CN108285413A - 2,3 dihydroxybutanedioic acid pharmaceutical intermediate synthetic method - Google Patents
2,3 dihydroxybutanedioic acid pharmaceutical intermediate synthetic method Download PDFInfo
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- CN108285413A CN108285413A CN201710835773.5A CN201710835773A CN108285413A CN 108285413 A CN108285413 A CN 108285413A CN 201710835773 A CN201710835773 A CN 201710835773A CN 108285413 A CN108285413 A CN 108285413A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/04—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses 2,3 dyhydrobutanedioic acid pharmaceutical intermediate synthetic methods, include the following steps：2,3 dimethoxy butanedial of Isosorbide-5-Nitrae dibromo, n-heptane solution are added in the reaction vessel, 170 190rpm of mixing speed is controlled, solution temperature is increased to 40 46 DEG C, aqueous solution is added, dioctyl sebacate solution is added in dimethyl sulfoxide (DMSO) in batches in 20 40min, the reaction was continued 50 80min；Temperature is increased to 55 62 DEG C, potassium bromide solution, acetic acid zinc powder is added, the reaction was continued 2 3h reduce temperature to 10 16 DEG C, stand 30 50min, sodium nitrate solution is added, solution is layered, and detaches oil-yielding stratum, 30 50min are washed with 3 hexanol solution, it is recrystallized in ring valeric acid solution, dehydrating agent is dehydrated, and obtains 2,3 dyhydrobutanedioic acid of finished product.
Description
Technical field
The present invention relates to a kind of preparation methods of medicine intermediate, belong to organic synthesis field more particularly to 2,3- dihydroxies
Base succinic acid pharmaceutical intermediate synthetic method.
Background technology
2,3- dyhydrobutanedioic acids are mainly used for the industry such as medicine, food, process hides, weaving, are used as anti-oxidant synergist, delay
Solidifying agent, tanning agent, chelating agent, medicament；2,3- dyhydrobutanedioic acids are very important chiral ligand and chiral building block, can be used for
Prepare many famous chiral catalysts, and synthesize complicated natural products molecule as chiral source.Existing synthetic method
Big mostly use from glyoxal react then sour water solution with hydrogen cyanide and obtains, the reaction raw materials second two that this synthetic method uses
Aldehyde sucking, intake absorb harmful through skin；It is irritating to the skin effect, dermatitis can be caused；Steam or mist to eyes,
Mucous membrane and the upper respiratory tract have stimulation；These factors can all cause reaction raw materials glyoxal to generate production operation personnel health
Harm.Glyoxal is harmful to environment, can be polluted to air, increases Final pollution object processing cost.Reaction raw materials hydrogen
Cyanic acid belongs to hypertoxic substance, can inhibit respiratory enzyme, causes to suffocate into the cell；Acute cyanide severe intoxication performance is in deep coma
State, tachypnea, paroxysmal twitch or even tonic spasm.Therefore, it can be seriously endangered as reaction raw materials using hydrogen cyanide
The health of production operation personnel is unfavorable for keeping the safety in production.Therefore, there are many shortcomings for above-mentioned synthetic method, it is necessary to carry
Go out a kind of new synthetic method.
Invention content
Technical problems based on background technology, the present invention propose the synthesis of 2,3- dyhydrobutanedioic acid pharmaceutical intermediates
Method includes the following steps：
A:Bromo- 2, the 3- dimethoxys-butanedial of Isosorbide-5-Nitrae-two is added in the reaction vessel, n-heptane solution controls mixing speed
170-190rpm increases solution temperature to 40-46 DEG C, aqueous solution is added, and dimethyl sulfoxide (DMSO) is added in batches in 20-40min
Dioctyl sebacate solution, the reaction was continued 50-80min；
B:Temperature is increased to 55-62 DEG C, potassium bromide solution, acetic acid zinc powder is added, the reaction was continued 2-3h reduces temperature extremely
10-16 DEG C, 30-50min is stood, sodium nitrate solution is added, solution layering detaches oil-yielding stratum, 30- is washed with 3- hexanol solution
50min is recrystallized in ring valeric acid solution, and dehydrating agent dehydration obtains finished product 2,3- dyhydrobutanedioic acids.
Preferably, n-heptane solution mass fraction is 15-21%.
Preferably, dioctyl sebacate liquid quality fraction is 20-26%.
Preferably, potassium bromide solution mass fraction is 10-15%.
Preferably, sodium nitrate solution mass fraction is 20-26%.
Preferably, 3- hexanols liquid quality fraction is 40-45%.
Preferably, ring valeric acid liquid quality fraction is 60-67%.
Entire building-up process can be used following net reaction to indicate：
Compared to synthetic method disclosed in background technology, 2,3- dyhydrobutanedioic acids pharmaceutical intermediate provided by the invention closes
At method, glyoxal, hydrogen cyanide need not be used as reaction raw materials, glyoxal is avoided and production operation personnel health is generated
Harm and pollution on the environment, reduce Final pollution object processing cost.And it also avoids belonging to hypertoxic substance
Hydrogen cyanide reduce the danger coefficient of building-up process as reactant to be conducive to the health of production operation personnel.Reaction
Intermediate link reduces very much, and the reaction time also shortens much, and reaction yield also improves, while the present invention provides a kind of new
Synthetic route, for further promoted reaction yield lay a good foundation.
Description of the drawings
Fig. 1 is the infrared analysis spectrogram of finished product 2,3 dihydroxybutanedioic acid.
Specific implementation mode
Embodiment 1：
2,3- dyhydrobutanedioic acid pharmaceutical intermediate synthetic methods, include the following steps：
A:- two bromo- 2,3- dimethoxys-butanedial of 3mol Isosorbide-5-Nitraes is added in the reaction vessel, 900ml mass fractions are
15% n-heptane solution controls mixing speed 170rpm, increases solution temperature to 40 DEG C, 6mol aqueous solutions, 6mol dimethyl is added
Sulfoxide, it is 20% dioctyl sebacate solution that points 2 times, which are added a 6mol mass fractions, in 20min, the reaction was continued 50min；
B:Temperature is increased to 55 DEG C, addition 1.3L mass fractions are 10% potassium bromide solution, and 3mol acetic acid zinc powders continue
2h is reacted, reduces temperature to 10 DEG C, stands 30min, addition 700ml mass fractions are 20% sodium nitrate solution, and solution is layered, point
Oil reservoir is separated out, is that 40%3- hexanol solution washs 30min with mass fraction, is tied again in mass fraction is 60% ring valeric acid solution
Crystalline substance, anhydrous magnesium sulfate dehydrating agent dehydration, obtains finished product 2,3- dyhydrobutanedioic acid 439.65g, yield 97.7%.
Embodiment 2：
2,3- dyhydrobutanedioic acid pharmaceutical intermediate synthetic methods, include the following steps：
A:- two bromo- 2,3- dimethoxys-butanedial of 3mol Isosorbide-5-Nitraes is added in the reaction vessel, 900ml mass fractions are
18% n-heptane solution controls mixing speed 180rpm, increases solution temperature to 43 DEG C, 7mol aqueous solutions, 7mol dimethyl is added
Sulfoxide, it is 23% dioctyl sebacate solution, the reaction was continued 70min that 7mol mass fractions are added three times in 30min；
B:Temperature is increased to 58 DEG C, addition 1.3L mass fractions are 13% potassium bromide solution, and 4mol acetic acid zinc powders continue
2.5h is reacted, reduces temperature to 13 DEG C, stands 40min, addition 700ml mass fractions are 23% sodium nitrate solution, and solution is layered,
Oil-yielding stratum is detached, is that 43%3- hexanol solution washs 40min with mass fraction, the weight in mass fraction is 64% ring valeric acid solution
Crystallization, anhydrous magnesium sulfate dehydrating agent dehydration, obtains finished product 2,3- dyhydrobutanedioic acid 441.45g, yield 98.1%.
Embodiment 3：
2,3- dyhydrobutanedioic acid pharmaceutical intermediate synthetic methods, include the following steps：
A:- two bromo- 2,3- dimethoxys-butanedial of 3mol Isosorbide-5-Nitraes is added in the reaction vessel, 900ml mass fractions are
21% n-heptane solution controls mixing speed 190rpm, increases solution temperature to 46 DEG C, 8mol aqueous solutions, 8mol dimethyl is added
Sulfoxide, it is 26% dioctyl sebacate solution that points 4 times, which are added a 8mol mass fractions, in 40min, the reaction was continued 80min；
B:Temperature is increased to 62 DEG C, addition 1.3L mass fractions are 15% potassium bromide solution, and 5mol acetic acid zinc powders continue
3h is reacted, reduces temperature to 16 DEG C, stands 50min, addition 700ml mass fractions are 26% sodium nitrate solution, and solution is layered, point
Oil reservoir is separated out, is that 45%3- hexanol solution washs 50min with mass fraction, is tied again in mass fraction is 67% ring valeric acid solution
Crystalline substance, anhydrous magnesium sulfate dehydrating agent dehydration, obtains finished product 2,3- dyhydrobutanedioic acid 442.35g, yield 98.3%.
Fig. 1 is the infrared analysis spectrogram of finished product 2,3 dihydroxybutanedioic acid.
Table 1 is infrared analysis data.
1 infrared analysis data of table
It described in above example, is merely preferred embodiments of the present invention, but protection scope of the present invention not office
Be limited to this, any one skilled in the art in the technical scope disclosed by the present invention, the technique according to the invention
Scheme and its inventive concept are subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (8)
1.2,3- dyhydrobutanedioic acid pharmaceutical intermediate synthetic methods, is it is characterised in that it includes following steps：
A:Bromo- 2, the 3- dimethoxys-butanedial of Isosorbide-5-Nitrae-two, n-heptane solution, control mixing speed 170- are added in the reaction vessel
190rpm increases solution temperature to 40-46 DEG C, aqueous solution is added, and the last of the ten Heavenly stems two is added in dimethyl sulfoxide (DMSO) in batches in 20-40min
Dioctyl phthalate solution, the reaction was continued 50-80min；
B:Temperature is increased to 55-62 DEG C, potassium bromide solution, acetic acid zinc powder, the reaction was continued 2-3h, reduction temperature to 10- is added
16 DEG C, 30-50min is stood, sodium nitrate solution is added, solution layering detaches oil-yielding stratum, 30- is washed with 3- hexanol solution
50min is recrystallized in ring valeric acid solution, and dehydrating agent dehydration obtains finished product 2,3- dyhydrobutanedioic acids.
2. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the heptan
Alkane liquid quality fraction is 15-21%.
3. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the last of the ten Heavenly stems
Adipate liquid quality fraction is 20-26%.
4. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the bromine
Change potassium solution mass fraction is 10-15%.
5. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the nitre
Acid sodium solution mass fraction is 20-26%.
6. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the 3-
Hexanol liquid quality fraction is 40-45%.
7. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that the ring
Valeric acid liquid quality fraction is 60-67%.
8. 2,3- dyhydrobutanedioic acids pharmaceutical intermediate synthetic method according to claim 1, which is characterized in that including as follows
Step：
A:- two bromo- 2,3- dimethoxys-butanedial of 3mol Isosorbide-5-Nitraes is added in the reaction vessel, 900ml mass fractions were 21% heptan
Alkane solution controls mixing speed 190rpm, and raising solution temperature is to 46 DEG C, addition 8mol aqueous solutions, 8mol dimethyl sulfoxide (DMSO)s,
It is 26% dioctyl sebacate solution that points 4 times, which are added a 8mol mass fractions, in 40min, the reaction was continued 80min；
B:Temperature is increased to 62 DEG C, addition 1.3L mass fractions are 15% potassium bromide solution, and 5mol acetic acid zinc powders, the reaction was continued
3h reduces temperature to 16 DEG C, stands 50min, and addition 700ml mass fractions are 26% sodium nitrate solution, and solution layering is isolated
Oil reservoir is that 45%3- hexanol solution washs 50min with mass fraction, is recrystallized in mass fraction is 67% ring valeric acid solution,
Anhydrous magnesium sulfate dehydrating agent is dehydrated, and obtains finished product 2,3- dyhydrobutanedioic acids.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710835773.5A CN108285413A (en) | 2017-09-17 | 2017-09-17 | 2,3 dihydroxybutanedioic acid pharmaceutical intermediate synthetic method |
| GBGB1719123.0A GB201719123D0 (en) | 2017-09-17 | 2017-11-20 | 2,3-dihydroxy-succinic acid drug intermediates synthesis method |
| AU2018101143A AU2018101143A4 (en) | 2017-09-17 | 2018-08-12 | 2,3-dihydroxy-succinic acid drug intermediates synthesis method |
| IE20180284U IE20180284U1 (en) | 2017-09-17 | 2018-08-23 | 2,3-dihydroxy-succinic acid drug intermediates synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710835773.5A CN108285413A (en) | 2017-09-17 | 2017-09-17 | 2,3 dihydroxybutanedioic acid pharmaceutical intermediate synthetic method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108285413A true CN108285413A (en) | 2018-07-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710835773.5A Withdrawn CN108285413A (en) | 2017-09-17 | 2017-09-17 | 2,3 dihydroxybutanedioic acid pharmaceutical intermediate synthetic method |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN108285413A (en) |
| AU (1) | AU2018101143A4 (en) |
| GB (1) | GB201719123D0 (en) |
| IE (1) | IE20180284U1 (en) |
-
2017
- 2017-09-17 CN CN201710835773.5A patent/CN108285413A/en not_active Withdrawn
- 2017-11-20 GB GBGB1719123.0A patent/GB201719123D0/en not_active Ceased
-
2018
- 2018-08-12 AU AU2018101143A patent/AU2018101143A4/en not_active Ceased
- 2018-08-23 IE IE20180284U patent/IE20180284U1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB201719123D0 (en) | 2018-01-03 |
| IE20180284U1 (en) | 2020-10-14 |
| AU2018101143A4 (en) | 2018-09-13 |
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180717 |
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| WW01 | Invention patent application withdrawn after publication |