CN101343233A - Industrialized preparation method for special amylamine oxalate - Google Patents
Industrialized preparation method for special amylamine oxalate Download PDFInfo
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- CN101343233A CN101343233A CNA2007100939503A CN200710093950A CN101343233A CN 101343233 A CN101343233 A CN 101343233A CN A2007100939503 A CNA2007100939503 A CN A2007100939503A CN 200710093950 A CN200710093950 A CN 200710093950A CN 101343233 A CN101343233 A CN 101343233A
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- oxalate
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- amylamine
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Abstract
The invention relates to an industrialized preparation method of pivalic amine oxalate. The method solves the problems that the current pivalic amine preparation process is restricted to laboratory preparation and has no scale production, the method takes general pivalic amide which is easy in taking as a raw material, and obtains the pivalic amine oxalate through reduction and salification. A reduction reagent adopts aluminum lithium tetrahydride, a solvent in reduction reaction adopts tetrahydrofuran or methyl tetrahydrofuran, and a salification reagent uses oxalic acid dihydrate. The method creates a new pivalic amine salt preparation method, namely, the preparation of oxalate, and the method can be used to realize the industrialization, and the industrialized preparation method of pivalic amine oxalate has advantages of rather high overall yield and low preparation costs.
Description
Technical field:
The present invention relates to a kind of preparation method of special amylamine fine-chemical intermediate, particularly a kind of industrialized process for preparing of special amylamine oxalate.
Background technology:
Special amylamine is the fine-chemical intermediate of outbalance, generally all be to prepare liquid unhindered amina, the special amylamine hydrochloride of the breadboard macro preparation of minority bibliographical information is also arranged, but the method, the especially preparation of industrialization that up to the present do not prepare this product oxalate.Once reported four kinds of preparation methods commonly used in the document, method one is a raw material with tertiary butyl ethanamide, and rearrangement reaction obtains special amylamine (J.Am.Chem.Soc. through Hofmann; 59; 1937; 2567; ); Method two is a raw material with special valeral, generates oxime with the oxammonium hydrochloride reaction, and reduction obtains special amylamine (J.Am.Chem.Soc. then; 60; 1938; 660); Method three is a raw material with special valeronitrile, obtains special amylamine (J.Org.Chem. through the reduction of reductive agents such as borine and lithium aluminum hydride; 47; 16; 1982; 3153-316); Method four is a raw material with pivaloyl amine, obtains special amylamine (J.Org.Chem. through borine or lithium aluminium hydride reduction; 47; 16; 1982; 3153-316);
Document synthetic route 1:
Said synthesis route 1 is not suitable for the technical scale batch reaction, this be because:
(a) the raw material that uses expensive, the cost height for example, must be used tertiary butyl ethanamide;
(b) it is higher that danger is amplified in reaction, requires operation strict, because liquid bromine corrodibility is bigger, has gas to produce during rearrangement reaction, and temperature of reaction is than difficult control.
Document synthetic route 2:
Said synthesis route 2 is not suitable for the technical scale batch reaction, this be because:
(a) the raw material that uses expensive, the cost height for example, must be used special valeral;
(b) need two-step reaction, the production cycle is longer.
(b) yield of this reaction (52%) on the low side
Document synthetic route 3:
Document synthetic route 4:
Above-mentioned two synthetic route (3﹠amp; 4) all be the method for synthesizing special amylamine preferably
(a) special valeronitrile of the raw material that uses and pivaloyl amine, the wide cost of originating is low.
(b) product is by becoming the hydrochloride purifying, and shortcoming is that hydrochloric acid corrosion resistance is bigger, has relatively high expectations to producing zoom facility.
(c) only limit to prepared in laboratory.
Summary of the invention:
The objective of the invention is: the industrialized process for preparing that the special amylamine oxalate that a kind of whole yield is higher, preparation cost is lower is provided.The technical issues that need to address of the present invention are: solved existing special amylamine preparation technology and be confined to prepared in laboratory, do not had large-scale production and by the hydrochloric acid salify equipment is caused the corrosive problem; Started a kind of preparation method---preparation of oxalate of special amylamine salt newly, and this method has been implemented in industrialization.
Technical scheme of the present invention:
The present invention is a raw material with pivaloyl amine conventional, that be easy to get, obtains special amylamine oxalate by reduction and salify.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we use tetrahydrochysene lithium aluminium reducing pivaloyl amine earlier.Optional tetrahydrofuran (THF) or 2-methyltetrahydrofuran are made reaction solvent, the response situation unanimity, but from cost consideration, preferred tetrahydrofuran (THF) is made solvent; Tetrahydrochysene lithium aluminium is gone back original reagent, generally uses 1 equivalent, if then react incomplete less than 1 equivalent; Very exothermic when pivaloyl amine is reinforced can suitably be cooled off, and control reaction temperature is no more than 60 ℃, considers the safety operation of factory, and preferred control reaction temperature is no more than 25 ℃, and insulation reaction is 2～3 hours then; It is 10%～20% sodium hydroxide solution that the reaction cancellation can be selected mass percentage concentration for use, and the concentration of sodium hydroxide solution is high more during cancellation, and heat release is severe more, and reaction solution is then thick more, so preferred 10% sodium hydroxide solution is controlled the cancellation temperature simultaneously and is no more than 25 ℃; The reaction solution cancellation is intact to continue to stir 1 hour to guarantee abundant reaction.Reacting liquid filtering obtains the tetrahydrofuran solution of crude product then.Crude product solution adds oxalic acid two aquations and the direct salify purifying of thing, product can directly be separated out from reaction solution, for abundant salify, after adding oxalic acid two hydrates, reaction solution at room temperature continues to stir about 1～1.3 hour, filter then, filter cake washs with amount of ethyl acetate, can obtain pure product.Productive rate is 73～80%.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally, and it has adopted, and economy is easy to get, the raw material pivaloyl amine of energy large-scale production is raw material, obtains special amylamine oxalate by reduction and salify.Its overall yield reaches 73～80%.The invention solves existing special amylamine preparation technology and be confined to prepared in laboratory, do not have the problem of large-scale production, and solved the equipment corrosion problem that the laboratory adopts the hydrochloric acid salify to cause; Started a kind of preparation method---preparation of oxalate of special amylamine salt newly, and this method has been implemented in industrialization, the industrialized process for preparing of the special amylamine oxalate that a kind of whole yield is higher, preparation cost is lower is provided.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
Synthesizing of special amylamine oxalate
LiAlH under nitrogen protection
4(55g 1.44mol) adds tetrahydrofuran (THF) (6.25L) in batches, and controlled temperature is no more than 25 ℃, add then in batches pivaloyl amine (145g, 1.44mol), controlled temperature is no more than 25 ℃, after adding, insulation reaction 2～3 hours.After detection reaction finishes, reaction solution is cooled to 0～5 ℃, (150g 0.38mol) slowly drops to reaction solution to 10% sodium hydroxide solution, 0～5 ℃ of controlled temperature, drip off, stirred 1 hour, controlled temperature is no more than 25 ℃, filters, filter cake washs three times with ethyl acetate (625mL*3), merging filtrate, and adding oxalic acid two hydrates (181g, 1.44mol), at room temperature vigorous stirring is 1 hour, filter, filter cake washs with amount of ethyl acetate, gets pure product special amylamine oxalate (202g, 1.14mol), productive rate: 79.6%.
1H?NMR(400MHz，DMSO-d
6)：δ7.90(br，S，2H)，2.60(s，2H)，0.91(s，9H)；Ms(M
++1，88.1)。
Embodiment 2
Synthetic (methyltetrahydrofuran) of special amylamine oxalate
LiAlH under nitrogen protection
4(15.4g 402.5mmol) adds 2-methyltetrahydrofuran (1750mL) in batches, and controlled temperature is no more than 25 ℃, add then in batches pivaloyl amine (40.6g, 402.5mmol), controlled temperature is no more than 25 ℃, after adding, insulation reaction 2～3 hours.After detection reaction finishes, reaction solution is cooled to 0～5 ℃, (42g 105mmol) slowly drops to reaction solution to 10% sodium hydroxide solution, 0～5 ℃ of controlled temperature, drip off, stirred 1 hour, controlled temperature is no more than 25 ℃, filters, filter cake washs three times with ethyl acetate (175mL*3), merging filtrate, and adding oxalic acid two aquations and thing (50.75g, 402.5mmol), at room temperature vigorous stirring is 1 hour, filter, filter cake washs with amount of ethyl acetate, gets pure product special amylamine oxalate (54.5g, 307.9mmol), productive rate: 76.5%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 3
Synthetic (20%NaOH) of special amylamine oxalate
LiAlH under nitrogen protection
4(28.6g 747.5mmol) adds tetrahydrofuran (THF) (3250mL) in batches, and controlled temperature is no more than 25 ℃, add then in batches pivaloyl amine (75.4g, 747.5mmol), controlled temperature is no more than 25 ℃, after adding, insulation reaction 2～3 hours.After detection reaction finishes, reaction solution is cooled to 0～5 ℃, (39g 195mmol) slowly drops to reaction solution to 20% sodium hydroxide solution, 0～5 ℃ of controlled temperature, drip off, stirred 1 hour, controlled temperature is no more than 25 ℃, filters, filter cake washs three times with ethyl acetate (325mL*3), merging filtrate, and adding oxalic acid two hydrates (94.3g, 747.5mmol), at room temperature vigorous stirring is 1 hour, filter, filter cake washs with amount of ethyl acetate, gets pure product special amylamine oxalate (96.8g, 547.2mmol), productive rate: 73.2%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 4
Synthetic (60 ℃ of the temperature of reaction) of special amylamine oxalate
LiAlH under nitrogen protection
4(4.4g 115.0mmol) adds tetrahydrofuran (THF) (500mL) in batches, and controlled temperature is no more than 25 ℃, add then in batches pivaloyl amine (11.6g, 115.0mmol), controlled temperature is no more than 60 ℃, after adding, insulation reaction 1～2 hour.After detection reaction finishes, reaction solution is cooled to 0～5 ℃, (12g 30mmol) slowly drops to reaction solution to 10% sodium hydroxide solution, 0～5 ℃ of controlled temperature, drip off, stirred 1 hour, controlled temperature is no more than 25 ℃, filters, filter cake washs three times with ethyl acetate (50mL*3), merging filtrate, and adding oxalic acid two hydrates (14.5g, 115mmol), at room temperature vigorous stirring is 1 hour, filter, filter cake washs with amount of ethyl acetate, gets pure product special amylamine oxalate (15.0g, 84.5mmol), productive rate: 73.5%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 5
Synthetic (amplify and produce) of special amylamine oxalate
LiAlH under nitrogen protection
4(5.7kg 149.5mol) adds tetrahydrofuran (THF) (650L) in batches, and controlled temperature is no more than 25 ℃, add then in batches pivaloyl amine (15.1kg, 149.5mol), controlled temperature is no more than 20 ℃, after adding, insulation reaction 2～3 hours.After detection reaction finishes, reaction solution is cooled to 0～5 ℃, (15.6kg 39mol) slowly drops to reaction solution to 10% sodium hydroxide solution, 0～5 ℃ of controlled temperature, drip off, stirred 1 hour, controlled temperature is no more than 25 ℃, filters, filter cake washs three times with ethyl acetate (65L*3), merging filtrate, and adding oxalic acid two aquations and thing (18.8kg, 149.5mol), at room temperature vigorous stirring is 1.2 hours, filter, filter cake washs with amount of ethyl acetate, gets pure product special amylamine oxalate (20.1kg, 118.4mol), productive rate: 79.2%.Its test data is shown in above-mentioned embodiment 1.
Claims (7)
1, the industrialized process for preparing of special amylamine oxalate, with pivaloyl amine conventional, that be easy to get is raw material, it is characterized in that pivaloyl amine obtains special amylamine oxalate by reduction and salify, also original reagent is selected tetrahydrochysene lithium aluminium for use, solvent is tetrahydrofuran (THF) or methyltetrahydrofuran in the reduction reaction, and salt-forming reagent is selected oxalic acid two aquations and thing for use.
2, the industrialized process for preparing of special amylamine oxalate according to claim 1 is characterized in that, the control reduction reaction temperature was≤60 ℃ when pivaloyl amine was reinforced, and it is 10%～20% sodium hydroxide solution that the reaction cancellation can be selected mass percentage concentration for use.
3, the industrialized process for preparing of special amylamine oxalate according to claim 2 is characterized in that, the reduction reaction solvent is selected tetrahydrofuran (THF) for use.
4, the industrialized process for preparing of special amylamine oxalate according to claim 2 is characterized in that, when pivaloyl amine feeds in raw material, and control reaction temperature≤25 ℃.
5, the industrialized process for preparing of special amylamine oxalate according to claim 2 is characterized in that, during the reaction cancellation, selecting mass percentage concentration for use is 10% sodium hydroxide solution.
6, the industrialized process for preparing of special amylamine oxalate according to claim 2 is characterized in that, the time of reduction reaction is 2～3 hours.
7, the industrialized process for preparing of special amylamine oxalate according to claim 1 is characterized in that, salt-forming reaction need at room temperature be stirred 1～1.3 hour.
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| CNA2007100939503A CN101343233A (en) | 2007-07-13 | 2007-07-13 | Industrialized preparation method for special amylamine oxalate |
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| CNA2007100939503A CN101343233A (en) | 2007-07-13 | 2007-07-13 | Industrialized preparation method for special amylamine oxalate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234234A (en) * | 2010-04-29 | 2011-11-09 | 上海药明康德新药开发有限公司 | Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4495369A (en) * | 1979-07-17 | 1985-01-22 | Bayer Aktiengesellschaft | Process for the preparation of neopentylamine |
-
2007
- 2007-07-13 CN CNA2007100939503A patent/CN101343233A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4495369A (en) * | 1979-07-17 | 1985-01-22 | Bayer Aktiengesellschaft | Process for the preparation of neopentylamine |
Non-Patent Citations (3)
| Title |
|---|
| HERBERT C. BROWN等: "Selective Reductions. 29. A Simple Technique To Achieve an Enhanced Rate of Reduction of Representative Organic Compounds by Borane-Dimethyl Sulfide", 《J. ORG. CHEM.》 * |
| HUA-JIE ZHU等: "Reduction of amides with NaBH4 in diglyme at 162℃", 《NEW J. CHEM》 * |
| SEYILOUR L. SHAPIRO等: "Hypoglycemic Agents. III.1-3 N1-Alkyl- and Aralkylbiguanides", 《J.AM.CHEM. SOC.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234234A (en) * | 2010-04-29 | 2011-11-09 | 上海药明康德新药开发有限公司 | Method for synthesizing (1R,2R)-(-)-N,N-dimethyl-1,2-cyclohexanediamine oxalate |
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Application publication date: 20090114 |