CN109851542A - One kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride and its synthetic method - Google Patents
One kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride and its synthetic method Download PDFInfo
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- CN109851542A CN109851542A CN201910082302.0A CN201910082302A CN109851542A CN 109851542 A CN109851542 A CN 109851542A CN 201910082302 A CN201910082302 A CN 201910082302A CN 109851542 A CN109851542 A CN 109851542A
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Abstract
The invention discloses a kind of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride and its synthetic methods, belong to organic chemical synthesis technical field.The synthetic method includes following process: using (R) -3- pyridone -1- carboxylic acid tert-butyl ester as raw material; by four-step reaction, that is, synthesizing methanesulfonic acid ester, methylamine, upper acetyl group, de- tertbutyloxycarbonyl at salt to get (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride.The synthetic method safe ready of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride provided by the invention, it is economical, resulting (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride performance is stablized, and can easily store, transport.
Description
Technical field
The present invention relates to organic chemical synthesis technical fields, more particularly to one kind (S)-N- methyl-N- (pyrrolidin-3-yl)
Acetamid dihydrochloride and its synthetic method.
Background technique
(S)-N- methyl-N- (pyrrolidin-3-yl) acetamide is the weight for synthesizing certain chiral drugs and bioactive substance
Want intermediate.Patent WO2009076387A1 and US20110118261A1 etc. report the method for synthesizing the intermediate.But
In production and use process, it has been found that the intermediate is unstable, is not easy to store and transport；By this field knowledge analysis, ammonia
Matrix manufacturing can increase its stability at mono-salt.But in actually synthesis, (S)-N- methyl-N- (pyrrolidin-3-yl) acetamide
Mono-salt it is also unstable.The pleasantly surprised discovery of the present inventor, the dihydrochloride of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamide
It is more stable, it may be convenient to produce, store and transport, and currently without about (S)-N- methyl-N- (pyrrolidin-3-yl) second
The dihydrochloride of amide and its report of synthetic method.
The present invention provides a kind of low cost, the simple methods of synthetic route to synthesize (S)-N- methyl-N- (pyrrolidines-
3- yl) acetamid dihydrochloride.
Summary of the invention
In view of the above problems, the present invention provides a kind of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamides two
Hydrochloride and its synthetic method, this method safety is convenient, economical, resulting (S)-N- methyl-N- (pyrrolidin-3-yl) acetyl
Amine dihydrochloride performance is stablized, and can easily store, transport.
The technical solution of the present invention is as follows:
A kind of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, chemical formula C7H14N2O·2HCl。
Further, described one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, chemical structure
Formula are as follows:
A kind of synthetic method of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, synthetic route are as follows:
Step are as follows:
A, 1 Mesylation of compound in the presence of solvent, is obtained by compound 2 using mesyl chloride；
B, under the conditions of non-alkaline, after carrying out methylamine to compound 2 using methylamine-methanol solution, extraction, washing are obtained
Compound 3；
C, compound 3 is soluble in water, while buck and chloroacetic chloride or acetic anhydride is added dropwise, acetylation is carried out to compound 3,
Extraction, washing, drying, obtain compound 4；
D, removing Boc group is carried out into salt treatment to compound 4 using hydrogen chloride, obtains compound 5 i.e. (S)-N- methyl-N-
(pyrrolidin-3-yl) acetamid dihydrochloride.
Preferably, solvent described in the step a is the methylene chloride and triethylamine mixed liquor that mass ratio is 10:1.
Preferably, the molar ratio of mesyl chloride described in the step a and compound 1 is 1.0~1.1:1, reaction time 2
~2.5h.
Preferably, the mass ratio of methylamine-methanol solution described in the step b and compound 2 is 1.1:0.12~0.14, instead
75~90 DEG C of temperature are answered, 25~30h of reaction time.
Preferably, the molar ratio of compound 3 described in the step c and chloroacetic chloride or acetic anhydride is 1:1.6, reaction temperature
It is -5~5 DEG C, 1.8~2h of reaction time.
Preferably, the sodium hydrate aqueous solution that buck described in the step c is 20%~25%.
Preferably, extraction described in the step b and c is MTBE or methylene chloride with solvent.
Preferably, the reaction temperature of the step d is 25~35 DEG C.
In conclusion beneficial effects of the present invention show themselves in that the present invention provides one kind (S)-N- methyl-N- (pyrrolidines-
3- yl) acetamid dihydrochloride synthetic method safe ready, economic, resulting (S)-N- methyl-N- (pyrrolidin-3-yl) second
Carboxamide dihydrochloride performance is stablized, and can easily store, transport.
Detailed description of the invention
The synthetic route of Fig. 1 (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride；
The thermal multigraph of Fig. 2 (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride.
Specific embodiment
Embodiment of the present invention can be replaced by the difference of specific range based on the above technical solution,
Available numerous embodiment, therefore, several embodiments as described below are only merely the more excellent reality in numerous embodiment
Example is applied, any technology replacement done in above-mentioned technical proposal all belongs to the scope of protection of the present invention.
Embodiment 1
A kind of synthetic method of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride:
A. reaction kettle is subjected to nitrogen purge, injects 380g methylene chloride from feed inlet and 38g triethylamine stirs several minutes
Afterwards, 58g compound 1 is added from feed inlet, is then slowly dropped into 39g methylsufonyl chloride, after being added dropwise, insulation reaction 2h, water
It washes, be concentrated to get compound 2, yield 82.2g.
B. under room temperature, 660g methylamine methanol solution is added into autoclave, adds 82g compound 2, enclosed high pressure kettle,
Be warming up to 80 DEG C of reaction 28h, be cooled to room temperature, be concentrated under reduced pressure into it is substantially solvent-free distillate, be added 320g methylene chloride and
82g water separates organic phase, and water phase uses 100g methylene chloride to extract again, merges organic phase, is successively washed using 30g, 30g 15%
Salt washing, is then added appropriate amount of acid and 250g MTBE is stirred several minutes, and filtering is dried to get compound 3, yield 88g.
C. at normal temperature, 300g water is added into reaction kettle, adds compound 3 (88g, 1.00eq) progress 10min and stirs
It mixes, is then cooled to 5 DEG C, with 25% sodium hydrate aqueous solution tune pH to 8, be slowly dropped into chloroacetic chloride (1.60eq), and simultaneously
25% sodium hydrate aqueous solution is instilled, control pH is 8~10, reacts 2h, and MTBE is then added and extracts to obtain organic phase, organic phase is used
Saturated common salt washing；Anhydrous sodium sulfate, active carbon stirring 3h are added, filtering obtains compound 4.
D. under room temperature, above compound 4 is added in 50g dehydrated alcohol, then is cooled to 5 DEG C, is then slowly introducing 30g
HCl gas after having led to, is to slowly warm up to 25 DEG C and is reacted, and TLC monitors raw material fully reacting.It filters under nitrogen protection, very
Sky is drying to obtain (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, yield 34g.
Embodiment 2
A kind of synthetic method of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride:
A. reaction kettle is subjected to nitrogen purge, injects 360g methylene chloride from feed inlet and 36g triethylamine stirs several minutes
Afterwards, 58g compound 1 is added from feed inlet, is then slowly dropped into 35.5g methylsufonyl chloride, after being added dropwise, insulation reaction
2.5h, washing are concentrated to get compound 2, yield 79.2g.
B. under room temperature, 660g methylamine methanol solution is added into autoclave, adds 79.2g compound 2, enclosed high pressure
Kettle is warming up to 75 DEG C of reaction 30h, is cooled to room temperature, be concentrated under reduced pressure into it is substantially solvent-free distillate, be added 310g methylene chloride
With 80g water, organic phase is separated, water phase uses 100g methylene chloride to extract again, merges organic phase, successively washes using 25g, 25g
The washing of 15% salt, is then added appropriate amount of acid and 250g MTBE is stirred several minutes, and filtering is dried to get compound 3, and yield is
84g。
C. at normal temperature, 300g water is added into reaction kettle, adds compound 3 (88g, 1.00eq) progress 10min and stirs
It mixes, is then cooled to -5 DEG C, with 22% sodium hydrate aqueous solution tune pH to 8~9, be slowly dropped into chloroacetic chloride (1.60eq), and
22% sodium hydrate aqueous solution is instilled simultaneously, and control pH is 8~9, reacts 1.8h, and MTBE is then added and extracts to obtain organic phase, has
Machine is mutually washed with saturated common salt；Anhydrous sodium sulfate, active carbon stirring 3h are added, filtering obtains compound 4.
D. under room temperature, above compound 4 is added in 50g dehydrated alcohol, then is cooled to 5 DEG C, is then slowly introducing 30g
HCl gas after having led to, is to slowly warm up to 28 DEG C and is reacted, and TLC monitors raw material fully reacting.It filters under nitrogen protection, very
Sky is drying to obtain (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, yield 32g.
Embodiment 3
A kind of synthetic method of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride:
A. reaction kettle is subjected to nitrogen purge, injects 380g methylene chloride from feed inlet and 38g triethylamine stirs several minutes
Afterwards, 58g compound 1 is added from feed inlet, is then slowly dropped into 37g methylsufonyl chloride, after being added dropwise, insulation reaction 2.2h,
Washing is concentrated to get compound 2, yield 80.1g.
B. under room temperature, 660g methylamine methanol solution is added into autoclave, adds 92.4g compound 2, enclosed high pressure
Kettle is warming up to 90 DEG C of reaction 25h, is cooled to room temperature, be concentrated under reduced pressure into it is substantially solvent-free distillate, be added 340g methylene chloride
With 90g water, organic phase is separated, water phase uses 100g methylene chloride to extract again, merges organic phase, successively washes using 40g, 40g
The washing of 15% salt, is then added appropriate amount of acid and 260g MTBE is stirred several minutes, and filtering is dried to get compound 3, and yield is
86g。
C. at normal temperature, 300g water is added into reaction kettle, adds compound 3 (88g, 1.00eq) progress 10min and stirs
It mixes, is then cooled to 0 DEG C, with 20% sodium hydrate aqueous solution tune pH to 9~10, be slowly dropped into acetic anhydride (1.60eq), and
20% sodium hydrate aqueous solution is instilled simultaneously, and control pH is 9~10, reacts 1.9h, and MTBE is then added and extracts to obtain organic phase, has
Machine is mutually washed with saturated common salt；Anhydrous sodium sulfate, active carbon stirring 3h are added, filtering obtains compound 4.
D. under room temperature, above compound 4 is added in 50g dehydrated alcohol, then is cooled to 5 DEG C, is then slowly introducing 30g
HCl gas after having led to, is to slowly warm up to 35 DEG C and is reacted, and TLC monitors raw material fully reacting.It filters under nitrogen protection, very
Sky is drying to obtain (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, yield 30g.
Fig. 1 is the synthetic route of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride；
(S) nuclear magnetic data of-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride are as follows:
1HNMR(400MHz,D2O), δ ppm
4.74 (m, 1H), 3.60 (m, 1H), 3.48 (m, 2H), 3.22 (m, 1H), 3.03 (s, 3H),
2.82(s,1H),2,38(m,1H),2,33(m,1H),2.16(m,1H),2.10(s,3H)。
Fig. 2 is the thermal multigraph of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, it can be seen that (S)-
N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride is when less than 230 DEG C, better heat stability, meets transport and requires.
The invention is not limited to specific embodiments above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (10)
1. a kind of (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride, which is characterized in that chemical formula is
C7H14N2O·2HCl。
2. one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as described in claim 1, feature exist
In chemical structural formula are as follows:
3. the synthesis of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 1 or 2
Method, which is characterized in that synthetic route is as follows:
Step are as follows:
A, 1 Mesylation of compound in the presence of solvent, is obtained by compound 2 using mesyl chloride；
B, under the conditions of non-alkaline, after carrying out methylamine to compound 2 using methylamine-methanol solution, extraction, washing obtain chemical combination
Object 3；
C, compound 3 is soluble in water, while buck and chloroacetic chloride or acetic anhydride is added dropwise, acetylation is carried out to compound 3, extract,
Washing, drying, obtain compound 4；
D, removing Boc group is carried out into salt treatment to compound 4 using hydrogen chloride, obtains compound 5 i.e. (S)-N- methyl-N- (pyrrole
Cough up alkane -3- base) acetamid dihydrochloride.
4. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that solvent described in the step a is the methylene chloride and triethylamine mixed liquor that mass ratio is 10:1.
5. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that the molar ratio of mesyl chloride described in the step a and compound 1 is 1.0~1.1:1, reaction time 2
~2.5h.
6. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that the mass ratio of methylamine-methanol solution described in the step b and compound 2 is 1.1:0.12~0.14, instead
75~90 DEG C of temperature are answered, 25~30h of reaction time.
7. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that the molar ratio of compound 3 described in the step c and chloroacetic chloride or acetic anhydride is 1:1.6, reaction temperature is-
5~5 DEG C, 1.8~2h of reaction time.
8. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that the sodium hydrate aqueous solution that buck described in the step c is 20%~25%.
9. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that extraction described in the step b and c is MTBE or methylene chloride with solvent.
10. the synthesis side of one kind (S)-N- methyl-N- (pyrrolidin-3-yl) acetamid dihydrochloride as claimed in claim 3
Method, which is characterized in that the reaction temperature of the step d is 25~35 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433114A (en) * | 2022-09-23 | 2022-12-06 | 爱斯特（成都）生物制药股份有限公司 | Synthetic method of 3-hydroxy tetrahydropyrrole compound |
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| CN102015684A (en) * | 2007-12-10 | 2011-04-13 | 葛兰素集团有限公司 | Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists |
| CN102149718A (en) * | 2008-09-08 | 2011-08-10 | 株式会社Lg生命科学 | Fused heterocyclic compound |
| WO2011160020A2 (en) * | 2010-06-18 | 2011-12-22 | Fob Synthesis | Carbapenem antibacterials with gram-negative activity |
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2019
- 2019-01-28 CN CN201910082302.0A patent/CN109851542A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090326246A1 (en) * | 2006-07-28 | 2009-12-31 | Kaneka Corporation | Method for Production of Optically Active 3-Amino-Nitrogenated Compound |
| CN102015684A (en) * | 2007-12-10 | 2011-04-13 | 葛兰素集团有限公司 | Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists |
| CN102149718A (en) * | 2008-09-08 | 2011-08-10 | 株式会社Lg生命科学 | Fused heterocyclic compound |
| WO2011160020A2 (en) * | 2010-06-18 | 2011-12-22 | Fob Synthesis | Carbapenem antibacterials with gram-negative activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115433114A (en) * | 2022-09-23 | 2022-12-06 | 爱斯特（成都）生物制药股份有限公司 | Synthetic method of 3-hydroxy tetrahydropyrrole compound |
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