CN106928069B - A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate - Google Patents
A kind of preparation method of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate Download PDFInfo
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- CN106928069B CN106928069B CN201710170599.7A CN201710170599A CN106928069B CN 106928069 B CN106928069 B CN 106928069B CN 201710170599 A CN201710170599 A CN 201710170599A CN 106928069 B CN106928069 B CN 106928069B
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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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Abstract
One kind 4 of the invention; the preparation method of 5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate; include the following steps: (1) by 4; 5- dihydric ethyl benzoate is first reacted with protective agent; then 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is obtained with nitric acid reaction under acid catalysis；(2) it by the first Deprotection in the presence of alkali of 6- nitro -4', 5'- methylene-dioxy ethyl benzoate, is directly added into the chloro- 2- Ethyl Methyl Ether of 1- and a small amount of catalyst reaction obtains product.The present 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 carried out large-scale production, have a good application prospect.
Description
Technical field
The present invention relates to Tarceva intermediate preparation fields, in particular to one kind 4,5- bis- (2- methoxy ethoxy)-
The preparation method of 2- ethyl nitrobenzoate.
Background technique
Tarceva (Erlotinib) is by Roche (Roche), western (OSI) biopharmaceutical company difficult to understand and Genentech
(Genentech) a kind of cancer treatment drugs of drugmaker's joint development are to lose for treating at least one chemotherapy regimen
The original new drug of the Locally Advanced or Metastatic Nsclc (NSCLC) that lose.It is epidermal growth factor that Tarceva, which is a kind of,
Sub- receptor tyrosine kinase inhibitors (EGFR-TK), it can selectively block human epidermal growth factor acceptor (EGFR) junket
Histidine kinase and the autophosphorylation for reducing EGFR grow stopping and apoptosis so as to cause cell, swell to EGFR overexpression
The phosphate cpd of oncocyte has apparent inhibitor effect.
4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate is the key that intermediate during preparing Tarceva
Body.The published method for preparing 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate is (see document WO9630347；
US5747498；CN1137037):
Existing preparation method causes to produce because having used the bromo- 2- Ethyl Methyl Ether of 1- or the iodo- 2- Ethyl Methyl Ether of 1-
The production cost of object is higher.
Summary of the invention
The main purpose of the present invention is to provide a kind of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoates
Preparation method, this method provides more pratical and feasible and economic method, yield is higher and product is purer；Cost is relatively low, and
And using the reagent being easily obtained, it can be carried out large-scale production, have a good application prospect.
The present invention provides the preparation method of one kind 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate, packets
Include following steps:
(1) by 4,5- dihydric ethyl benzoate in organic solvent A first with reacted under protective agent room temperature (16 DEG C -30 DEG C)
1-2h adds water quenching to go out, liquid separation, concentration, and then 24-36h with 0-20 DEG C of nitric acid is reacted in 1:1 ~ 2 in molar ratio under acid catalysis, uses
Organic solvent B extraction, dry, concentration obtains 6- nitro -4', 5'- methylene-dioxy ethyl benzoate；
(2) 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A and is taken off in the presence of alkali
Protecting group, 1-3h is reacted with chloro- 40-80 DEG C of 2- Ethyl Methyl Ether of 1- in 1:1 ~ 3 in molar ratio, is extracted with organic solvent B, dry,
Concentration, obtains 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate.
Further, protective agent is methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three in the step (1)
One of ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The molar ratio of ester is 1-1.2:1.
Preferably, the protective agent is ethyl chloroformate.
Further, the acid in the step (1) is organic acid or inorganic acid；Acid and 4,5- dihydric ethyl benzoate
Molar 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 organic solvent A in the step (1) and (2) is methanol, ethyl alcohol, ethyl acetate, acetonitrile, tetrahydro
One or more of the tertiary ether of furans, petroleum ether, first, methylene chloride.
Preferably, the organic solvent A is methanol.
Further, the organic solvent B in the step (1) and (2) be methylene chloride, tetrahydrofuran, acetonitrile, ether,
One or more of ethyl acetate, chloroform.
Preferably, the organic solvent B is methylene chloride or ethyl acetate.
Further, the alkali in the step (2) is organic base or inorganic base；Alkali and 6- nitro -4', 5'- (methylenedioxy)
The molar 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 bicarbonate, sodium hydroxide or potassium hydroxide.
Preferably, alkali is sodium carbonate.
Further, potassium iodide is added in the step (2) as catalyst.
Preferably, the reaction temperature in the step (1) is 0-5 DEG C.
The present invention is used for the starting material of the method and reagent can be commercially available or known in the literature.It holds
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 for preparation 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate provide it is 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 carried out extensive
Production, has a good application prospect.
Detailed description of the invention
The attached drawing constituted part of this application is used to provide further understanding of the present invention, schematic reality of the invention
It applies example and its explanation is used to explain the present invention, do not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 is the HMNR figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains；
Fig. 2 is the HPLC figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains；
Fig. 3 is the MS figure of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate that embodiment 1 obtains.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.The present invention will be described in detail below with reference to the accompanying drawings and embodiments.
In order to enable those skilled in the art to better understand the solution of the present invention, below in conjunction in the embodiment of the present invention
Attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only
The embodiment of a part of the invention, instead of all the embodiments.Based on the embodiments of the present invention, in ordinary skill
Personnel do not make every other embodiment obtained under the premise of creative work, and protection model of the invention all should belong to
It encloses.
It should be noted that description and claims of this specification and term " first " in above-mentioned attached drawing, "
Two " etc. be to be used to distinguish similar objects, without being used to describe a particular order or precedence order.It should be understood that using in this way
Data be interchangeable under appropriate circumstances, so as to the embodiment of the present invention described herein can in addition to illustrating herein or
Sequence other than those of description is implemented.In addition, term " includes " and " having " and their any deformation, it is intended that cover
It covers and non-exclusive includes.
Embodiment 1
(1) preparation of 6- nitro -4', 5'- methylene-dioxy ethyl benzoate
4,5- dihydric ethyl benzoate (45.5g, 0.25mol) it is molten arrive 50ml tetrahydrofuran, be added triethylamine (50.5g,
0.5mol), (0-5 DEG C) is added dropwise to triphosgene (77g, 0.26mol) under ice-water bath, mechanical stirring 2h, and 300ml water quenching is added and goes out,
Liquid separation, dry concentration.It is then dissolved in 100ml acetic acid, temperature in reaction flask is controlled in ice-water bath and is not higher than 5 DEG C, 19ml is added dropwise
(65%, 0.27mol) concentrated nitric acid.It is added dropwise, at room temperature mechanical stirring 24 hours.Reaction solution is poured into 1000mL water, second is used
Acetoacetic ester extracts (5*150ml), and anhydrous sodium sulfate is 2 hours dry, is concentrated to give 54g pale yellow oily liquid, it is not necessary to purify, directly
For the next step.
(2) preparation of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate
The resulting oily liquids of upper step (54g) and sodium carbonate (75.3g, 0.711mol) are dissolved in 200mL first alcohol and water
In mixed solution (V:V=3:1), about 65 DEG C of return stirring 1.5h(), be then added dropwise the chloro- 2- Ethyl Methyl Ether of 1- (49.2g,
Methanol solution 0.52mol), and 0.1 gram of potassium iodide is added as catalyst, mechanic whirl-nett reaction two hours.After cooling, will
The NaHCO of pH=11 is poured into reaction3It in aqueous solution, is extracted with ethyl acetate (200mL × 5), merges organic layer, use anhydrous slufuric acid
Magnesium is dry, and vacuum concentration obtains yellow oily liquid 60g.As 4,5- bis- (2- methoxy ethoxy) -2- nitrobenzoic acid second
Ester, 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 foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. one kind 4, the preparation method of 5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate, include the following steps:
(1) 4,5- dihydric ethyl benzoate is first reacted into 1-2h with protective agent in organic solvent A at room temperature, water quenching is added to go out,
Liquid separation, concentration, then 24-36h with 0-20 DEG C of nitric acid is reacted in 1:1 ~ 2 in molar ratio under acid catalysis, is extracted with organic solvent B,
Dry, concentration obtains 6- nitro -4', 5'- methylene-dioxy ethyl benzoate；
(2) 6- nitro -4', 5'- methylene-dioxy ethyl benzoate is dissolved in organic solvent A and is deprotected in the presence of alkali
Base, 1-3h is reacted with chloro- 40-80 DEG C of 2- Ethyl Methyl Ether of 1- in 1:1 ~ 3 in molar ratio, is extracted with organic solvent B, dry, concentration,
Obtain 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate.
2. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the protective agent in the step (1) is methylchloroformate, ethyl chloroformate, triphosgene, orthoformic acid front three
One of ester, triethyl orthoformate, trimethyl orthoacetate, triethly orthoacetate；Protective agent and 4,5- dihydroxy-benzoic acid second
The molar ratio of ester is 1-1.2:1.
3. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the acid in the step (1) is organic acid or inorganic acid；Acid rubs with 4,5- dihydric ethyl benzoate
You are than being 0.8-1:1.
4. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate 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. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the organic solvent A in the step (1) and (2) is methanol, ethyl alcohol, ethyl acetate, acetonitrile, tetrahydro furan
It mutters, one or more of petroleum ether, the tertiary ether of first, methylene chloride.
6. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the alkali in the step (2) is organic base or inorganic base；Alkali and 6- nitro -4', 5'- methylenedioxybenzenes
The molar ratio of Ethyl formate is 3-4:1.
7. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate 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, sodium hydroxide or potassium hydroxide.
8. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: the organic solvent B in the step (1) and (2) is methylene chloride, tetrahydrofuran, acetonitrile, ether, acetic acid
One or more of ethyl ester, chloroform.
9. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: 6- nitro -4', 5'- methylene-dioxy ethyl benzoate and the chloro- 2- methoxyl group of 1- in the step (2)
Ethane is previously dissolved in methanol.
10. a kind of preparation side of 4,5- bis- (2- methoxy ethoxy) -2- ethyl nitrobenzoate according to claim 1
Method, it is characterised in that: potassium iodide is added in the step (2) as catalyst.
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| CA2682013C (en) * | 2007-04-04 | 2015-06-30 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
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