CN108276307A - The synthetic method of 3- cyano -4- oxyl benzoic ethers - Google Patents
The synthetic method of 3- cyano -4- oxyl benzoic ethers Download PDFInfo
- Publication number
- CN108276307A CN108276307A CN201810044011.8A CN201810044011A CN108276307A CN 108276307 A CN108276307 A CN 108276307A CN 201810044011 A CN201810044011 A CN 201810044011A CN 108276307 A CN108276307 A CN 108276307A
- Authority
- CN
- China
- Prior art keywords
- cyano
- compound
- synthetic method
- benzoic ethers
- oxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *C(C=CC1O*)=CC1C#N Chemical compound *C(C=CC1O*)=CC1C#N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
Abstract
The invention discloses a kind of synthetic method of 3 cyano, 4 oxyl benzoic ether, reaction formula is as follows：
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical fields, more particularly relate to 3- cyano -4- oxyl benzoic ethers
Synthetic method.
Background technology
3- cyano -4- oxyls benzoic ether is mainly used in synthetic drug, pesticide point as a kind of important compound
In son.It is also a kind of highly important fine-chemical intermediate simultaneously.3- cyano -4- oxyl benzoic ethers have larger conjunction
At difficulty.And the synthesis step of 3- cyano -4- oxyl benzoic ethers is generally in two steps, wherein the first step is to oxyl benzene first
It is the most key that 3 of acid esters introduce aldehyde radical.It is cyano that second step, which is by the convert aldehyde groups of introducing,.
Present invention is generally directed to the preparation of 3- cyano -4- isopropoxy methyl benzoates, the 3- cyanogen in industrialized production
The first step of base -4- isopropoxy methyl benzoates, preparation 3- aldehyde radical -4- isopropoxy methyl benzoate main techniques have as follows
Two kinds：
The traditional handicraft for preparing 3- aldehyde radical -4- isopropoxy methyl benzoates is as follows：
Bigger defect existing for the technique is to be susceptible to a large amount of jellies in technical process, influences to stir, make
The uneven easy reaction of temperature in the kettle is not thorough and has security risk, and post-processes trouble, need to use a large amount of hydrochloric acid.
The technique has a drawback in that reaction system is strong acid, is easy to release a large amount of acid gas corrosion equipment and pollution ring
Border, and reaction temperature is higher, increases equipment energy consumption.
Both the above method all has limitation, and the environmental requirement reacted is stringent, and post-processing is relatively complicated, uncomfortable
Suitable industrialized production.
Invention content
1, goal of the invention.
The present invention proposes a kind of synthetic method of 3- cyano -4- oxyl benzoic ethers.
2, the technical solution adopted in the present invention.
A kind of synthetic method of 3- cyano -4- oxyl benzoic ethers, reaction formula are as follows：
Wherein R1For isopropyl or other alkyl；R2For alkyl.
Preferably, step is：
(1) compound A and 1,1- dichlormethyl ethers, and drying are added in subzero 15-10 DEG C of reaction bulb and removed water
The dichloromethane solution of titanium tetrachloride is added dropwise in dichloromethane under ice salt bath, and after the reaction was complete, ice water is quenched, and obtains compound
C；
(2) acetonitrile/N, N- dimethyl methyls is added in the compound C and hydroxylamine hydrochloride that are obtained in previous step, chloroacetic chloride
Amide in the mixed solvent is added, heating stirring reaction, after being cooled to room temperature, EA is added, several times, water phase back extraction is several for washing
It is secondary, it is associated with organic layer, sodium sulphate drying, filtering is threaded to half-dried, precipitation solid, suction filtration, and EA is washed several times, obtains pink
Crude product filters, and dichloromethane is washed several times, and compound D, as 3- cyano -4- oxyl benzoic ethers are obtained.
Preferably, 1, the 1- dichlormethyl ethers are 1.2 equivalents of compound A.
Preferably, the titanium tetrachloride is no less than 2.5 equivalents of compound A, the dichloromethane solution concentration of titanium tetrachloride
It is diluted with the dry methylene chloride of 1mL for 1g titanium tetrachlorides.
Preferably, the hydroxylamine hydrochloride and chloroacetic chloride are 1.3 equivalents of compound C, acetonitrile/n,N-Dimethylformamide
Mixed solvent total volume is to correspond to 1g compound C, acetonitrile/n,N-Dimethylformamide in the mixed solvent, acetonitrile and N, N- per 6mL
The volume ratio of dimethylformamide is 1：3.
Preferably, heating stirring reaction temperature is 80 DEG C in step (2), and the time is 2 hours.
3, technique effect caused by the present invention.
This method reaction condition is mild, and raw material is simple and easy to get, and yield is high, and post-processing is simple, can be carried for industrialized production
For important references.
Specific implementation mode
Embodiment 1
The preparation of following chemical compound 3-cyano -4- isopropoxy methyl benzoates, by being to isopropoxy methyl benzoate
Raw material reacts, and is prepared as follows：
The first step：
Under ice salt bath, into 100ml round-bottomed flasks, it is added molten to isopropoxy methyl benzoate (9.7g, 50.0mmol)
In the dichloromethane (50ml) of Xie Yu dryings, 1,1- dichlormethyl ethers (6.9g, 60.0mmol) are added, TiCl is slowly added dropwise4
(23.75g, 125.0mmol) keeps stirring 4 hours at a temperature of this.
Detection reaction, after the reaction was complete, under the conditions of ice-water bath, into reaction bulb ice water is slowly added dropwise is quenched, liquid separation, water phase
It is extracted with ethyl acetate three times, merges institute's organic phase, it is dry, solvent is removed, yellow viscous liquid 9.2g, yield 82.8% are obtained.
1HNMR(400MHz,CDCl3) δ 10.47 (s, 1H), 8.49 (d, J=2.3Hz, 1H), 8.20 (dd, J=8.8,
2.3Hz, 1H), 7.03 (d, J=8.9Hz, 1H), 4.85-4.75 (m, 1H), 3.90 (s, 3H), 1.45 (d, J=6.0Hz, 6H).
Second step：
The said goods 9.2g 41.1mmol, hydroxylamine hydrochloride 3.8g54.28mmol and acetonitrile/DMF is added in the flask of 250L
45mL/15mL, room temperature 0.5 hour are added chloroacetic chloride 4.3g/3.9mL 54.28mmol, 80 DEG C of heating stirrings 2 hours.It is cooled to
After room temperature, EA is added, three times, water phase is stripped twice, is associated with organic layer for washing, sodium sulphate drying, filtering, be threaded to it is half-dried,
Solid is precipitated, filters, if EA is washed twice, obtains pink crude product, filters, dichloromethane is washed twice, and pink solid 6.9g is obtained
Yield 78%, as 3- cyano -4- isopropyls p-methoxybenzoic acid ester.
1H NMR(400MHz,CDCl3) δ 8.25 (d, J=1.9Hz, 1H), 8.19 (dd, J=8.9,2.2Hz, 1H), 7.00
(d, J=8.9Hz, 1H), 4.76 (d, J=6.1Hz, 1H), 3.92 (s, 3H), 1.45 (d, J=6.1Hz, 6H).
Embodiment 2
According to 1 method of embodiment, prepare compound 3- cyano -4- methoxyl methyl benzoates.
The place different with 1 method of embodiment is that raw material is changed to methyl p-methoxybenzoate.According to identical operation, with
And identical equivalent, carry out operation reaction.
White solid, yield 84.1%.1H NMR(400MHz,CDCl3) δ 10.5 (1H, s), 8.51 (1H, d, J=
2.2Hz), 8.25 (1H, dd, J=9.0,2.2Hz), 7.05 (1H, d, J=9.0Hz), 4.01 (3H, s), 3.91 (3H, s).
Yellow solid, yield 68.4%.1H NMR(400MHz,DMSO-d6) δ 8.23 (d, J=2.2Hz, 1H), 8.20
(dd, J=8.8,2.2Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 3.99 (s, 3H), 3.83 (s, 3H).
Embodiment 3
According to 1 method of embodiment, prepare compound 3- cyano -4- methoxyl methyl benzoates.
The place different with 1 method of embodiment is that raw material is changed to methyl p-methoxybenzoate.According to identical operation, with
And identical equivalent, carry out operation reaction.
White solid, yield 81.2%.1H NMR(400MHz,CDCl3) δ 10.45 (1H, s), 8.49 (1H, d, J=
2.5Hz), 8.25 (1H, dd, J=8.8,2.5Hz), 7.04 (1H, d, J=8.8Hz), 4.37 (2H, q, J=7.1Hz), 4.00
(3H, s), 1.39 (3H, t, J=7.1Hz).
Yellow color solid, yield 71.5%.1H NMR(400MHz,CDCl3) δ 8.50 (1H, d, J=2.2Hz), 8.22
(1H, dd, J=8.8,2.5Hz), 7.21 (1H, d, J=8.5Hz), 4.26 (2H, q, J=6.4Hz), 3.83 (3H, s), 1.39
(3H, t, J=7.1Hz).
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (6)
1. a kind of synthetic method of 3- cyano -4- oxyl benzoic ethers, reaction formula are as follows：
Wherein R1For isopropyl or other alkyl；R2For alkyl.
2. the synthetic method of 3- cyano -4- oxyl benzoic ethers according to claim 1, step are：
(1) compound A and compound B 1,1- dichlormethyl ethers, and drying are added in subzero 15-10 DEG C of reaction bulb to remove
The dichloromethane solution of titanium tetrachloride is added dropwise in the dichloromethane of water under ice salt bath, and after the reaction was complete, ice water is quenched, and is changed
Close object C；
(2) the compound C and hydroxylamine hydrochloride, the chloroacetic chloride that are obtained in previous step are added to acetonitrile/N, N- dimethyl formyls
After being cooled to room temperature, EA is added, several times, water phase is stripped several times, is closed for washing in amine in the mixed solvent, heating stirring reaction
And have organic layer, sodium sulphate drying, filtering is threaded to half-dried, precipitation solid, suction filtration, and EA is washed several times, obtains pink crude product,
It filters, dichloromethane is washed several times, and compound D, as 3- cyano -4- oxyl benzoic ethers are obtained.
3. the synthetic method of 3- cyano -4- oxyl benzoic ethers according to claim 2, it is characterised in that：Described 1,
1- dichlormethyl ethers are 1.2 equivalents of compound A.
4. the synthetic method of 3- cyano -4- oxyl benzoic ethers according to claim 2, it is characterised in that：Described four
Titanium chloride is no less than 2.5 equivalents of compound A, a concentration of 1g titanium tetrachlorides of dichloromethane solution the doing with 1mL of titanium tetrachloride
Dry dichloromethane dilutes.
5. the synthetic method of 3- cyano -4- oxyl benzoic ethers according to claim 2, it is characterised in that：The salt
Sour azanol and 1.3 equivalents that chloroacetic chloride is compound C, acetonitrile/n,N-Dimethylformamide mixed solvent total volume are per 6mL
Corresponding 1g compound C, acetonitrile/n,N-Dimethylformamide in the mixed solvent, the volume ratio of acetonitrile and n,N-Dimethylformamide
It is 1：3.
6. the synthetic method of 3- cyano -4- oxyl benzoic ethers according to claim 2, it is characterised in that：Step (2)
Middle heating stirring reaction temperature is 80 DEG C, and the time is 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810044011.8A CN108276307A (en) | 2018-01-17 | 2018-01-17 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810044011.8A CN108276307A (en) | 2018-01-17 | 2018-01-17 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108276307A true CN108276307A (en) | 2018-07-13 |
Family
ID=62803885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810044011.8A Pending CN108276307A (en) | 2018-01-17 | 2018-01-17 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108276307A (en) |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965741A (en) * | 1994-08-31 | 1999-10-12 | Zeneca Limited | Ortho-substituted aromatic ether compounds and their use in pharmaceutical compositions for pain relief |
| JP2003128640A (en) * | 2001-10-25 | 2003-05-08 | Sankyo Co Ltd | Benzene derivative |
| EP1698618A1 (en) * | 2003-12-26 | 2006-09-06 | Chugai Seiyaku Kabushiki Kaisha | Benzamide derivative |
| CN101023057A (en) * | 2004-05-06 | 2007-08-22 | 赛特凯恩蒂克公司 | Certain chemical entities, compositions, and methods |
| WO2010008521A1 (en) * | 2008-07-14 | 2010-01-21 | Cropsolution, Inc. | Modulators of acetyl-coenzyme a carboxylase and methods of use thereof |
| CN102858745A (en) * | 2009-11-02 | 2013-01-02 | 赛诺菲 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
| WO2013067248A1 (en) * | 2011-11-04 | 2013-05-10 | Vertex Pharmaceuticals Incorporated | Benzoxazines as modulators of ion channels |
| CN103827088A (en) * | 2011-09-26 | 2014-05-28 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors |
| CN104136442A (en) * | 2012-01-16 | 2014-11-05 | 沃泰克斯药物股份有限公司 | Pyran-spirocyclic piperidine amides as modulators of ion channels |
| CN106674053A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of 3-cyano-4-isopropoxy methyl benzoate |
| CN106674044A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
-
2018
- 2018-01-17 CN CN201810044011.8A patent/CN108276307A/en active Pending
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965741A (en) * | 1994-08-31 | 1999-10-12 | Zeneca Limited | Ortho-substituted aromatic ether compounds and their use in pharmaceutical compositions for pain relief |
| JP2003128640A (en) * | 2001-10-25 | 2003-05-08 | Sankyo Co Ltd | Benzene derivative |
| EP1698618A1 (en) * | 2003-12-26 | 2006-09-06 | Chugai Seiyaku Kabushiki Kaisha | Benzamide derivative |
| CN101023057A (en) * | 2004-05-06 | 2007-08-22 | 赛特凯恩蒂克公司 | Certain chemical entities, compositions, and methods |
| WO2010008521A1 (en) * | 2008-07-14 | 2010-01-21 | Cropsolution, Inc. | Modulators of acetyl-coenzyme a carboxylase and methods of use thereof |
| CN102858745A (en) * | 2009-11-02 | 2013-01-02 | 赛诺菲 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
| CN103827088A (en) * | 2011-09-26 | 2014-05-28 | 奇斯药制品公司 | Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors |
| WO2013067248A1 (en) * | 2011-11-04 | 2013-05-10 | Vertex Pharmaceuticals Incorporated | Benzoxazines as modulators of ion channels |
| CN104136442A (en) * | 2012-01-16 | 2014-11-05 | 沃泰克斯药物股份有限公司 | Pyran-spirocyclic piperidine amides as modulators of ion channels |
| CN106674053A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Preparation method of 3-cyano-4-isopropoxy methyl benzoate |
| CN106674044A (en) * | 2016-12-27 | 2017-05-17 | 苏州山青竹生物医药有限公司 | Method for preparing 3-cyano-4-isopropoxybenzoic acid |
Non-Patent Citations (2)
| Title |
|---|
| JING REN ETAL: "Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization", 《BIOORG. MED. CHEM. LETT.》 * |
| KOSUKE OHSAWA ETAL: "A Direct and Mild Formylation Method for Substituted Benzenes Utilizing Dichloromethyl Methyl Ether−Silver Trifluoromethanesulfonate", 《J. ORG. CHEM.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN102766138B (en) | A kind of preparation method of Azilsartan | |
| CN104628722B (en) | A kind of banisterine amides compound and its preparation method and application | |
| CN103396362B (en) | A kind of method preparing dihydroketoacridine acetic acid | |
| CN104513223B (en) | The preparation method of fluorenes ethanone derivatives | |
| CN106967003A (en) | A kind of method for synthesizing the assimilation compound of 1,3 benzoxazine 4 | |
| WO2022161469A1 (en) | Intermediate for thiohydantoin drug, and preparation method therefor and use thereof | |
| CN106946972A (en) | A kind of ursolic acid derivative with antitumor activity and preparation method thereof | |
| CN110396063A (en) | A kind of preparation method of the miscellaneous Shandong amine of grace | |
| CN104086545A (en) | Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride | |
| CN103772400A (en) | Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | |
| CN108997305A (en) | A kind of new compound 3- methyl -4,5- dichloro-thiophene -2- carboxylic acid and preparation method thereof | |
| CN106831397B (en) | A kind of anthraquinone analog compound and preparation method thereof and medical application | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN110862372B (en) | Synthesis of clopidogrel intermediate (S) -2- (2-thiophenoethylamine) - (2-chlorophenyl) -methyl acetate | |
| CN108276307A (en) | The synthetic method of 3- cyano -4- oxyl benzoic ethers | |
| CN103012288A (en) | Preparation method of 6-chloro-1,3-dimethyluracil | |
| CN111333613A (en) | Preparation method of trifluoromethyl tetralone compound | |
| CN103804187B (en) | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| CN105367478B (en) | The preparation process of zafirlukast | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| CN108976228A (en) | A kind of preparation method of 7- azaindole | |
| CN104478852A (en) | Novel diazo benzothiapyrone photosensitive protecting groups and synthesis method thereof | |
| CN110028409A (en) | A kind of polysubstituted naphthalene derivatives and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180713 |
|
| WD01 | Invention patent application deemed withdrawn after publication |