CN106831540A - It is a kind of（S）The preparation method of 3 piperidine carboxylic acids - Google Patents
It is a kind of（S）The preparation method of 3 piperidine carboxylic acids Download PDFInfo
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- CN106831540A CN106831540A CN201710138723.1A CN201710138723A CN106831540A CN 106831540 A CN106831540 A CN 106831540A CN 201710138723 A CN201710138723 A CN 201710138723A CN 106831540 A CN106831540 A CN 106831540A
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- acid
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- piperidine
- nipecotic
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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
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation method of (S) 3 piperidine carboxylic acid, comprise the following steps：3 piperidine formamides or its salt react in concentrated hydrochloric acid, obtain (S) 3 piperidine carboxylic acid salt, are then converted to (S) 3 piperidine carboxylic acid, obtain final product.The present invention reacts 3 piperidine formamides or its salt in concentrated hydrochloric acid, has the effect of chiral resolution while hydrolysis, can avoid using chiral resolving agent to split 3 piperidine formamides or 3 piperidine carboxylic acids.And, preparation technology post-processing operation of the present invention is simple, and the method without being protected using N with deprotection, Atom economy is high, and cost is relatively low, for synthesis (S) 3 piperidine carboxylic acid provides a kind of simple possible, production method with low cost.
Description
Technical field
The present invention relates to a kind of preparation method of (S)-nipecotic acid, belong to field of medicaments.
Background technology
Nipecotic acid is a kind of non-protein beta-amino acids containing rigid piperidine ring, with 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, with optical activity, its enantiomter (S)-nipecotic acid is the various chiral drugs of synthesis
With the important intermediate of bioactivator.
At present, report preparing be related to add the method for (S)-nipecotic acid more the splitting step of chiral resolving agent and
The step of N protections and deprotection.Such as, patent CN103492392A is reported with the 3- piperazines of (S)-camphorsulfonic acid resolution of racemic
Pyridine formic acid, the method so as to obtain (S)-nipecotic acid-(S)-camsilate.Patent CN104093699A report with
(S)-N- tertbutyloxycarbonyls-nipecotic acid is raw material, takes off Boc by methanesulfonic acid, then obtain free with acid with triethylamine
(S)-nipecotic acid.There is obvious defect in above-mentioned synthesis technique：Resolution yield is relatively low, N protection and deprotection process into
This higher, route is cumbersome, Atom economy is not high etc..Therefore, a kind of offer more easy, low production cost of operation is provided badly
(S)-nipecotic acid synthesis technique.
The content of the invention
It is an object of the invention to provide a kind of preparation method of (S)-nipecotic acid.
The invention provides a kind of preparation method of (S)-nipecotic acid, comprise the following steps：
3- piperidine formamides or its salt react in acid, obtain (S)-nipecotic acid salt, are then converted to (S) -3- piperidines
Formic acid, obtains final product.
Further, the 3- piperidine formyls amine salt is the hydrochloride of 3- piperidine formamides.
Further, described acid is organic acid or inorganic acid；Preferably, described acid is sulfuric acid or hydrochloric acid.
Further, the hydrochloric acid is aqueous hydrochloric acid solution that concentration is 0.5~35%w/w；Preferably, the hydrochloric acid is dense
It is 28~35%w/w to spend.
Further, the reaction temperature of the 3- piperidine formamides or its salt in acid is 60~65 DEG C.
Further, the 3- piperidine formamides or its salt and the mass volume ratio of acid are 1：(1~10)；Preferably, institute
It is 1 that 3- piperidine formamides or its salt are stated with the mass volume ratio of acid：4.
Further, S configurations account for 60-95% in the 3- piperidine formamides or its salt；Preferably, S configurations account for 73-
77%.
Further, it is by the method that (S)-nipecotic acid salt is converted into (S)-nipecotic acid：Add alkali lye regulation
PH to 6.5~7.5.
Further, the alkali lye is that mass ratio is 1：Potassium hydroxide/the sodium and the mixed solution of methyl alcohol of (3~8)；It is preferred that
Ground, potassium hydroxide/sodium：Methanol quality ratio is 1：4.
Further, alkali lye is added in less than 10 DEG C.
The process of the addition alkali lye is reacted at being preferably 0-10 DEG C, after regulation pH before first time has been concentrated under reduced pressure,
Temperature must be controlled below 30 DEG C, otherwise easy racemization.
Further, described preparation method also includes following purification step：(S)-nipecotic acid salt be converted into (S)-
Concentration of reaction solution after nipecotic acid, adds methyl alcohol stirring, filtering to concentrate filtrate, adds precipitating reagent stirring, and filtering is collected
Filter cake, obtains final product refined (S)-nipecotic acid.
Further, (S)-nipecotic acid salt is converted into (S)-nipecotic acid after less than 30 DEG C concentration of reaction solution.
Further, the precipitating reagent is ethanol or ethanol/petroleum ether mixed solvent；Preferably, the precipitating reagent is second
Alcohol/petroleum ether volume ratio 1：1 mixed solvent.
The invention provides a kind of preparation method of (S)-nipecotic acid, by 3- piperidine formamides or its salt in concentrated hydrochloric acid
Middle reaction, effect while hydrolysis with chiral resolution can avoid using chiral resolving agent to split 3- piperidine formamides or 3-
Piperidine carboxylic acid.And, preparation technology post-processing operation of the present invention is simple, the method without being protected using N with deprotection, atom warp
Ji property is high, and cost is relatively low, for synthesis (S)-nipecotic acid provides a kind of simple possible, production method with low cost.
Obviously, the above of the invention, according to the ordinary technical knowledge and customary means of this area, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, is replaced or is changed.
The specific embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following example.It is all based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Specific embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
(the S)-nipecotic acid preparation technology of the invention of embodiment 1
1st, the preparation of (S) nipecotic acid hydrochloride crude product
100g 3- piperidine formyls amine hydrochlorate (wherein S configurations account for 75.1%) are added in 400ml concentrated hydrochloric acids, are heated up
To 60-65 DEG C of reaction 3h.After TLC monitoring 3- piperidine formamides disappear, it is kept stirring for, reaction solution is cooled to 15~20 DEG C, stirs
Mix 6h.Suction filtration, solid shares 50g ethanol rinses rear suction filtration twice, obtains white solid, and 99.8%ee is directly transferred to reactor.
2nd, the preparation of (S) nipecotic acid
Stirring is opened, 5-10 DEG C is cooled to, (40g potassium hydroxide is added in 160g methyl alcohol, stirs molten clear by 174g alkali 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 under reduced pressure into dry, addition 100g methyl alcohol, room
Temperature stirring 0.5h.Suction filtration, takes filtrate, and 55-60 DEG C is concentrated under reduced pressure.50g ethanol is added, 3h is stirred at room temperature and is separated out white solid.Take out
Filter, and with suction filtration after common 30gEtOH drip washing twice, it is put into 60~65 DEG C of forced air dryings of drying room.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 technology of the invention of embodiment 2
1st, the preparation of (S) nipecotic acid hydrochloride crude product
500g 3- piperidine formyls amine hydrochlorate (wherein S configurations account for 75.1%) are added in 2000ml concentrated hydrochloric acids, are heated up
To 60-65 DEG C of reaction 3h.After TLC monitoring 3- piperidine formamides disappear, it is kept stirring for, reaction solution is cooled to 15~20 DEG C, stirs
Mix 6h.Suction filtration, solid shares 250g ethanol rinses rear suction filtration twice, obtains white solid, and 99.6%ee is directly transferred to reaction
Kettle.
2nd, the preparation of (S) nipecotic acid
Stirring is opened, 5-10 DEG C is cooled to, (0.2kg potassium hydroxide is added in 0.8kg methyl alcohol, stirring by 920g alkali lye
It is molten it is clear after, be cooled to 5-10 DEG C) be added thereto, adjust pH to 7.25-30 DEG C of reaction solution is concentrated under reduced pressure into dry, addition 1kg methyl alcohol,
15-20 DEG C of stirring 0.5h.Suction filtration, takes filtrate, and 55-60 DEG C is concentrated under reduced pressure.0.2kg ethanol is added, 0.5h is stirred；Add 0.16kg
Petroleum ether, 15-20 DEG C of stirring 3h separates out white solid.Suction filtration, and with suction filtration after 0.1kgEtOH+0.08kgPE drip washing twice, put
Enter 60~65 DEG C of forced air dryings of drying room.Dry to obtain 217g white solids, yield 67%, 96.8%ee, HPLC-ELSD 98.8%.
Purifying：It is stirred at room temperature down, adds 4 times of most of solids of weight MeOH dissolvings, 15-20 DEG C of stirring 0.5h.Suction filtration, takes
Filtrate, 55-60 DEG C is concentrated under reduced pressure.0.2kg ethanol is added, 0.5h is stirred；Add 0.16kg petroleum ethers, 15-20 DEG C of stirring 3h analysis
Go out white solid.Suction filtration, is put into 60~65 DEG C of forced air dryings of drying room.Dry to obtain 183g white solids, yield 57%, 97.8%
Ee, HPLC-ELSD 98.9%.
(the S)-nipecotic acid preparation technology of the invention of embodiment 3
50g 3- piperidine formyls amine hydrochlorate (wherein S configurations account for 75.1%) are added in 200ml concentrated hydrochloric acids, are warming up to
60-65 DEG C of reaction 3h.Naturally cool to room temperature.Suction filtration, solid shares 100ml ethanol rinses, obtains white solid, adds saturation
NaOH ethanol solutions 230ml, 30 DEG C of concentration half solvents, surveys pH is 7-7.5, and filtering, filtrate is spin-dried for, addition 50ml ethanol and
100ml petroleum ethers, quick stirring 1 hour, filtering, 60 DEG C of dryings.Obtain white solid (S) nipecotic acid 3.5g, 99.4%
ee。
(the S)-nipecotic acid preparation technology of the invention of embodiment 4
50g 3- piperidine formyls amine hydrochlorate (wherein S configurations account for 75.1%) are added in 200ml concentrated hydrochloric acids, are warming up to
60-65 DEG C of reaction 3h.Naturally cool to room temperature.Suction filtration, solid shares 100ml ethanol rinses, obtains white solid, adds saturation
KOH ethanol solutions 146ml, pH be 7-7.5,40 DEG C of concentration half solvents, it is 7-7.5, filtering, filter to add KOH ethanol and adjust pH
Liquid is spin-dried for, and adds 100ml ethanol and 100ml petroleum ethers, and quick stirring 1 hour, filtering obtains white solid (S) 3- piperidines first
Sour 10g, 96.5%ee.
Claims (13)
1. a kind of preparation method of (S)-nipecotic acid, it is characterized in that：Comprise the following steps：
3- piperidine formamides or its salt react in acid, obtain (S)-nipecotic acid salt, are then converted to (S)-nipecotic acid,
Obtain final product.
2. preparation method as claimed in claim 1, it is characterized in that：The 3- piperidine formyls amine salt is the salt of 3- piperidine formamides
Hydrochlorate.
3. preparation method as claimed in claim 1, it is characterized in that：Described acid is organic acid or inorganic acid；Preferably, it is described
Acid be sulfuric acid or hydrochloric acid.
4. preparation method as claimed in claim 3, it is characterized in that：The hydrochloric acid is hydrochloric acid water that concentration is 0.5~35%w/w
Solution；Preferably, the concentration of the hydrochloric acid is 28~35%w/w.
5. preparation method as claimed in claim 1, it is characterized in that：The reaction temperature of the 3- piperidine formamides or its salt in acid
Spend is 60~65 DEG C.
6. preparation method as claimed in claim 1, it is characterized in that：The 3- piperidine formamides or its salt and sour quality volume
Than being 1：(1~10)；Preferably, the 3- piperidine formamides or its salt and the mass volume ratio of acid are 1：4.
7. preparation method as claimed in claim 1, it is characterized in that：S configurations account for 60- in the 3- piperidine formamides or its salt
95%；Preferably, S configurations account for 73-77%.
8. preparation method as claimed in claim 1, it is characterized in that：(S)-nipecotic acid salt is converted into (S) -3- piperidines first
Acid method be：Add alkali lye regulation pH to 6.5~7.5.
9. preparation method as claimed in claim 8, it is characterized in that：The alkali lye is that mass ratio is 1：The hydroxide of (3~8)
The mixed solution of potassium/sodium and methyl alcohol；Preferably, potassium hydroxide/sodium：Methanol quality ratio is 1：4.
10. preparation method as claimed in claim 8, it is characterized in that：Alkali lye is added in less than 10 DEG C.
11. preparation methods as claimed in claim 1, it is characterized in that：Also include following purification step：(S)-nipecotic acid salt
Concentration of reaction solution after (S)-nipecotic acid is converted into, adds methyl alcohol stirring, filtering to concentrate filtrate, add precipitating reagent stirring,
Filtering, collects filter cake, obtains final product refined (S)-nipecotic acid.
12. preparation methods as claimed in claim 11, it is characterized in that：(S)-nipecotic acid salt is converted into (S) -3- piperidines first
Acid is after less than 30 DEG C concentration of reaction solution.
13. preparation methods as claimed in claim 11, it is characterized in that：The precipitating reagent is ethanol or ethanol/petroleum ether mixing
Solvent；Preferably, the precipitating reagent is ethanol/petroleum ether volume ratio 1：1 mixed solvent.
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Cited By (1)
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| TWI760542B (en) * | 2017-08-11 | 2022-04-11 | 太景生物科技股份有限公司 | Trans-isomeric heterocyclic compounds and preparation thereof |
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