CN106496036A - A kind of preparation method of 5 methoxyl group of anticoagulation medicine intermediate, 2 nitrobenzoic acid - Google Patents
A kind of preparation method of 5 methoxyl group of anticoagulation medicine intermediate, 2 nitrobenzoic acid Download PDFInfo
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- CN106496036A CN106496036A CN201610862310.3A CN201610862310A CN106496036A CN 106496036 A CN106496036 A CN 106496036A CN 201610862310 A CN201610862310 A CN 201610862310A CN 106496036 A CN106496036 A CN 106496036A
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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
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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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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Abstract
The invention discloses a kind of preparation method of 5 methoxyl group of anticoagulation medicine intermediate, 2 nitrobenzoic acid, belongs to pharmaceutical intermediate synthesis field.With 3 cheap chlorobenzoic acids as raw material, optionally carry out nitration reaction synthesis 5 chlorine, 2 nitrobenzoic acid in appropriate temperature, then carry out chlorine with methanol substitution reaction under alkali effect obtaining 5 methoxyl group of required intermediate, 2 nitrobenzoic acid.The present invention is anticoagulation medicine betrixaban（Betrixaban）Key intermediate provide that step is short, reaction is simple, low cost, can realize stable industrialized production preparation method.
Description
Technical field
The present invention relates to a kind of anticoagulation medicine betrixaban (Betrixaban) intermediate 5- methoxyl group -2- nitrobenzoyls
The preparation method of sour (II), belongs to pharmaceutical intermediate synthesis field.
Background technology
Betrixaban (Betrixaban) is a kind of novel anticoagulation medicine of Portola companies exploitation, and has listed
Anticoagulation medicine is compared, and drug interaction danger is low, and the medicine passes through bile excretion, and renal insufficiency thrombosis patients will
Therefrom benefit, therefore betrixaban is a kind of new anticoagulation medicine, has wide market prospect.
5- methoxyl group -2- nitrobenzoic acids are the key intermediates of betrixaban (Betrixaban).
The method for preparing 5- methoxyl groups -2- nitrobenzoic acids (II) that has reported at present has：
WO03097641A2.With the chloro- 2- nitrobenzoic acids of 5- as raw material in patent, first replace chloro with sodium hydroxide hydrolysis
Into 5- hydroxyl -2- nitrobenzoic acids, then hydroxyl and acidic group iodomethane carry out double methylation reactions and obtain 5- methoxyl group -2- nitre
Yl benzoic acid methyl ester, obtains 5- methoxyl groups -2- nitrobenzoic acid intermediate (II) finally by hydrolysis generation.The method uses valency
Lattice are more expensive and the big iodomethane of toxicity, meanwhile, synthesis step is relatively long, long the production cycle, relatively costly, is not suitable for amplifying
Industrialized production.
Content of the invention
In order to overcome the relatively long synthesis step of prior art, long the production cycle, relatively costly, be not suitable for amplify industry
The defect that metaplasia is produced, the present invention provide a kind of shorter synthesis step, reduces cost, are suitable in the anticoagulation medicine of industrialized production
The preparation method of mesosome 5- methoxyl group -2- nitrobenzoic acids.
Reaction equation is as follows：
With 3- chlorobenzoic acids as raw material, the chloro- 2- nitrobenzoic acids of nitration reaction synthesis 5- are first carried out, then is made in alkali (Base)
Substitution reaction is carried out with lower methanol to chlorine obtains required intermediate 5- methoxyl groups -2- nitrobenzoic acids (II).
For solving above-mentioned technical problem, the technical solution used in the present invention is：
A kind of anticoagulation medicine betrixaban (Betrixaban) intermediate 5- methoxyl groups -2- nitrobenzoic acids (II), its
Molecular structural formula is as follows：
Preparation method is as follows：With 3- chlorobenzoic acids as raw material, the chloro- 2- nitrobenzoic acids of nitration reaction synthesis 5- are first carried out,
Substitution reaction is carried out with methanol to chlorine under alkali effect again obtains required intermediate 5- methoxyl groups -2- nitrobenzoic acids (II).
Synthetic route is as follows：
Specifically include following steps：
Step 1) 3- chlorobenzoic acids carry out nitration reaction with the mixed acid of nitric acid and sulphuric acid in -5-0 degree and obtain intermediate compound I；
3- chlorobenzoic acids are 1 with nitric acid mol ratio:1.1、1:1.2 or 1:1.5；Nitric acid refers to nitric acid molecule.60% nitric acid and concentrated sulphuric acid
Mass ratio is 1:1.2、1:1.5 or 1:2.
Step 2) intermediate compound I alkali effect under chlorine is carried out with methanol substitution reaction obtain required intermediate 5- methoxyl groups-
2- nitrobenzoic acids (II).Step 2) reaction carry out in reaction dissolvent.Intermediate compound I is 1 with methanol molar ratio:1.3、1：
1.5 or 1:2.
Step 2) in, reaction dissolvent is tetrahydrofuran, methyl tertiary butyl ether(MTBE), in glycol dimethyl ether one or two with
Upper mixed solvent, alkali are sodium hydride, sodium hexamethyldisilazide, lithium diisopropylamine and LHMDS
It it is 50-125 DEG C Deng, reaction temperature, the response time is 10-25 hours.
Relative to prior art, beneficial effects of the present invention：A kind of 5- methoxyl groups -2- nitrobenzoic acids that the present invention is provided
Preparation method, provide a brand-new synthetic method for anticoagulation medicine betrixaban (Betrixaban) intermediate；Specifically
It is related to one kind with 3- chlorobenzoic acids as raw material, first carries out the chloro- 2- nitrobenzoic acids of nitration reaction synthesis 5-, then use under alkali effect
Methanol carries out the industrialized production preparation side that substitution reaction obtains required intermediate 5- methoxyl groups -2- nitrobenzoic acids (II) to chlorine
Method, reactions steps are short, low cost, can realize prepared by stable industrialized production.
Specific embodiment
The present invention is further described with reference to specific embodiment.
A kind of preparation method of anticoagulation medicine betrixaban (Betrixaban) intermediate 5- methoxyl group -2- nitrobenzoic acids,
Embodiment one：Take 3- chlorobenzoic acid 393g to be dissolved in 1000mL concentrated sulphuric acids, be cooled to -5-0 DEG C, Deca sulphuric acid/nitre
Sour (60% salpeter solution：Concentrated sulphuric acid mass ratio=1:1.5,60% accounts for the mass percent of salpeter solution for nitric acid, and concentrated sulphuric acid is
98% sulfuric acid solution) mixed acid solution (125mL/189mL), after adding, stir 1 hour at this temperature, reactant liquor is added to
In 3000g ice cubes, stir 0.5 hour, filter, filter cake is washed with a little cold water, dries purification and obtain intermediate compound I.
Embodiment two：916g anhydrous tetrahydro furans and 390g methanol is added in reaction flask, under ice-water bath cooling, slowly
600g sodium hydrogen (60%) is added, after adding, is stirred 30 minutes, under room temperature, add 1000g intermediate compound Is, reaction to be slowly ramped to back
Stream, stirs 12 hours, is cooled to room temperature, and tetrahydrofuran is removed in decompression rotation, under frozen water cooling, adds 2000mL water quenchings to go out reaction,
36% hydrochloric acid adjusts pH=2～3,1000mL ethyl acetate to extract, and separates organic faciess, and water is mutually again with 1000mL ethyl acetate extraction 1
Secondary, merge organic faciess, be spin-dried for obtaining crude product, purifying crude obtains intermediate II.
Product appearance：Faint yellow to off-white powder, fusing point：129～135 DEG C,1H NMR(CDCl3)：3.96 (s, 3H),
7.09 (dd, 1H), 7.21 (d, 1H), 8.03 (d, 1H), 8.3 (s, 1H).
The above is only the preferred embodiment of the present invention, it should be pointed out that：Ordinary skill people for the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (5)
1. a kind of preparation method of anticoagulation medicine intermediate 5- methoxyl group -2- nitrobenzoic acids, 5- methoxyl group -2- nitrobenzoyls
Acid molecular structures formula is as follows：
Characterized in that, preparation method is as follows：With 3- chlorobenzoic acids as raw material, optionally in carboxylic under -5-0 degrees celsius
The nitrated in position of base ortho position 2 is synthesized the chloro- 2- nitrobenzoic acids of 5-, then carries out substitution reaction with methanol to chlorine under alkali effect and obtain
Arrive required intermediate 5- methoxyl groups -2- nitrobenzoic acids；
Synthetic route is as follows：
2. the preparation method of a kind of anticoagulation medicine intermediate 5- methoxyl group -2- nitrobenzoic acids according to claim 1,
Specifically include following steps：
Step 1) under -5-0 degrees celsius, optionally nitration reaction obtains intermediate compound I to 3- chlorobenzoic acids；3- chlorobenzoic acids
It is 1 with nitric acid mol ratio:1.1、1:1.2 or 1:1.5；
Step 2) intermediate compound I, there is substitution reaction with methanol under alkali effect and obtain product II；Intermediate compound I and methanol molar ratio
For 1:1.3、1：1.5 or 1:2.
3. the preparation method of a kind of anticoagulation medicine intermediate 5- methoxyl group -2- nitrobenzoic acids according to claim 2,
It is characterized in that：Step 2) in, when there is substitution reaction in intermediate compound I and methanol under alkali effect, reaction dissolvent be tetrahydrofuran,
One or more in methyl tertiary butyl ether(MTBE), glycol dimethyl ether.
4. the preparation method of a kind of anticoagulation medicine intermediate 5- methoxyl group -2- nitrobenzoic acids according to claim 2,
It is characterized in that：Step 2) in, alkali is sodium hydride, sodium hexamethyldisilazide, two silicon of lithium diisopropylamine or hexamethyl
Base amido lithium, reaction temperature are 50-125 DEG C, and the response time is 10-25 hours.
5. the preparation method of a kind of anticoagulation medicine intermediate 5- methoxyl group -2- nitrobenzoic acids according to claim 2,
It is characterized in that：Step 1) in, 3- chlorobenzoic acids carry out nitration reaction with the mixed acid of concentrated sulphuric acid in -5-0 degree with nitric acid and obtain
Intermediate compound I；60% nitric acid is 1 with concentrated sulphuric acid mass ratio:1.2、1:1.5 or 1:2.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070500A1 (en) * | 2001-03-02 | 2002-09-12 | F. Hoffmann-La Roche Ag | Alkoxycarbonylamino benzoic acid or alkoxycarbonylamino tetrazolyl phenyl derivatives as ip antagonists |
| CN1655788A (en) * | 2002-05-21 | 2005-08-17 | 诺瓦提斯公司 | 1H-imidazo[4,5-c]quinoline derivatives in the treatment of protein kinase dependent diseases |
| CN102050793A (en) * | 2009-11-03 | 2011-05-11 | 中国医学科学院药物研究所 | 4(3H) quinazolinone derivatives with antitumor activity |
| CN105348187A (en) * | 2015-12-02 | 2016-02-24 | 安徽省逸欣铭医药科技有限公司 | Betrixaban structural analogue as well as preparation method and application thereof |
| CN105693634A (en) * | 2016-03-17 | 2016-06-22 | 清华大学 | Compound and application thereof |
-
2016
- 2016-09-29 CN CN201610862310.3A patent/CN106496036A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070500A1 (en) * | 2001-03-02 | 2002-09-12 | F. Hoffmann-La Roche Ag | Alkoxycarbonylamino benzoic acid or alkoxycarbonylamino tetrazolyl phenyl derivatives as ip antagonists |
| CN1655788A (en) * | 2002-05-21 | 2005-08-17 | 诺瓦提斯公司 | 1H-imidazo[4,5-c]quinoline derivatives in the treatment of protein kinase dependent diseases |
| CN102050793A (en) * | 2009-11-03 | 2011-05-11 | 中国医学科学院药物研究所 | 4(3H) quinazolinone derivatives with antitumor activity |
| CN105348187A (en) * | 2015-12-02 | 2016-02-24 | 安徽省逸欣铭医药科技有限公司 | Betrixaban structural analogue as well as preparation method and application thereof |
| CN105693634A (en) * | 2016-03-17 | 2016-06-22 | 清华大学 | Compound and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| BERTRAND, HELENE 等: "Synthesis, Properties, and Remarkable 2D Self-Assembly at the Liquid/Solid Interface of a Series of Triskele-Shaped 5,11,17-Triazatrinaphthylenes", 《CHEM.EUR.J.》 * |
| OKAZAKI,YOZO 等: "New Dimeric Compounds of Avenanthramide Phytoalexin in Oats", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 赵华 等: "贝曲西班的合成工艺", 《中国新药杂志》 * |
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Application publication date: 20170315 |