CN108976140A - A kind of Preparation Method And Their Intermediate of 2- amino -6- ethyl benzoate - Google Patents
A kind of Preparation Method And Their Intermediate of 2- amino -6- ethyl benzoate Download PDFInfo
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- CN108976140A CN108976140A CN201710409074.4A CN201710409074A CN108976140A CN 108976140 A CN108976140 A CN 108976140A CN 201710409074 A CN201710409074 A CN 201710409074A CN 108976140 A CN108976140 A CN 108976140A
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- 0 CCC(CC)*(C)C1C(*2)*2(CN=C)*C1 Chemical compound CCC(CC)*(C)C1C(*2)*2(CN=C)*C1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/61—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
The invention discloses a kind of Preparation Method And Their Intermediates of 2- amino -6- ethyl benzoate.This method includes the following steps: in solvent, under the action of catalyst and hydrogen source, the fatty amine salt of compound II is carried out catalytic hydrogenation and obtains compound I；The catalytic hydrogenation existsIn the presence of carry out, or do not carried out in the presence of alkali.Using fatty amine is simple as the fatty amine salt preparation method of alkali prepare compound II, reaction condition is mild, raw material is cheap and easy to get.The catalytic hydrogenation can be without using expensive catalyst Pt O2, be conducive to the recovery of catalyst and the continuous operation of production, reduce costs and environmentally protective, and easy to operate, be suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of Preparation Method And Their Intermediates of 2- amino -6- ethyl benzoate.
Background technique
Paquinimod (N, 5- diethyl -1,2- dihydro -4- hydroxyl -1- methyl -2- oxo-N-phenyl -3- quinoline formyl
Amine) it is novel non-peptide para-immunity regulator, the treatment (clinical II phase) for systemic loupus erythematosus.Its structural formula is as follows；2-
Starting material of the amino -6- ethyl benzoate (I) as synthesis Paquinimod, plays the synthesis of the molecule vital
Effect.
WO2011054874A1 reports the synthetic method of I, and the document is starting with 2- acetyl group -6- nitrobenzoic acid II
Raw material prepares the sodium salt of II with sodium hydroxide and system pH is adjusted to 12, then successively through PtO2, Raney-Ni catalytic hydrogenation obtains
To I.
WO2011054874A1 is to react into salt with compound II with the alkali of alkali or alkaline earth metal or carbonate, but urge
Change step of hydrogenation and uses PtO2, two kinds of catalyst of Raney-Ni, while increasing cost also be unfavorable for reaction serialization
Operation.
Summary of the invention
Problem to be solved by this invention is for higher cost of the existing technology and the serialization for being unfavorable for reacting
The defects of operation, and propose a kind of preparation method of 2- amino -6- ethyl benzoate.The present invention compared with prior art, can be with
Without using expensive catalyst Pt O2, and the continuous operation easy to operate for being conducive to production.
The present invention provides a kind of preparation methods of 2- amino -6- ethyl benzoate comprising following step: in solvent,
Under the action of catalyst and hydrogen source, the fatty amine salt of compound II is subjected to catalytic hydrogenation as follows and obtains chemical combination
Object I；The catalytic hydrogenation existsIn the presence of carry out, or do not carried out in the presence of alkali；
Wherein, R1、R2And R3It is each independently H, C1-C6Alkyl (such as methyl, ethyl, n-propyl, isopropyl, just
Butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl, isohesyl or tertiary hexyl) or C3-C6Naphthenic base
(such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl), and R1、R2And R3It is not simultaneously H, preferably R1、R2And R3It is simultaneously second
Base；Or, R1And R2For isopropyl, R3For ethyl；Or, R1And R2For hydrogen, R3For cyclohexyl, more preferably R1、R2And R3It is simultaneously second
Base.
The solvent can be the Conventional solvents of the such reaction of organic synthesis field, preferably organic solvent and/or water.Institute
The organic solvent stated is preferably alcohols solvent, preferably one of methanol, ethyl alcohol and isopropanol or several.The solvent
Dosage is the conventional amount used of such reaction, as long as not influencing the progress of reaction, the preferred fatty amine salt of itself and compound II
Volume mass ratio be 5~25mL/g, more preferably 8~15mL/g, such as 10mL/g.
The catalytic hydrogenation existsIn the presence of when carrying out, it is describedPreferably triethylamine,
Diisopropylethylamine or cyclohexylamine, more preferably triethylamine.DescribedMolar ratio with the triethylamine salt of II is
1~8, more preferably 2~5.
The catalyst is the conventional catalyst that organic synthesis field carries out such reaction, for example, Raney-Ni, Pd/
C, the present invention are preferably Raney-Ni.The dosage of the catalyst is the conventional amount used of such reaction, as long as not influencing to react
Progress, preferably the mass values of itself and the fatty amine salt of compound II are 0.05~1, more preferably 0.1~0.3, example
Such as: 0.16.
The hydrogen source is preferably one of hydrogen, formic acid derivates and cyclohexene or a variety of, more preferably hydrogen.
The temperature of the catalytic hydrogenation is ordinary temperature required for the such reaction of organic synthesis field, as long as not
Reaction is influenced to carry out, the present invention is preferably 80 DEG C~130 DEG C, more preferably 110~130 DEG C, for example, 120 DEG C.It is described
The pressure of catalytic hydrogenation be that organic synthesis field carries out normal pressures required for such reaction, as long as not influencing to react
It carries out, the present invention is preferably 10~30Atm, more preferably 12~30Atm, such as: 12Atm, 20Atm or 30Atm.
The process of the catalytic hydrogenation can using in this field routine monitoring method (such as TLC, HPLC or
NMR it) is monitored, generally to monitor that the fatty amine salt of compound II disappears for reaction end, for example, the catalytic hydrogenation
The reaction time of reaction is 8h.
The catalytic hydrogenation can also further comprise post-processing, and the post-processing approach is the normal of such reaction
Advise post-processing approach, preferably the following steps: filtering adjusts filtrate to acidity, and organic solvent extraction is dry, is concentrated to get chemical combination
Object I.Such as: filtering, filtrate are adjusted to acidity with hydrochloric acid, and n-butyl acetate extraction, organic phase is dry with anhydrous sodium sulfate, and decompression is de-
Solvent.
The preparation method of the compound I can further comprise also following step: in solvent, by compound II and such asAcid-base neutralization reaction as follows is carried out, the fatty amine salt of the compound II is obtained；
Wherein, R1、R2And R3As described above.
The acid-base neutralization reaction can be used the method and condition of organic chemistry filed routine, preferably following in the present invention
Reaction condition:
The solvent is the Conventional solvents of organic synthesis field, preferably organic solvent and/or water, more preferably toluene
Or water.The solvent usage be such reaction conventional amount used, as long as do not influence reaction progress, preferably with chemical combination
The volume mass ratio of object II is 3~15mL/g, more preferably 5~10mL/g, such as 7.5mL/g.
DescribedMolar ratio with compound II is 1~2, more preferably 1~1.3, such as 1.1.
The feed way of the acid-base neutralization reaction can be the Conventional feed introduction mode of such chemical reaction, as long as not influencing
Reaction carries out, it is specifically preferred according to the invention to mix compound II and fatty amine in a solvent, stir to get compound II
Fatty amine salt.
The reaction temperature of the acid-base neutralization reaction is preferably 20~100 DEG C, and further preferably 20~60 DEG C, such as:
50℃。
The reaction process of the acid-base neutralization reaction can using in this field routine monitoring method (such as TLC,
HPLC or NMR) it is monitored, generally to monitor that compound II disappears for reaction end, for example, the reaction time is
3h。
The acid-base neutralization reaction preferably includes following post-processing step: reaction solution is cooling, filtering, filter wash cake dry
It is dry.Such as: it is cooled to 0-5 DEG C, filtering, filter cake is eluted with cold toluene.50 DEG C of decompression dryings, obtain near-white solid.
The present invention provides a kind of preparation methods of 2- amino -6- ethyl benzoate comprising following step:
(1) in solvent, by compound II withAcid-base neutralization reaction as follows is carried out, the change is obtained
Close the fatty amine salt of object II；
(2) step (1) is not after reaction, post-treated, under the action of catalyst and hydrogen source, step (1) is anti-
Reaction solution after answering carries out catalytic hydrogenation as follows；
Wherein, R1、R2And R3As described above.
The present invention also provides the fatty amine salt of compound II a kind of, structure is as follows:
Wherein, R1、R2And R3As described above.
The present invention also provides the preparation method of the fatty amine salt of the compound II, the condition of this method institute as above
It states.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The compound of the present invention II can refer to document Pest Manage.Sci.2001,57,205-224 preparations, Qi Tashi
Agent is commercially available.
The positive effect of the present invention is that: the preparation method for the fatty amine salt for preparing II using fatty amine as alkali is simple,
Reaction condition is mild, raw material is cheap and easy to get.The fatty amine salt of II of the present invention carries out catalytic hydrogenation with single catalyst Raney-Ni,
Single step reaction obtains I, can be without using expensive catalyst Pt O2, be conducive to catalyst recovery and production it is continuous
Change operation, reduce costs and environmentally protective, and easy to operate, is suitble to industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
The preparation of the fatty amine salt of embodiment 1II
In 250mL there-necked flask, 10.10g compound II, 75mL toluene are put into, is added dropwise fatty amine (1.1 molar equivalent), is risen
Temperature is to 50 DEG C of stirring 3h.It is cooled to 0-5 DEG C, filtering, filter cake cold toluene elutes.50 DEG C of drying, obtain near-white solid.Three second of II
Amine salt 14.70g, yield 98.1%, elemental analysis, measured value: C, 57.82；H,7.18；N,8.89；Calculated value: C, 58.05；H,
7.15；N,9.03；The diisopropylethylamine salt 15.65g of II, yield 95.7%.Elemental analysis, measured value: C, 60.25；H,
7.80；N,8.52；Calculated value: C, 60.34；H,7.74；N,8.29.
The preparation of embodiment 2I
In 100mL hydriding reactor, the triethylamine salt of 3.10g II, 30mL water is added, a certain amount of alkali (being shown in Table 1) is stirred at room temperature
To dissolved clarification.0.50g Raney-Ni is added, is passed through hydrogen, (is shown in Table 1) under certain temperature and hydrogenation pressure, reacts 8h.It crosses and filters out
Raney-Ni, reaction solution hydrochloric acid tune pH=3.0~3.5 are removed, n-butyl acetate extracts (25mL × 3), organic phase anhydrous slufuric acid
Sodium is dry, depressurizes desolventizing, obtains near-white solid, 50 DEG C are dried under reduced pressure.1H-NMR(DMSO-d6):8.04(bs,2H),7.03
(t,1H),6.58(dd,1H),6.42(d,1H),2.70(q,2H),1.11(t,3H)；13C-NMR(DMSO-d6):170.70,
149.05,144.82,131.45,117.43,115.08,114.29,28.14,16.59。
Differential responses conditional outcome is shown in Table 1, and eq represents the molar equivalent ratio of triethylamine salt of the alkali with respect to II in table,
HPLC/% is the HPLC area normalization purity of reaction solution, and yield/% is to be dried under reduced pressure rear product yield.
Reaction process is as follows:
The catalytic hydrogenation conditions of the triethylamine salt of 1 II of table screen
Embodiment 3 " one kettle way " prepares I
In 250mL hydriding reactor, 6.57g II, 90mL water is added, a certain amount of alkali (being shown in Table 2) is stirred at room temperature to dissolved clarification.It is added
1.50g Raney-Ni is passed through hydrogen, (is shown in Table 2) under certain temperature and hydrogenation pressure, reacts 8h.Raney-Ni is filtered to remove,
Reaction solution hydrochloric acid tune pH=3.0~3.5, n-butyl acetate extract (75mL × 3), and organic phase anhydrous sodium sulfate is dry, decompression
Desolventizing obtains near-white solid, and 50 DEG C are dried under reduced pressure.
Differential responses conditional outcome is shown in Table 2, and eq represents molar equivalent ratio of the alkali with respect to II in table, and HPLC/% is reaction
The HPLC area normalization purity of liquid, yield/% are to be dried under reduced pressure rear product yield.
Table 2 " one kettle way " prepares the screening of I reaction condition
Claims (11)
1. a kind of preparation method of 2- amino -6- ethyl benzoate, it is characterised in that: it includes the following steps: in solvent, is urging
Under the action of agent and hydrogen source, the fatty amine salt of compound II is subjected to catalytic hydrogenation as follows and obtains compound I
?；The catalytic hydrogenation existsIn the presence of carry out, or do not carried out in the presence of alkali；
Wherein, R1、R2And R3It is each independently H, C1-C6Alkyl or C3-C6Naphthenic base, and R1、R2And R3It is not simultaneously H.
2. preparation method as described in claim 1, which is characterized in that the C1-C6Alkyl be methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl, isohesyl or tertiary hexyl；
And/or the C3-C6Naphthenic base be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
3. preparation method as described in claim 1, which is characterized in that
The R1、R2And R3It is simultaneously ethyl；Or, R1And R2For isopropyl, R3For ethyl；Or, R1And R2For hydrogen, R3For hexamethylene
Base.
4. preparation method as described in claim 1, which is characterized in that the solvent is organic solvent and/or water；
And/or the volume mass ratio of the fatty amine salt of the solvent and compound II is 5~25mL/g；
And/or the catalyst is Raney-Ni or Pd/C；
And/or the mass values of the fatty amine salt of the catalyst and compound II are 0.05~1；
And/or the hydrogen source is one of hydrogen, formic acid derivates and cyclohexene or a variety of；
And/or the reaction temperature of the catalytic hydrogenation is 80 DEG C~130 DEG C；
And/or the reaction pressure of the catalytic hydrogenation is 10~30Atm.
5. preparation method as claimed in claim 4, which is characterized in that the organic solvent is alcohols solvent；
And/or the volume mass ratio of the fatty amine salt of the solvent and compound II is 8~15mL/g；
And/or the catalyst is Raney-Ni；
And/or the mass values of the fatty amine salt of the catalyst and compound II are 0.1~0.3；
And/or the hydrogen source is hydrogen；
And/or the reaction temperature of the catalytic hydrogenation is 110~130 DEG C；
And/or the reaction pressure of the catalytic hydrogenation is 12~30Atm.
6. preparation method as described in claim 1, which is characterized in that the preparation method still further comprises following steps
It is rapid: in solvent, by compound II withAcid-base neutralization reaction as follows is carried out, obtains the compound II's
Fatty amine salt；
Wherein, R1、R2And R3With described in claim any one of 1-3.
7. preparation method as claimed in claim 6, which is characterized in that the solvent is organic solvent and/or water；
And/or the volume mass ratio of the solvent and compound II are 3~15mL/g；
And/or it is describedMolar ratio with compound II is 1~2；
And/or the reaction temperature of the acid-base neutralization reaction is 20~100 DEG C.
8. preparation method as claimed in claim 7, which is characterized in that the solvent is toluene or water；
And/or the volume mass ratio of the solvent and compound II are 5~10mL/g；
And/or it is describedMolar ratio with compound II is 1~1.3；
And/or the reaction temperature of the acid-base neutralization reaction is 20~60 DEG C.
9. a kind of preparation method of 2- amino -6- ethyl benzoate, it is characterised in that: it includes the following steps:
(1) in solvent, by compound II withAcid-base neutralization reaction as follows is carried out, the compound II is obtained
Fatty amine salt；
(2) step (1) is not after reaction, post-treated, under the action of catalyst and hydrogen source, step (1) is reacted and is tied
Reaction solution after beam carries out catalytic hydrogenation as follows；
Wherein, R1、R2And R3With described in claim any one of 1-3.
10. a kind of fatty amine salt of compound II, structure are as follows:
Wherein, R1、R2And R3With described in claim any one of 1-3.
11. a kind of preparation method of the fatty amine salt of compound II as claimed in claim 10, which is characterized in that under it includes
Column step: in solvent, by compound II withAcid-base neutralization reaction as follows is carried out, the compound is obtained
The fatty amine salt of II；
Wherein, R1、R2And R3With described in claim any one of 1-3；
The condition of the acid-base neutralization reaction is the same as described in claim any one of 6-8.
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| CN201710409074.4A CN108976140B (en) | 2017-06-02 | 2017-06-02 | Preparation method and intermediate of 2-amino-6-ethylbenzoic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716314A (en) * | 2022-04-01 | 2022-07-08 | 恒翼生物医药(上海)股份有限公司 | Salt containing benzene ring compounds, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2316818A1 (en) * | 2009-11-03 | 2011-05-04 | Active Biotech AB | Method for the preparation of 2-amino-6-ethylbenzoic acid |
| WO2016067238A1 (en) * | 2014-10-29 | 2016-05-06 | Westfaelische Wilhelms-Universitaet Muenster | Quinoline-3-carboxamide compounds and their use in diagnosis |
-
2017
- 2017-06-02 CN CN201710409074.4A patent/CN108976140B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2316818A1 (en) * | 2009-11-03 | 2011-05-04 | Active Biotech AB | Method for the preparation of 2-amino-6-ethylbenzoic acid |
| WO2016067238A1 (en) * | 2014-10-29 | 2016-05-06 | Westfaelische Wilhelms-Universitaet Muenster | Quinoline-3-carboxamide compounds and their use in diagnosis |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716314A (en) * | 2022-04-01 | 2022-07-08 | 恒翼生物医药(上海)股份有限公司 | Salt containing benzene ring compounds, preparation method and application thereof |
| CN114716314B (en) * | 2022-04-01 | 2024-01-02 | 恒翼生物医药(上海)股份有限公司 | Salt containing benzene ring compound, preparation method and application thereof |
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