CN108689908A - A kind of environmental-friendly preparation 4, the method for bis- halogen substituted indole -2- Ethyl formates of 6- - Google Patents
A kind of environmental-friendly preparation 4, the method for bis- halogen substituted indole -2- Ethyl formates of 6- Download PDFInfo
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- CN108689908A CN108689908A CN201810307476.8A CN201810307476A CN108689908A CN 108689908 A CN108689908 A CN 108689908A CN 201810307476 A CN201810307476 A CN 201810307476A CN 108689908 A CN108689908 A CN 108689908A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses one kind 4, the preparation method of bis- halogen substituted indole -2- Ethyl formates of 6-, it is characterized in that with ethyl pyruvate -3, bis- halogen phenylhydrazones of 5- are raw material, cyclization generates 3 under polyphosphoric acids and toluene Mixed Solvent system, bis- halogen substituted indole -2- Ethyl formates of 5-, and pass through the isolated target compound of liquid-liquid extraction to reaction mixture.This method is easy to operate, no effuent discharge, environmentally protective and suitable industrialized production.
Description
Technical field
A kind of synthetic method and post-processing technology preparing bis- halogen substituted indole -2- Ethyl formates of 4,6-.
Background technology
Fischer indole synthesis is the method for generally acknowledging that synthesis of indole ring is most convenient and economic.Classical Fischer indoles
Synthetic reaction is to be condensed into corresponding therewith, then urge in acid using aliphatic aldehyde, ketone and phenylhydrazine derivant as raw material
Change effect is lower to reset cyclization, ultimately produces indole derivatives.In recent years, on the basis of classical liquid phase method, researcher carries out again
The research of liquid-liquid two phase process and solid phase method, makes some progress.But solid phase method is limited by the limitation of its scale, difficult
To meet the needs of largely preparing, thus still liquid phase method more suitable for industrialized production, but existing method exist it is same
Technology shortcoming:1, post-reaction treatment will produce a large amount of waste water, be caused stress to environmental protection;2, crude product character is not good enough, purifying
Technology requires height, yield to decline, and cost further increases.
NITD-304 and NITD-349 is the exploitation of Novarits companies, to the clinical candidates for treating tuberculosis.
NITD-304 and NITD-349 belongs to MmpL3 inhibitor, can inhibit the transport process of fucose list mycolate, to block
The biosynthesis of Mycobacterium tuberculosis cell wall has well responsive type, drug-resistant type, multi-drug resistant type and extensive drug-resistant type TB
Inhibitory activity is a kind of structure novel and the anti-TB drug candidates with new mechanism of action, before having good development and application
Scape.
4,6- bis- halogen substituted indole -2- Ethyl formates are the key intermediates for synthesizing NITD-304 and NITD-349,
It is reacted with 4,4- dimethyl cyclohexyl amines after hydrolysis, you can target product is prepared.According to existing open source literature, 4,6- dihalo-s
Plain substituted indole -2- Ethyl formates are mainly obtained by two halogen phenylhydrazones of ethyl pyruvate -3,5- through Fischer indole synthesis cyclizations
It arrives, experiment condition and its post-processing approach include mainly:
1,WO2014037900
Ethyl pyruvate -3,5- dichloros phenylhydrazone and polyphosphoric acids (its quality is 10 times of material quality) exist in the route
110 DEG C are stirred 3 hours.Reaction solution is poured into a large amount of ice water after reaction and is stirred, is then filtered, filter cake unsaturated carbonate hydrogen
Sodium solution alkalize, be then extracted with ethyl acetate three times afterwards extraction obtain crude product, through column chromatography purify with 70% or so receipts
Rate obtains target product.Post-processing operation is cumbersome in this route, generates a large amount of acid, alkali waste water, and environmental pollution is serious;It uses
Column chromatography purifies, and is unfavorable for industrialized production.
2,Org Pro Res Dev,2000,4(6):477-487
In the route, as mixed solvent, polyphosphoric acids dosage is 20 times of material quality or more for polyphosphoric acids and toluene,
Under nitrogen protection, it is reacted two hours at 95-100 DEG C.After reaction, 80 DEG C are cooled to, toluene is removed under reduced pressure, residue falls
Enter in ice water, and stir half an hour at 35-50 DEG C, then filter, with massive laundering filter cake to neutrality, then air-dries target production
Product.Polyphosphoric acids dosage is big in this route, equally generates a large amount of waste water, causes seriously to pollute to environment, and post-processing operation is numerous
It is trivial.
Invention content
The purpose of the present invention is to provide a kind of anti-TB drug candidates NITD-304 and NITD-349 key intermediate 4,6-
The preparation method of two halogen substituted indole -2- Ethyl formates, can effectively avoid the deficiency of the above method.With ethyl pyruvate-
3,5- bis- halogen phenylhydrazones are raw material, and cyclization generation 3,5-, bis- halogens replace Yin under polyphosphoric acids and nonpolar solvent mixed system
Diindyl -2- Ethyl formates, and by extracting to obtain target compound to reaction mixture with solvent.This method is easy to operate, and zero is useless
Water discharges, and is suitble to industrialized production.
The synthesis step of the present invention is as follows:
Under the atmosphere of inert gas shielding, mixed solvent of the compound (II) in polyphosphoric acids (PPA) and nonpolar solvent
Compound (I) is generated through Fisher indole synthesis cyclizations in system, and target compound is obtained through solvent extraction.
Above-described compound (I) and (II), R are preferably fluorine, chlorine, bromine, iodine, and most preferably R is fluorine, chlorine.
The preparation method of above-mentioned synthesis step, it is characterised in that:Compound (II) is in nonpolar solvent, in polyphosphoric acids
Under the action of, it stirs in a heated condition, cyclization obtains compound (I).Reaction can carry out under the atmosphere of inert gas shielding,
Inert gas is selected from argon gas, nitrogen, preferably argon gas;Solvent be selected from toluene, dimethylbenzene, benzene, preferred solvent be toluene and
Dimethylbenzene;Polyphosphoric acids dosage is 0.5-20 times of compound (II) quality, and preferred polyphosphoric acids dosage is compound (II)
2-5 times;Reaction temperature is 40-120 DEG C, and preferred reaction temperature is 85-100 DEG C;Reaction time is 0.5-5 hours, preferably
Reaction time be 2-4 hours.
The post-processing approach of above-mentioned synthesis step, it is characterised in that:For raw material after the reaction was complete, stratification is molten by upper layer
After oxidant layer is concentrated to give product or separates solvent layer, then solvent is added into reaction bulb in batches, each solvent dosage is that 0.1-4mL is molten
Agent/1g polyphosphoric acids, preferred solvent dosage every time is 0.5-1.5mL solvents/1g polyphosphoric acids;It is followed by stirring for 5-15 minutes,
Preferred mixing time is 8-10 minutes;It is then allowed to stand layering, then upper layer solvent liquid is poured out, so repeats extraction 1-9 times, it is excellent
The repetition extraction time of choosing is 2-3 times;Merge solvent liquid, concentration removes solvent up to target compound (I).
It is an advantage of the current invention that the addition of cosolvent, reduces the viscosity of reaction system, while can reduce polyphosphoric acids
Dosage;After reaction, with solvent, reaction mixture is repeatedly extracted, in addition to target product, by-product and impurity,
Pigment etc. stays in residue substantially, and solvent, which is evaporated off, in merging can obtain product, be not required to further purify, and solvent is recyclable
It uses, cost reduction while is also more environmentally friendly;In entire production technology, no waste water generates, and is closed with classical Fischer indoles
It is compared at method, more environment friendly.
Specific implementation mode
The present invention is described further by way of examples below, but is not intended to be limited to the protection model of the present invention
It encloses.
The synthesis of embodiment 1,3,5- dichloro substituted indole -2- Ethyl formates
Ethyl pyruvate -3,5- dichloros phenylhydrazone (II) is (according to document Org Pro Res Dev, 2000,4 (6):477-487
Preparing) 15g is placed in 500mL three-necked bottles, and polyphosphoric acids is preheated to 60-70 DEG C, then weighs 35g polyphosphoric acids and three-necked bottle is added
In, 30mL toluene is added, 90 DEG C are warming up under argon gas protection, mechanical agitation rotating speed is 120r/min, is reacted 3 hours.It stands, inclines
Upper toluene liquid is poured out, 30mL toluene is then added into reaction bulb, is stirred for 10min, then stands, upper toluene is poured out
Liquid.It is so repeated 3 times, combining methylbenzene liquid is concentrated to dryness, and obtains faint yellow solid 13.66g, yield 97%.mp:187-188
℃;HRMS(ESI):m/z[M-H]-Calcd.For C11H8NO2Cl2:255.9927;Found:255.9930;1H NMR
(400MHz,DMSO-D6)δ12.41(s,1H),7.44(s,1H),7.27(s,1H),7.10(s,1H),4.43–4.30(q,
2H),1.34(d,3H);13C NMR(151MHz,CDCl3)δ161.69,137.08,131.00,128.45,128.37,
125.31,121.26,110.52,107.07,61.56,14.32;IR(cm-1):3314.3,2987.6,1700.2,1615.8,
1566.2,1523.7,1487.2,1323.3,1247.2,1072.4,840.1,770.2.
The synthesis of embodiment 2,3,5- difluoro substituted indole -2- Ethyl formates
Ethyl pyruvate -3,5- difluoros phenylhydrazone (II) is (according to document Org Pro Res Dev, 2000,4 (6):477-487
Preparing) 40g is placed in 500mL three-necked bottles, and polyphosphoric acids is preheated to 60-70 DEG C, then weighs 94g polyphosphoric acids and three-necked bottle is added
In, 100mL toluene is added, 90 DEG C are warming up under argon gas protection, mechanical agitation rotating speed is 120r/min, is reacted 3 hours.It stands,
Upper toluene liquid is poured out, 100mL toluene is then added into reaction bulb, is stirred for 10min, then stands, upper layer is poured out
Toluene liquid.It is so repeated 3 times, combining methylbenzene liquid is concentrated to dryness, and obtains faint yellow solid 37.00g, yield 99%.mp:
154-155℃;HRMS(ESI):m/z[M-H]-Calcd.For C11H8NO2F2:224.0518;Found:224.0519;1H
NMR(400MHz,DMSO-D6)δ12.33(s,1H),7.17(s,1H),7.06(d,1H),7.00–6.89(m,1H),4.52–
4.30(q,1H),1.34(d,2H);IR(cm-1):3316.6,2990.5,1707.0,1645.2,1592.9,1520.9,
1451.7,1287.6,1212.1,826.2,768.2.
Embodiment 3, toluene are to the recovery rates of 3,5- difluoro substituted indole -2- Ethyl formates
Ethyl pyruvate -3,5- difluoros phenylhydrazone (II) is (according to document Org Pro Res Dev, 2000,4 (6):477-487
Preparing) 40g is placed in 500mL three-necked bottles, and polyphosphoric acids is preheated to 60-70 DEG C, then weighs 94g polyphosphoric acids and three-necked bottle is added
In, 100mL toluene is added, 90 DEG C are warming up under argon gas protection, mechanical agitation rotating speed is 120r/min, is reacted 3 hours.It stands,
Upper toluene liquid is poured out, 100mL toluene is then added into reaction bulb, is stirred for 10min, then stands, upper layer is poured out
Toluene liquid.It is so repeated four times, each toluene liquid pair 3, the extracted amount of 5- difluoro substituted indole -2- Ethyl formates is shown in Table 1.
Fusing point is consistent with embodiment 2 with nuclear magnetic data.
Extracted amount of 1 toluene of table to 3,5- difluoro substituted indole -2- Ethyl formates
It is prepared by embodiment 4, the feather weight of 3,5- dichloro substituted indole -2- Ethyl formates
15kg polyphosphoric acids is added in reaction kettle, is preheating to 70 DEG C or so, then by 3kg ethyl pyruvate -3,5- dichloros
Phenylhydrazone, 10L toluene sequentially add in reaction kettle, are warming up to 90~100 DEG C of reactions.After 2.5h, TLC determines that reaction is completed, extraction
Upper toluene liquid, and start to cool down.After forty minutes, temperature drops to 70 DEG C, and ethyl acetate (10Lx3) extracts lower layer three times, every time
It is stirred 10 minutes after solvent is added, extracts ethyl acetate layer out, merged organic phase, be evaporated to obtain product 2.70kg, yield 99.5%.
Fusing point is consistent with embodiment 1 with nuclear magnetic data.
It is prepared by embodiment 5, the feather weight of 3,5- difluoro substituted indole -2- Ethyl formates
16kg polyphosphoric acids is added in reaction kettle, is preheating to 70 DEG C or so, then by 3.2kg ethyl pyruvates -3,5- bis-
Fluorobenzene hydrazone, 10.6L toluene sequentially add in reaction kettle, are warming up to 90~100 DEG C of reactions.After 2h, TLC determines that reaction is completed, and takes out
Go out upper toluene liquid, and starts to cool down.After half an hour, temperature drops to 70 DEG C, and ethyl acetate (10Lx3) extracts lower layer three times, often
It is stirred 10 minutes after secondary addition solvent, extracts ethyl acetate layer out, merged organic phase, be evaporated to obtain product 2.97kg, yield 100%.
Fusing point is consistent with embodiment 2 with nuclear magnetic data.
Claims (5)
1. one kind 4, the preparation method of bis- halogen substituted indole -2- Ethyl formates of 6-, it is characterised in that:Including following synthesis step
And its post-processing approach:
Synthesis step:Compound (II) is in nonpolar solvent, under the action of polyphosphoric acids, stirs and heats reaction, cyclization
Generate compound (I);Raw material is after the reaction was complete,
Post-processing approach:
(1), continue stratification after stirring, upper layer solvent layer is concentrated to give compound (I);
Or
(2), continue stratification after stirring, after separating solvent layer, then detach, merge molten after solvent, stirring, standing is added by several times
Oxidant layer is concentrated to give compound (I).
2. preparation method according to claim 1, it is characterised in that:Atmosphere of the reaction in inert gas shielding in synthesis step
Enclose lower progress;Solvent is selected from toluene, dimethylbenzene, benzene;Polyphosphoric acids dosage is 0.5-20 times of compound (II) quality;Reaction temperature
Degree is 40-120 DEG C;Reaction time is 0.5-5 hours.
3. preparation method according to claim 1, it is characterised in that:When solvent being added in the post-processing approach (2), often
Secondary solvent dosage is 0.1-4mL solvents/1g polyphosphoric acids, is followed by stirring for 5-15 minutes, is then allowed to stand layering, it is molten to further take out upper layer
Agent liquid so repeats extraction 1-9 times.
4. preparation method according to claim 2, it is characterised in that:The inert gas is argon gas, and solvent is selected from first
Benzene, dimethylbenzene, polyphosphoric acids dosage are 2-5 times of compound (II) quality, and reaction temperature is 85-100 DEG C, reaction time 2-
4 hours.
5. preparation method according to claim 3, it is characterised in that:Each solvent dosage is that 0.5-1.5mL solvents/1g is more
Polyphosphoric acid stirs 8-10 minutes, repeats extraction 2-3 times.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160895A (en) * | 2018-10-24 | 2019-01-08 | 河南师范大学 | A kind of preparation method of 4,6- dichloro-indole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008088136A (en) * | 2006-10-05 | 2008-04-17 | Sankyo Co Ltd | Pharmaceutical comprising substituted indole compound |
| JP2009196984A (en) * | 2008-01-25 | 2009-09-03 | Mitsubishi Tanabe Pharma Corp | Pharmaceutical composition |
-
2018
- 2018-04-08 CN CN201810307476.8A patent/CN108689908A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008088136A (en) * | 2006-10-05 | 2008-04-17 | Sankyo Co Ltd | Pharmaceutical comprising substituted indole compound |
| JP2009196984A (en) * | 2008-01-25 | 2009-09-03 | Mitsubishi Tanabe Pharma Corp | Pharmaceutical composition |
Non-Patent Citations (2)
| Title |
|---|
| MERYEM KOSE等: "Development of [3H]2-Carboxy-4,6-dichloro-1H-indole-3-propionic Acid ([3H]PSB-12150): A Useful Tool for Studying GPR17", 《ACS MED. CHEM. LETT.》 * |
| TIMOTHY J. N. WATSON等: "Organic Process Research & Development", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160895A (en) * | 2018-10-24 | 2019-01-08 | 河南师范大学 | A kind of preparation method of 4,6- dichloro-indole |
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