CN106928069A - A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates - Google Patents
A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates Download PDFInfo
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- CN106928069A CN106928069A CN201710170599.7A CN201710170599A CN106928069A CN 106928069 A CN106928069 A CN 106928069A CN 201710170599 A CN201710170599 A CN 201710170599A CN 106928069 A CN106928069 A CN 106928069A
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- nitrobenzoates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The preparation method of of the invention a kind of 4,5 two (2 methoxy ethoxy) 2 ethyl nitrobenzoates, comprises the following steps：（1）By 4,5 dihydric ethyl benzoates first react with protective agent, then obtain 6 nitro 4', 5' methylene-dioxy ethyl benzoates with nitric acid reaction under acid catalysis；（2）By the first Deprotection in the presence of alkali of 6 nitro 4', 5' methylene-dioxy ethyl benzoates, it is directly added into the Ethyl Methyl Ether of 1 chlorine 2 and a small amount of catalyst reaction obtains product.The invention provides more pratical and feasible and economic method, yield is higher and product is purer；Cost is relatively low, and using the reagent being easily obtained, can be mass produced, and has a good application prospect.
Description
Technical field
The present invention relates to Tarceva intermediate preparation field, more particularly to one kind 4,5- bis- (2- methoxy ethoxies)-
The preparation method of 2- ethyl nitrobenzoates.
Background technology
Tarceva (Erlotinib) is by Roche (Roche), west (OSI) biopharmaceutical company difficult to understand and Genentech
(Genentech) a kind of cancer treatment drugs of drugmaker's joint development, are for treating to the mistake of at least one chemotherapy regimen
The original new drug of the Locally Advanced or Metastatic Nsclc (NSCLC) that lose.Tarceva is a kind of for epidermal growth factor
Sub- receptor tyrosine kinase inhibitors (EGFR-TK), it can optionally block human epidermal growth factor acceptor (EGFR) junket
Histidine kinase simultaneously reduces the autophosphorylation of EGFR, so as to cause cell growth to stop and apoptosis, EGFR overexpressions is swollen
There is the phosphate cpd of oncocyte obvious inhibitor to act on.
4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates are prepared in the middle of the key during Tarceva
Body.The published method for preparing 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates（See document WO9630347；
US5747498；CN1137037）：
Existing preparation method causes product because having used the bromo- 2- Ethyl Methyl Ethers of 1- or the iodo- 2- Ethyl Methyl Ethers of 1-
Production cost is higher.
The content of the invention
It is a primary object of the present invention to provide a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates
Preparation method, this method provide more pratical and feasible and economic method, and yield is higher and product is purer；Cost is relatively low, and
And using the reagent being easily obtained, can be mass produced, have a good application prospect.
The invention provides the preparation method of one kind 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates, bag
Include following steps：
（1）By 4,5- dihydric ethyl benzoates in organic solvent A first with protective agent room temperature（16℃-30℃）Lower reaction 1-
2h, add water be quenched, point liquid, concentration, then in molar ratio 1 under acid catalysis:1 ~ 2 with 0-20 DEG C of nitric acid reaction 24-36h, with having
Machine solvent B is extracted, and is dried, and concentration obtains 6- nitros -4', 5'- methylene-dioxy ethyl benzoate；
（2）6- nitros -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A the deprotection in the presence of alkali
Base, in molar ratio 1:1 ~ 3 and 40-80 DEG C of reaction 1-3h of 1- chloro- 2- Ethyl Methyl Ethers, is extracted with organic solvent B, is dried, concentration,
Obtain 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates.
Further, the step（1）Middle protective agent is methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three
One kind in ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The mol ratio of ester is 1-1.2:1.
Preferably, described protective agent is ethyl chloroformate.
Further, the step（1）In acid be organic acid or inorganic acid；Acid and 4,5- dihydric ethyl benzoates
Mol ratio is 0.8-1：1.
Further, the organic acid is acetic acid；Inorganic acid is sulfuric acid or phosphoric acid.
Preferably, the acid is acetic acid.
Further, the step（1）With（2）In organic solvent A be methyl alcohol, ethanol, ethyl acetate, acetonitrile, tetrahydrochysene
One or more in the tertiary ether of furans, petroleum ether, first, dichloromethane.
Preferably, the organic solvent A is methyl alcohol.
Further, the step（1）With（2）In organic solvent B for dichloromethane, tetrahydrofuran, acetonitrile, ether,
One or more in ethyl acetate, chloroform.
Preferably, the organic solvent B is dichloromethane or ethyl acetate.
Further, the step（2）In alkali be organic base or inorganic base；Alkali and 6- nitros -4', 5'- (methylenedioxy)
The mol ratio of yl benzoic acid ethyl ester is 3-4:1.
Further, the organic base is triethylamine, diisopropylethylamine or pyridine；Inorganic base be sodium carbonate, potassium carbonate,
Sodium acid carbonate, NaOH or potassium hydroxide.
Preferably, alkali is sodium carbonate.
Further, the step（2）Middle addition KI is used as catalyst.
Preferably, the step（1）In reaction temperature be 0-5 DEG C.
The present invention can be commercially available, or known in the literature for the initiation material and reagent of methods described.Hold
Technology needed for this reaction of row and purified reaction product is known to those of ordinary skill in the art.Method of purification includes
Crystallization, distillation, positive or RP chromatography.
Beneficial effect
The present invention provides more pratical and feasible and economy to prepare 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates
Method, yield is higher and product is purer；Cost is relatively low, and using the reagent being easily obtained, can be mass produced,
Have a good application prospect.
Brief description of the drawings
The accompanying drawing for constituting the part of the application is used for providing a further understanding of the present invention, schematic reality of the invention
Apply example and its illustrate, for explaining the present invention, not constitute inappropriate limitation of the present invention.In the accompanying drawings：
Fig. 1 is the HMNR figures of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates that embodiment 1 is obtained；
Fig. 2 is the HPLC figures of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates that embodiment 1 is obtained；
Fig. 3 is the MS figures of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates that embodiment 1 is obtained.
Specific embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase
Mutually combination.Describe the present invention in detail below with reference to the accompanying drawings and in conjunction with the embodiments.
In order that those skilled in the art is better understood from the present invention program, below in conjunction with the embodiment of the present invention
Accompanying drawing, is clearly and completely described to the technical scheme in the embodiment of the present invention, it is clear that described embodiment is only
The embodiment of a part of the invention, rather than whole embodiments.Based on the embodiment in the present invention, in ordinary skill
Personnel do not make the every other embodiment obtained under the premise of creative work, should all belong to protection model of the invention
Enclose.
It should be noted that term " first ", " in description and claims of this specification and above-mentioned accompanying drawing
Two " it is etc. for distinguishing similar object, without for describing specific order or precedence.It should be appreciated that so using
Data can exchange in the appropriate case, so as to embodiments of the invention described herein can with except illustrating herein or
Order beyond those of description is implemented.Additionally, term " comprising " and " having " and their any deformation, it is intended that cover
Lid is non-exclusive to be included.
Embodiment 1
（1）The preparation of 6- nitros -4', 5'- methylene-dioxy ethyl benzoate
4,5- dihydric ethyl benzoates (45.5g, 0.25mol) is molten to 50ml tetrahydrofurans, add triethylamine（50.5g,
0.5mol）, under ice-water bath（0-5℃）It is added dropwise to triphosgene（77g, 0.26mol）, mechanical agitation 2h, add 300ml water quenchings go out,
Divide liquid, dry concentration.100ml acetic acid is then dissolved in, controls temperature in reaction bulb to be not higher than 5 DEG C in ice-water bath, 19ml is added dropwise
（65%, 0.27mol）Concentrated nitric acid.Completion of dropping, at room temperature mechanical agitation 24 hours.Reaction solution is poured into 1000mL water, second is used
Acetoacetic ester extracts (5*150ml), and anhydrous sodium sulfate drying 2 hours is concentrated to give 54g pale yellow oily liquids, it is not necessary to purify, directly
For the next step.
（2）The preparation of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates
Oily liquids (54g) and sodium carbonate (75.3g, 0.711mol) obtained by upper step is dissolved in the mixing of 200mL first alcohol and waters
In solution（V:V=3:1）, it is refluxed 1.5h（About 65 DEG C）, the chloro- 2- Ethyl Methyl Ethers of 1- are then added dropwise（49.2g, 0.52mol）
Methanol solution, and add 0.1 gram of KI as catalyst, mechanic whirl-nett reaction two hours.After cooling, reaction is poured into
The NaHCO of pH=113In the aqueous solution, extracted with ethyl acetate (200mL × 5), merge organic layer, dried with anhydrous magnesium sulfate, very
Sky concentration, obtains yellow oily liquid 60g.As 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates, two step yields
70%, HPLC purity are 97%.HNMR(CDCl3):7.5(s,1H),7.1(S,1H),4.36 (q, 2H, J=7.2 Hz),4.23
(m, 4H), 3.80 (m, 4H), 3.45 (s, 6H),1.35 (t, 2H, J=7.2 Hz); M/e:344(M+H+);
361 (M+NH4+), are shown in Fig. 1-3.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (10)
1. one kind 4, the preparation method of 5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates, comprise the following steps：
（1）By 4,5- dihydric ethyl benzoates in organic solvent A first with protective agent react 1-2h at room temperature, add water be quenched,
Point liquid, concentration, then in molar ratio 1 under acid catalysis:1 ~ 2 and 0-20 DEG C of reaction 24-36h of nitric acid, is extracted with organic solvent B,
Dry, concentration obtains 6- nitros -4', 5'- methylene-dioxy ethyl benzoate；
（2）6- nitros -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A the deprotection in the presence of alkali
Base, in molar ratio 1:1 ~ 3 and 40-80 DEG C of reaction 1-3h of 1- chloro- 2- Ethyl Methyl Ethers, is extracted with organic solvent B, is dried, concentration,
Obtain 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates.
2. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（1）In protective agent be methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three
One kind in ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The mol ratio of ester is 1-1.2:1.
3. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（1）In acid be organic acid or inorganic acid；Acid rubs with 4,5- dihydric ethyl benzoates
You are than being 0.8-1：1.
4. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 3
Method, it is characterised in that：The organic acid is acetic acid；Inorganic acid is sulfuric acid or phosphoric acid.
5. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（1）With（2）In organic solvent A be methyl alcohol, ethanol, ethyl acetate, acetonitrile, tetrahydrochysene furan
Mutter, one or more in petroleum ether, the tertiary ether of first, dichloromethane.
6. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（2）In alkali be organic base or inorganic base；Alkali and 6- nitros -4', 5'- methylenedioxybenzenes
The mol ratio of Ethyl formate is 3-4:1.
7. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 6
Method, it is characterised in that：The organic base is triethylamine, diisopropylethylamine or pyridine；Inorganic base is sodium carbonate, potassium carbonate, carbon
Sour hydrogen sodium, NaOH or potassium hydroxide.
8. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（1）With（2）In organic solvent B be dichloromethane, tetrahydrofuran, acetonitrile, ether, acetic acid
One or more in ethyl ester, chloroform.
9. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（2）In 6- nitros -4', 5'- methylene-dioxy ethyl benzoate and the chloro- 2- methoxyl groups of 1-
Ethane is previously dissolved in methyl alcohol.
10. the preparation side of a kind of 4,5- bis- (2- methoxy ethoxies) -2- ethyl nitrobenzoates according to claim 1
Method, it is characterised in that：The step（2）Middle addition KI is used as catalyst.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004206A (en) * | 2019-12-12 | 2020-04-14 | 苏州诚和医药化学有限公司 | Synthetic method of biphenyl diester intermediate |
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