CN106831540B - A kind of preparation method of (S)-nipecotic acid - Google Patents
A kind of preparation method of (S)-nipecotic acid Download PDFInfo
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- CN106831540B CN106831540B CN201710138723.1A CN201710138723A CN106831540B CN 106831540 B CN106831540 B CN 106831540B CN 201710138723 A CN201710138723 A CN 201710138723A CN 106831540 B CN106831540 B CN 106831540B
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- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses a kind of preparation methods of (S)-nipecotic acid, include the following steps: that 3- piperidine formamide or its salt react in concentrated hydrochloric acid, (S)-nipecotic acid salt, be then converted to (S)-nipecotic acid to get.The present invention reacts 3- piperidine formamide or its salt in concentrated hydrochloric acid, and hydrolysis while has the effect of chiral resolution, can avoid splitting 3- piperidine formamide or nipecotic acid using chiral resolving agent.Moreover, preparation process post-processing operation of the present invention is simple, the method protected and be deprotected using N, Atom economy is high, and cost is relatively low, provides a kind of simple possible, low-cost production method for synthesis (S)-nipecotic acid.
Description
Technical field
The present invention relates to a kind of preparation methods of (S)-nipecotic acid, belong to field of medicaments.
Background technique
Nipecotic acid is a kind of non-protein beta-amino acids containing rigid piperidine ring, has preferable neurotransmitter γ-
Aminobutyric acid (GABA) transport protein inhibitory activity, can be used to synthesize GABA uptake inhibitors, antineoplastic etc..Nipecotic acid
Contain a chiral carbon in molecule, there is optical activity, enantiomter (S)-nipecotic acid is a variety of chiral drugs of synthesis
With the important intermediate of bioactive substance.
Currently, report prepared (S)-nipecotic acid method more be related to add chiral resolving agent splitting step and
The step of N protection and deprotection.For example, patent CN103492392A is reported with the 3- of (S)-camphorsulfonic acid resolution of racemic
Piperidinecarboxylic acid, to obtain (S)-nipecotic acid-(S)-camsilate method.Patent CN104093699A report with
(S)-N- tertbutyloxycarbonyl-nipecotic acid is raw material, takes off Boc by methanesulfonic acid, then is obtained with triethylamine neutralizing acid free
(S)-nipecotic acid.There are apparent defects for above-mentioned synthesis technology: resolution yield is lower, N protection and deprotection process at
This is higher, route is cumbersome, Atom economy is not high etc..Therefore, it is urgent to provide a kind of more easy, low production costs of operation
(S)-nipecotic acid synthesis technology.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of (S)-nipecotic acid.
The present invention provides a kind of preparation methods of (S)-nipecotic acid, include the following steps:
3- piperidine formamide or its salt react in acid, obtain (S)-nipecotic acid salt, are then converted to (S) -3- piperidines
Formic acid to get.
Further, the 3- piperidine formyl amine salt is the hydrochloride of 3- piperidine formamide.
Further, the acid is organic acid or inorganic acid；Preferably, the acid is sulfuric acid or hydrochloric acid.
Further, the hydrochloric acid is the aqueous hydrochloric acid solution that concentration is 0.5~35%w/w；Preferably, the hydrochloric acid is dense
Degree is 28~35%w/w.
Further, the reaction temperature of the 3- piperidine formamide or its salt in acid is 60~65 DEG C.
Further, the mass volume ratio of the 3- piperidine formamide or its salt and acid is 1:(1~10)；Preferably, institute
The mass volume ratio for stating 3- piperidine formamide or its salt and acid is 1:4.
Further, S configuration accounts for 60-95% in the 3- piperidine formamide or its salt；Preferably, S configuration accounts for 73-
77%.
Further, the method for converting (S)-nipecotic acid for (S)-nipecotic acid salt are as follows: lye is added and adjusts
PH to 6.5~7.5.
Further, it is 1:(3~8 that the lye, which is mass ratio) potassium hydroxide/sodium and methanol mixed solution；It is preferred that
Ground, potassium hydroxide/sodium: methanol quality ratio is 1:4.
Further, in 10 DEG C or less addition lye.
The process that lye is added is preferably to react at 0-10 DEG C, after adjusting pH before being concentrated under reduced pressure for the first time,
Temperature must be controlled at 30 DEG C hereinafter, being otherwise easy racemization.
Further, the preparation method further includes following purification step: (S)-nipecotic acid salt is converted into (S)-
Methanol stirring is added in concentration of reaction solution after nipecotic acid, and filtrate is concentrated in filtering, adds precipitating reagent stirring, filters, collects
Filter cake is to get purification (S)-nipecotic acid.
Further, (S)-nipecotic acid salt is converted into after (S)-nipecotic acid in 30 DEG C or less concentration of reaction solution.
Further, the precipitating reagent is ethyl alcohol or ethyl alcohol/petroleum ether mixed solvent；Preferably, the precipitating reagent is second
Alcohol/petroleum ether volume ratio 1:1 mixed solvent.
The present invention provides a kind of preparation methods of (S)-nipecotic acid, by 3- piperidine formamide or its salt in concentrated hydrochloric acid
Middle reaction, hydrolysis while, have the effect of chiral resolution, can avoid splitting 3- piperidine formamide or 3- using chiral resolving agent
Piperidinecarboxylic acid.Moreover, preparation process post-processing operation of the present invention is simple, and the method do not protected and be deprotected using N, atom warp
Ji property is high, and cost is relatively low, provides a kind of simple possible, low-cost production method for synthesis (S)-nipecotic acid.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
(the S)-nipecotic acid preparation process of the invention of embodiment 1
1, the preparation of (S) nipecotic acid hydrochloride crude product
100g 3- piperidine formyl amine hydrochlorate (wherein S configuration accounts for 75.1%) is added in 400ml concentrated hydrochloric acid, is heated up
To 60-65 DEG C of reaction 3h.After TLC monitors the disappearance of 3- piperidine formamide, it is kept stirring, reaction solution is cooled to 15~20 DEG C, is stirred
Mix 6h.It filters, solid shares 50g ethanol rinse and filters afterwards twice, obtains white solid, 99.8%ee is directly transferred to reaction kettle.
2, the preparation of (S) nipecotic acid
Stirring is opened, is cooled to 5-10 DEG C, (40g potassium hydroxide is added in 160g methanol, stirs dissolved clarification by 174g lye
Afterwards, it is cooled to 5-10 DEG C) it is added thereto, adjust pH to 7.25-30 DEG C of reaction solution is concentrated to dryness, and 100g methanol, room is added
Temperature stirring 0.5h.It filters, takes filtrate, 55-60 DEG C of reduced pressure.50g ethyl alcohol is added, 3h is stirred at room temperature, white solid is precipitated.It takes out
Filter, and filtered afterwards twice with total 30gEtOH elution, it is put into 60~65 DEG C of forced air dryings of drying chamber.Obtain white solid 25.2g, yield
39%, 99.4%ee.
HPLC-ELSD 99.7%.1H NMR(401MHz,D2O) δ 3.34 (dd, J=12.6,3.6Hz, 1H), 3.29-
3.19(m,1H),3.15–2.98(m,2H),2.66–2.55(m,1H),2.06–1.96(m, 1H),1.95–1.82(m,1H),
1.82–1.63(m,2H)。
(the S)-nipecotic acid preparation process of the invention of embodiment 2
1, the preparation of (S) nipecotic acid hydrochloride crude product
500g 3- piperidine formyl amine hydrochlorate (wherein S configuration accounts for 75.1%) is added in 2000ml concentrated hydrochloric acid, is heated up
To 60-65 DEG C of reaction 3h.After TLC monitors the disappearance of 3- piperidine formamide, it is kept stirring, reaction solution is cooled to 15~20 DEG C, is stirred
Mix 6h.It filters, solid shares 250g ethanol rinse and filters afterwards twice, obtains white solid, 99.6%ee is directly transferred to reaction
Kettle.
2, the preparation of (S) nipecotic acid
Stirring is opened, is cooled to 5-10 DEG C, (0.2kg potassium hydroxide is added in 0.8kg methanol, stirring by 920g lye
After dissolved clarification, it is cooled to 5-10 DEG C) it is added thereto, adjust pH to 7.25-30 DEG C of reaction solution is concentrated to dryness, and 1kg methanol is added,
15-20 DEG C of stirring 0.5h.It filters, takes filtrate, 55-60 DEG C of reduced pressure.0.2kg ethyl alcohol is added, stirs 0.5h；0.16kg is added
White solid is precipitated in petroleum ether, 15-20 DEG C of stirring 3h.It filters, and is filtered afterwards twice with 0.1kgEtOH+0.08kgPE elution,
It is put into 60~65 DEG C of forced air dryings of drying chamber.Dry to obtain 217g white solid, yield 67%, 96.8%ee, HPLC-ELSD
98.8%.
Purifying: being stirred at room temperature down, and 4 times of weight MeOH are added and dissolve most of solid, 15-20 DEG C of stirring 0.5h.It filters, takes
Filtrate, 55-60 DEG C of reduced pressure.0.2kg ethyl alcohol is added, stirs 0.5h；0.16kg petroleum ether, 15-20 DEG C of stirring 3h analysis is added
White solid out.It filters, is put into 60~65 DEG C of forced air dryings of drying chamber.Dry to obtain 183g white solid, yield 57%, 97.8%
Ee, HPLC-ELSD 98.9%.
(the S)-nipecotic acid preparation process of the invention of embodiment 3
50g 3- piperidine formyl amine hydrochlorate (wherein S configuration accounts for 75.1%) is added in 200ml concentrated hydrochloric acid, is warming up to
60-65 DEG C of reaction 3h.Cooled to room temperature.It filters, solid shares 100ml ethanol rinse, obtains white solid, and saturation is added
NaOH ethanol solution 230ml, 30 DEG C of concentration half solvents, survey pH is 7-7.5, and filtering, filtrate is spin-dried for, be added 50ml ethyl alcohol and
100ml petroleum ether, quickly stirring 1 hour, is filtered, 60 DEG C of dryings.Obtain white solid (S) nipecotic acid 3.5g, 99.4%
ee。
(the S)-nipecotic acid preparation process of the invention of embodiment 4
50g 3- piperidine formyl amine hydrochlorate (wherein S configuration accounts for 75.1%) is added in 200ml concentrated hydrochloric acid, is warming up to
60-65 DEG C of reaction 3h.Cooled to room temperature.It filters, solid shares 100ml ethanol rinse, obtains white solid, and saturation is added
KOH ethanol solution 146ml, pH 7-7.5,40 DEG C of concentration half solvents, add KOH ethyl alcohol tune pH be 7-7.5, filter, filter
Liquid is spin-dried for, and 100ml ethyl alcohol and 100ml petroleum ether is added, quickly stirring 1 hour, and filtering obtains white solid (S) 3- piperidines first
Sour 10g, 96.5%ee.
Claims (16)
1. a kind of preparation method of (S)-nipecotic acid, it is characterized in that: including the following steps:
3- piperidine formyl amine salt reacts in acid, obtains (S)-nipecotic acid salt, is then converted to (S)-nipecotic acid, i.e.,
?；
Wherein, the 3- piperidine formyl amine salt is the hydrochloride of 3- piperidine formamide；The acid is hydrochloric acid.
2. preparation method as described in claim 1, it is characterized in that: the hydrochloric acid is that the hydrochloric acid that concentration is 0.5 ~ 35%w/w is water-soluble
Liquid.
3. preparation method as claimed in claim 2, it is characterized in that: the concentration of the hydrochloric acid is 28 ~ 35%w/w.
4. preparation method as described in claim 1, it is characterized in that: reaction temperature of the 3- piperidine formyl amine salt in acid is
60~65℃。
5. preparation method as described in claim 1, it is characterized in that: the mass volume ratio of the 3- piperidine formyl amine salt and acid is
1:(1 ~ 10).
6. preparation method as claimed in claim 5, it is characterized in that: the mass volume ratio of the 3- piperidine formyl amine salt and acid is
1:4.
7. preparation method as described in claim 1, it is characterized in that: S configuration accounts for 60-95% in the 3- piperidine formyl amine salt.
8. preparation method as claimed in claim 7, it is characterized in that: S configuration accounts for 73-77% in the 3- piperidine formyl amine salt.
9. preparation method as described in claim 1, it is characterized in that: converting (S) -3- piperidines first for (S)-nipecotic acid salt
The method of acid are as follows: lye is added and adjusts pH to 6.5 ~ 7.5.
10. preparation method as claimed in claim 9, it is characterized in that: it is 1:(3 ~ 8 that the lye, which is mass ratio) hydroxide
The mixed solution of potassium/sodium and methanol.
11. preparation method as claimed in claim 10, it is characterized in that: the potassium hydroxide/sodium: methanol quality ratio is 1:4.
12. preparation method as claimed in claim 9, it is characterized in that: in 10 DEG C or less addition lye.
13. preparation method as described in claim 1, it is characterized in that: further including following purification step: (S)-nipecotic acid salt
It is converted into concentration of reaction solution after (S)-nipecotic acid, methanol stirring is added, filtrate is concentrated in filtering, precipitating reagent stirring is added,
Filtering collects filter cake to get purification (S)-nipecotic acid.
14. preparation method as claimed in claim 13, it is characterized in that: (S)-nipecotic acid salt is converted into (S) -3- piperidines first
In 30 DEG C or less concentration of reaction solution after acid.
15. preparation method as claimed in claim 13, it is characterized in that: the precipitating reagent is ethyl alcohol or ethyl alcohol/petroleum ether mixing
Solvent.
16. preparation method as claimed in claim 15, it is characterized in that: the precipitating reagent is ethyl alcohol/petroleum ether volume ratio 1:1
Mixed solvent.
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| US5217963A (en) * | 1985-05-24 | 1993-06-08 | Ciba-Geigy Corporation | Certain phosphonic acid quinoline-2-carboxylic acids, esters or amides useful for treatment of disorders responsive to N-methyl D-aspartate receptor blockade |
| CN101209990B (en) * | 2006-12-26 | 2010-11-10 | 江苏天汁化学有限公司 | Resolution method for 3-piperidine formic acid ester |
| CN101712645B (en) * | 2009-11-20 | 2013-08-28 | 重庆威尔德·浩瑞医药化工有限公司 | Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof |
| CN103333930B (en) * | 2012-02-28 | 2015-04-15 | 苏州同力生物医药有限公司 | A synthetic method for (R)-praziquantel |
| CN103435538B (en) * | 2013-08-08 | 2015-10-28 | 爱斯特（成都）医药技术有限公司 | (R) preparation method of-3-amido piperidine hydrochlorate |
| CN104557677A (en) * | 2014-12-31 | 2015-04-29 | 大连联化化学有限公司 | Chemical resolution preparation method for optical pure 2-pipecolic acid |
| CN104803909B (en) * | 2015-05-25 | 2017-08-29 | 南京工业大学 | The separation method of L piperidine carboxylic acids |
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| A unified synthesis of all stereoisomers of 2-(aminomethyl)-cyclobutane-1-carboxylic acid;Virginie A. et al;《Tetrahedron》;20130226;第69卷;第3571-3576页 |
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