen atoms. In other embodiments, the compounds of formula (I) are used wherein R is1Is selected from C1-6Alkoxymethyl, benzyl, THP, Boc or 3-chloro-phenoxymethyl. In other embodiments, the compounds of formula (I) are used wherein R is1A compound of formula II which is methoxymethyl, ethoxymethyl or propoxymethyl.
The chlorinating agent used in this step may improve the selectivity or reactivity of chlorination. In some embodiments, the chlorinating agent is a 5-7 membered heteromonocyclic ring comprising one or more of the following amide moieties in the ring:
[ chemical formula 18]
The chlorinating agent specifically includes trichloroisocyanuric acid (TCICA), N-chlorosuccinimide (NCS) and 1, 3-dichloro-5, 5-dimethylhydantoin (DCDMH). In some embodiments, the chlorinating agent is a 5-or 6-membered heteromonocyclic ring comprising one or more, preferably two or three, chloroimine moieties or amide moieties. Examples of such chlorinating agents are TCICA or DCDMH. In other embodiments, the chlorinating agent is TCICA. In some embodiments, the amount of chlorinating agent is 0.3 to 3 equivalents relative to the compound of formula II. The amount of chlorinating agent can be adjusted such that the chlorinating agent comprises a stoichiometric amount of chlorine or more, for example 1 to 3 equivalents of chlorine, relative to the compound of formula II. When the chlorinating agent contains two chlorine atoms in the molecule, the amount of the chlorinating agent may be, for example, 0.5 to 2 equivalents with respect to the compound of formula II. When the chlorinating agent contains three chlorine atoms in the molecule, the amount of the chlorinating agent may be, for example, 0.3 to 2 equivalents with respect to the compound of formula II. When TCICA containing three chlorine atoms in a single molecule is used, 0.3 to 2 equivalents of TCICA may be added, for example, with respect to the amount of the compound of formula II. In some embodiments, the amount of TCICA is 0.5 to 0.8 equivalents.
The chlorination step (b) may be carried out in the presence of an activating agent to enhance the electropositivity of the chlorine of the chlorinating agent and to improve the chlorination selectivity or reactivity of the compound of formula II. In some embodiments, the activator is selected from compounds of formula III or IV. In other embodiments, the activator is selected from the group consisting of wherein R2And R3A compound of formula III in which at least one of R is hydrogen, or3A compound of formula IV which is hydrogen. In other embodiments, the activator is selected from compounds of formula III or IV wherein X is S. In other embodiments, the activators include urea, thiourea, thioacetamide, thiobenzamide, N-methylthiourea, 1, 3-dimethylthiourea, 2-imidazolidinethione, N-methylthioacetamide, benzamide, and (iPrO)3B. In other embodiments, the activators include thiourea, thioacetamide, thiobenzamide, N-methylthiourea, 1, 3-dimethylthiourea, 2-imidazolidinethione, and N-methylthioacetamide. In other embodiments, the activators include thiourea, thiobenzamide, N-methylthiourea, 1, 3-dimethylthiourea, and 2-imidazolidinethione. The amount of activator can be, for example, from 0.1 to 100 mol%/compound of the formula IIWithin the range of (1). In some embodiments, the amount of activator is in the range of 1 to 10 mol%.
The use of an activator can increase the reaction rate and enhance the regioselectivity of the chlorination reaction to reduce unreacted starting materials or to reduce the formation of by-products such as N-substituted 5-chlorinations and 2, 5-nitroimidazole dichloride. In some embodiments, the use of an activator can reduce the production of byproducts by as much as 20%. In other embodiments, the use of an activator can reduce the production of byproducts by as much as 10%.
This step may be carried out in a suitable solvent. Such solvents include, for example, esters, nitriles, halogenated hydrocarbons, and any mixtures thereof. In some embodiments, the solvent may be selected from the group consisting of ethyl acetate, n-propyl acetate, acetonitrile, dichloroethane, tetrachloroethane, and any mixtures thereof. In other embodiments, the solvent in this step is ethyl acetate, acetonitrile, dichloroethane, or any mixture thereof. The amount of solvent may, for example, be in the range of 3 to 20 parts by volume per 1 part by weight of the starting substrate (i.e. compound of formula II), hereinafter labeled 3 to 20V (i.e. mL/g starting substrate). The preferred amount of solvent may be in the range of 5 to 15V. More preferably, the amount of the solvent may be in the range of 7 to 13V. The solvent used in this step may be anhydrous and the water content in the solvent may be, for example, 0.5% or less, preferably 0.1% or less.
The reaction temperature in step (b) may be, for example, in the range of room temperature to 150 ℃. The preferred reaction temperature may be in the range of 60 ℃ to 80 ℃, more preferably in the range of 60 ℃ to 70 ℃.
The reaction time in step (b) may be, for example, 2 hours to 48 hours. The preferred reaction time may be 14 hours to 24 hours.
The chlorination step (b) may preferably be carried out under conditions wherein the compound of formula II may be selectively and reactively chlorinated and the production of by-products such as N-protected 5-chloro-4-nitroimidazole and N-protected 2, 5-dichloro-4-nitroimidazole may be suppressed. The combined use of a chlorinating agent and an activating agent can make the chlorination have good regioselectivity and reactivity in the step, andand less by-products are produced. In some embodiments, a combination of TCICA and thiourea is used. After chlorination in this step, a dechlorinating agent, such as sodium sulfite (Na)2SO3) The production of by-products, in particular dichloro by-products, can also be reduced.
In step (c), 2-chloro-4-nitroimidazole (2-CNI) may be prepared by deprotecting a compound of formula I. This step can be carried out under acidic conditions, i.e. in the presence of an acid. Such acids include, for example, aqueous hydrochloric acid, trifluoroacetic acid (TFA), and sulfuric acid. The preferred acid may be concentrated hydrochloric acid.
The reaction temperature in this step may be, for example, in the range of room temperature to 150 ℃. The preferred reaction temperature may be in the range of 70 ℃ to 110 ℃. The reaction time in this step may be, for example, 1 hour to 24 hours. The preferred reaction time may be 1 hour to 5 hours.
The process for preparing 2-chloro-4-nitroimidazole derivatives may further comprise a conventional purification step (d) after the deprotection step (c).
[ chemical formula 19]
The purification step (d) may be carried out according to any conventional method, such as crystallization, optionally in combination with resin adsorption. Such a resin may be any resin that can adsorb or remove impurities such as unreacted starting materials and by-products. Exemplary resins include ion exchange resins and synthetic adsorbent resins. In some embodiments, such a resin may be AmberliteTMXAD4、AmberliteTMXAD7HP and AmberlystTMA21, which is available from commercial sources (e.g., The Dow Chemical Company and Sigma-Aldrich Co. LLC.).
Abbreviations used herein are as follows.
NIM: 4-Nitro-imidazoles
2-CNI: 2-chloro-4-nitroimidazole
5-CNI: 5-chloro-4-nitroimidazole
2, 5-DCNI: 2, 5-dichloro-4-nitroimidazole
DCNI: dichloro nitroimidazole
EM-NIM: 1-ethoxymethyl-4-nitroimidazole
EM-CNI: 1-ethoxymethyl-2-chloro-4-nitroimidazole
EM-5-CNI: 1-ethoxymethyl-5-chloro-4-nitroimidazole
EM-2, 5-DCNI: 1-ethoxymethyl-2, 5-dichloro-4-nitroimidazole
THP: tetrahydropyranyl group
TCICA: trichloroisocyanuric acid
NCS: n-chlorosuccinimide
DCDMH: 1, 3-dichloro-5, 5-dimethylhydantoin
Ac: acetyl group
Boc: tert-butoxycarbonyl group
Cbz: phenylmethyloxycarbonyl radical
Tos: p-toluenesulfonyl group
Ms: mesyl radical
Bn: benzyl radical
Bz: benzoyl radical
ACN: acetonitrile
MeCN: acetonitrile
EtOAc: ethyl acetate
DCE: dichloroethane
CPME: cyclopentyl methyl ether
MeOAc: acetic acid methyl ester
EtOAc: ethyl acetate
n-PrOAc: n-propyl acetate
OctaOc: acetic acid octyl ester
THF: tetrahydrofuran (THF)
EtOH: ethanol
DMAc: dimethylacetamide
DMSO, DMSO: dimethyl sulfoxide
DMF: dimethyl formamide
NMP: n-methyl-2-pyrrolidone
And (3) DHP: dihydropyrans
TFA: trifluoroacetic acid
TEA: triethylamine
DMAP: 4-dimethylaminopyridine
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