CN108409639A - (S) preparation of -3-Boc- aminomethylpiperidines and structural confirmation new method - Google Patents
(S) preparation of -3-Boc- aminomethylpiperidines and structural confirmation new method Download PDFInfo
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- CN108409639A CN108409639A CN201810368264.0A CN201810368264A CN108409639A CN 108409639 A CN108409639 A CN 108409639A CN 201810368264 A CN201810368264 A CN 201810368264A CN 108409639 A CN108409639 A CN 108409639A
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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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses the preparation of (S) 3 Boc aminomethylpiperidines and structural confirmations, and by the way that compound 1 is Benzylation, reducing carbonyl, the method for protecting amino, catalytic hydrogenation obtain compound 5；Then derived compound 5 to obtain crystal, compound 5, which is (S) 3 Boc aminomethylpiperidines, to be shown to the test of crystal progress diffraction, analysis, optical activity 8.98, the method for further demonstrating prepare compound 5 is feasible.This preparation method uses cheap and easily-available chiral raw material compound 1, without using resolving agent, has advantage on yield and cost；Product is tested by derivative, diffraction mode, determines that correct configuration, this preparation and confirmation method form a system, favorably use industrial production, have broad application prospects.
Description
Technical field
The invention belongs to chemical fields, and in particular to the preparation of (S) -3-Boc- aminomethylpiperidines and structural confirmation are newly square
Method.
Background technology
(S) -3-Boc- aminomethylpiperidines, for white or off-white color crystalline powder, this compound is used for angiocardiopathy
Aspect effect is very good, belongs to one of such drug segment, and structural formula is as follows：
Currently, in prior art, (S) -3-Boc- aminomethylpiperidines are to split to be made by 3-Boc- aminomethylpiperidines
, it is that (- two pairs of toluyl tartaric acid of L- (-), yield is 33% hereinafter, yield by L-DTTA to prepare used resolving agent
It is relatively low, and the Material Cost for synthesizing 3-Boc- aminomethylpiperidines is higher, production process has three waste discharge.Preparation route is as follows：
Invention content
It is an object of the invention to：In view of the above problems, one kind (S) -3-Boc- aminomethylpiperidines are provided
Preparation and structural confirmation new method.By using cheap and easily-available chiral raw material, resolving agent, direct anamorphic zone hand need not be used
Property product, and on yield and cost have certain advantage；By cultivating crystal after derivative, it is true to carry out single crystal diffraction test
Fixed output quota product are S configurations, further prove the feasibility of preparation method.
The technical solution adopted by the present invention is as follows：(S) novel preparation method of -3-Boc- aminomethylpiperidines, synthetic route is such as
Under：
Wherein, the benzylic halides include benzyl bromide, one kind in benzyl chloride and benzyl iodide；The reducing agent includes hydrogen
Change one kind in aluminium lithium, diborane, sodium borohydride, aluminum hydride, amino lithium borohydride and sodium borohydride-titanium chloride；The weak base
Including one kind in triethylamine and potassium carbonate；The catalyst includes one kind in palladium/carbon, platinum/carbon, rhodium/carbon and ruthenium/carbon.
The specific preparation process of the compound 2 is：At room temperature, compound 1 is dissolved in n,N-Dimethylformamide, point
It criticizes and potassium carbonate is added, be cooled to 8-12 DEG C, benzylic halides are added dropwise, for temperature control at 10-20 DEG C, system reacts 18-22h；It will reaction
Liquid pours into ice water, stirs, centrifuges to obtain crude product；By crude product extraction, concentration, purification, drying compound 2.
Further, compound 1 described in 2 specific preparation process of the compound and the molar ratio of benzylic halides are 1：
1.0ˉ1：1.1；The compound 1 and the molar ratio of potassium carbonate are 1：2.5ˉ1：3.0；The compound 1 and N, N- dimethyl methyls
The mass ratio of amide is 1：10.6ˉ1：10.8.
3 specific preparation process of the compound is：At room temperature, reducing agent is added in tetrahydrofuran in batches, has been fed
System is warming up to 40 DEG C after finishing；Reaction is added in the compound 2 for being dissolved in tetrahydrofuran that mass percent is 50% -55%
In system, reacted at 40-55 DEG C of temperature control；After reaction, the tetrahydrofuran aqueous solution for being 500% -520% by mass percent
Reaction system is added, pad diatomite is filtered, washed, concentrates, drying to get yellow oily compound 3.
Further, compound 2 described in 3 specific preparation process of the compound and the molar ratio of reducing agent are 1：1.4ˉ
1：1.6；The mass ratio of the tetrahydrofuran and reducing agent is 20：1ˉ21：1.
4 specific preparation process of the compound is：At room temperature, potassium carbonate is added to the water in batches, additionization after dissolving
Object 3 is closed, is cooled to 15 DEG C；The Boc for being 62% -67% by mass percent2O- ethanol solutions are slowly dropped into, 10-20 DEG C of temperature control
Reaction；Reaction terminates, and filters, purifies up to compound 4.
Further, weak acid, compound 3, Boc described in 4 specific preparation process of the compound2The molar ratio of O is
1.30ˉ1.35：1.01ˉ1.06：1.00ˉ1.05；The mass ratio of the water and weak acid is 11：1ˉ13：1.
5 specific preparation process of the compound is：By compound 4,5%-8% catalyst is dissolved in methanol, at 20-25 DEG C
React 3-5h, the filtering of pad diatomite, concentration, purification, drying compound 5；The methanol, compound 4, the quality of catalyst
Than being 65-68：9.60ˉ10.00：1.00ˉ1.05.
Further, it is dichloromethane, methyl tertiary butyl ether(MTBE) that extractant used is extracted described in the specific preparation process
With one kind in ethyl tert-butyl ether (ETBE), preferably dichloromethane；The purification solvent for use is in petroleum ether, normal heptane and ether
One kind, preferably petroleum ether；The drier be anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and at least
One kind, preferably anhydrous sodium sulfate.
Specifically, (S) -3-Boc- aminomethylpiperidines are prepared by the above process, without using resolving agent, preparation method letter
Single, reaction condition is mild.
(S) the structural confirmation new method of -3-Boc- aminomethylpiperidines, specific derivatization reaction formula are：
Reacting concrete operation method is：By N- carbobenzyloxy-L-prolines, N-methylmorpholine is dissolved in tetrahydrofuran, ice
Salt is cooled to-5-0 DEG C, and ethyl chloroformate is added dropwise, is added dropwise, is stirred to react；After reaction, compound 5 is added dropwise, drips
Finish, rise again 12-15h of reaction naturally；Reaction is quenched with ice water, extraction, dry, filtering, concentration, crosses silicagel column at washing, obtains class
White solid is compound 5.
Further, the N- carbobenzyloxy-L-prolines, N-methylmorpholine, ethyl chloroformate mass ratio be 2.2-
2.5：1.3ˉ1.5：0.8ˉ1.0；The mass ratio of the compound 5 and N- carbobenzyloxy-L-prolines is 1：1.15ˉ1：1.18；
Extractant used in the extraction is at least one of ethyl acetate, butyl acetate and butanone, ethyl acetate；The drying
Agent be anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and at least one of, preferred anhydrous sodium sulfate.
Specifically, by will compound 5 derive after cultivate crystal, the correspondence configuration of crystal is measured with single crystal diffraction method,
The configuration for deducing compound 5 further demonstrates the feasibility of the new method of preparation (S) -3-Boc- aminomethylpiperidines.
In conclusion by adopting the above-described technical solution, the beneficial effects of the invention are as follows：Using the present invention (S) -3-
The preparation of Boc- aminomethylpiperidines and structural confirmation new method, with cheap and easily-available chiral raw material, direct anamorphic zone chirality
Product does not use resolving agent, all has advantage on yield and cost；Obtained product cultivates crystal, single crystal diffraction through derivative
Test mode, confirm the product produced using this synthetic method is configured as (S) -3-Boc- aminomethylpiperidines, optical purity>
99%, optical value is -8.98, further proves that this synthetic method is feasible；This synthetic method and confirmation means are formed
One production, detection architecture, are suitable for industrialized production, have broad application prospects.
Description of the drawings
Fig. 1 is the synthetic route of compound 5；
Fig. 2 is the derivatization reaction route of compound 5；
Fig. 3 is the structural formula of compound 5；
Fig. 4 is the single crystal diffraction figure of compound 6.
Specific implementation mode
Embodiment 1
It is prepared by compound 2
At room temperature, it is passed through nitrogen into 50L double-layer glass reaction kettles, n,N-Dimethylformamide (32.0kg) is added and changes
Object 1 (3.0kg, 18.22mol) is closed, after the dissolving of compound 1, potassium carbonate (6.23kg, 45.08mol) is added portionwise；By system
After being cooled to 10 DEG C, start that benzyl bromide (3.12kg, 18.24mol) is added dropwise, after completion of dropwise addition, temperature control is anti-at 10-20 DEG C
Answer 18h.
Reaction solution is poured into ice water (75.0kg), stirs 1h, the crude product of white solid is obtained by filtration in centrifuge；Crude product is with two
Chloromethanes (12.0kg) is extracted, and organic phase dries 1h with anhydrous sodium sulfate (2.0kg)；Precipitation is depressurized, until solvent-free distillation
Out, concentrate is poured slowly into petroleum ether (5.0kg) and stirs 1h；Filtering, obtains white solid wet product, subtracts for 50 DEG C in baking oven
Pressure drying, obtains off-white powder compound 2, yield 53.2%, HPLC=96.5%.
It is prepared by compound 3
It is passed through nitrogen into 50L double-layer glass reaction kettles, after tetrahydrofuran (10.7kg) is added, lithium aluminium hydride reduction is added portionwise
(0.52kg, 13.6mol) is warming up to 40 DEG C after charging；To be dissolved in tetrahydrofuran (3.6kg) compound 2 (2.0kg,
It 9.16mol) is slowly dropped into reaction system, control temperature is at 40-55 DEG C.Control raw material ＜ 0.2% in HPLC detections, reaction knot
Beam；Tetrahydrofuran (2.7kg) is added in water (0.52kg) and is slowly dropped into reaction kettle, pad diatomite filtering is washed with tetrahydrofuran
It washs twice, filtrate is concentrated under reduced pressure, and yellow oily compounds 3, yield 80%, HPLC=94.3% are obtained.
The preparation of compound 4
At room temperature, to 50L double-layer glass reaction kettles injection water (15.0kg), be added portionwise potassium carbonate (1.31kg,
9.48mol), compound 3 (1.5kg, 7.34mol) is cooled to 15 DEG C, and two carbonic acid of di-t-butyl (1.59kg, 7.28mol) is molten
It is slowly dropped into reaction kettle in ethyl alcohol (2.5kg), control temperature at 10-20 DEG C, react by system.Control raw material ＜ in HPLC detections
0.2%；After reaction, wet product is directly obtained by filtration in reaction solution, is purified with petroleum ether (7.0kg), obtains white solid
4 yield of compound is 86%, HPLC=99.1%.
The preparation of compound 5
It is passed through nitrogen into 20L autoclaves, methanol (13.0kg), raw material (1.92kg), 5% palladium/carbon (0.2kg) is added,
Close kettle cover.4-6h are reacted at 20-25 DEG C, under 0.5Mpa until middle control raw material disappears.Pad diatomite filtering, filtrate concentration；It is dense
Contracting liquid is poured slowly into petroleum ether (1.4kg), the crystallization at 10 DEG C, obtains white solid wet product, drying white solid
Close object 5, yield 74%, GC=97.9%, ee%=99.9%.
Embodiment 2
It is prepared by compound 2
At room temperature, it is passed through nitrogen into 50L double-layer glass reaction kettles, n,N-Dimethylformamide (32.0kg) is added and changes
Object 1 (3.0kg, 18.22mol) is closed, after the dissolving of compound 1, potassium carbonate (6.23kg, 45.08mol) is added portionwise；By system
After being cooled to 10 DEG C, start that benzyl chloride (2.31kg, 18.24mol) is added dropwise, after completion of dropwise addition, temperature control is anti-at 10-20 DEG C
Answer 18h.
Reaction solution is poured into ice water (75.0kg), stirs 1h, the crude product of white solid is obtained by filtration in centrifuge；Crude product is with two
Chloromethanes (12.0kg) is extracted, and organic phase dries 1h with anhydrous sodium sulfate (2.0kg)；Precipitation is depressurized, until solvent-free distillation
Out, concentrate is poured slowly into petroleum ether (5.0kg) and stirs 1h；Filtering, obtains white solid wet product, subtracts for 50 DEG C in baking oven
Pressure drying, obtains off-white powder compound 2, yield 51.0%, HPLC=95.5%.
It is prepared by compound 3
It is passed through nitrogen into 50L double-layer glass reaction kettles, after tetrahydrofuran (10.7kg) is added, sodium borohydride is added portionwise
(0.51kg, 13.6mol) is warming up to 40 DEG C after charging；To be dissolved in tetrahydrofuran (3.6kg) compound 2 (2.0kg,
It 9.16mol) is slowly dropped into reaction system, control temperature is at 40-55 DEG C.Control raw material ＜ 0.2% in HPLC detections, reaction knot
Beam；Tetrahydrofuran (2.7kg) is added in water (0.52kg) and is slowly dropped into reaction kettle, pad diatomite filtering is washed with tetrahydrofuran
It washs twice, filtrate is concentrated under reduced pressure, and yellow oily compounds 3, yield 70%, HPLC=93.3% are obtained.
The preparation of compound 4
At room temperature, to 50L double-layer glass reaction kettles injection water (15.0kg), be added portionwise triethylamine (0.959,
9.48mol), compound 3 (1.5kg, 7.34mol) is cooled to 15 DEG C, and two carbonic acid of di-t-butyl (1.59kg, 7.28mol) is molten
It is slowly dropped into reaction kettle in ethyl alcohol (2.5kg), control temperature at 10-20 DEG C, react by system.Control raw material ＜ in HPLC detections
0.2%；After reaction, wet product is directly obtained by filtration in reaction solution, is purified with petroleum ether (7.0kg), obtains white solid
4 yield of compound is 60%, HPLC=90.2%.
The preparation of compound 5
It is passed through nitrogen into 20L autoclaves, methanol (13.0kg), raw material (1.92kg), 5% palladium/carbon (0.2kg) is added,
Close kettle cover.4-6h are reacted at 20-25 DEG C, under 0.5Mpa until middle control raw material disappears.Pad diatomite filtering, filtrate concentration；It is dense
Contracting liquid is poured slowly into petroleum ether (1.4kg), the crystallization at 10 DEG C, obtains white solid wet product, drying white solid
Close object 5, yield 73%, GC=96%, ee%=99.4%.
Embodiment 3
It is prepared by compound 2
At room temperature, it is passed through nitrogen into 50L double-layer glass reaction kettles, n,N-Dimethylformamide (32.0kg) is added and changes
Object 1 (3.0kg, 18.22mol) is closed, after the dissolving of compound 1, potassium carbonate (6.23kg, 45.08mol) is added portionwise；By system
After being cooled to 10 DEG C, start that benzyl bromide (3.12kg, 18.24mol) is added dropwise, after completion of dropwise addition, temperature control is anti-at 10-20 DEG C
Answer 18h.
Reaction solution is poured into ice water (75.0kg), stirs 1h, the crude product of white solid is obtained by filtration in centrifuge；Crude product first
Base tertbutyl ether (12.0kg) is extracted, and organic phase dries 1h with anhydrous sodium sulfate (2.0kg)；Precipitation is depressurized, until solvent-free
It distills, concentrate is poured slowly into petroleum ether (5.0kg) and stirs 1h；Filtering, obtains white solid wet product, in baking oven 50
DEG C decompression drying, obtains off-white powder compound 2, yield 50.2%, HPLC=95.5%.
It is prepared by compound 3
It is passed through nitrogen into 50L double-layer glass reaction kettles, after tetrahydrofuran (11.398kg) is added, aluminum hydride is added portionwise
Lithium (0.556kg, 14.656mol), is warming up to 40 DEG C after charging；The compound 2 of tetrahydrofuran (3.6kg) will be dissolved in
(2.0kg, 9.16mol) is slowly dropped into reaction system, and control temperature is at 40-55 DEG C.Control raw material ＜ 0.2% in HPLC detections,
Reaction terminates；Tetrahydrofuran (2.7kg) is added in water (0.52kg) and is slowly dropped into reaction kettle, tetrahydrochysene is used in pad diatomite filtering
Furans washes twice, and filtrate is concentrated under reduced pressure, and obtains yellow oily compounds 3, yield 83%, HPLC=95.3%.
The preparation of compound 4
At room temperature, to 50L double-layer glass reaction kettles injection water (16.4kg), be added portionwise potassium carbonate (1.369kg,
9.909mol), compound 3 (1.575kg, 7.707mol) is cooled to 15 DEG C, by two carbonic acid of di-t-butyl (1.683kg,
It 7.707mol) is dissolved in ethyl alcohol (2.5kg) and being slowly dropped into reaction kettle, control temperature at 10-20 DEG C, react by system.HPLC is examined
Raw material ＜ 0.2% is controlled in survey；After reaction, wet product is directly obtained by filtration in reaction solution, is purified with petroleum ether (7.0kg),
It is 85%, HPLC=99.0% to obtain 4 yield of compound as white solid.
The preparation of compound 5
It is passed through nitrogen into 20L autoclaves, methanol (13.0kg), raw material (1.92kg), 5% platinum/carbon (0.2kg) is added,
Close kettle cover.4-6h are reacted at 20-25 DEG C, under 0.5Mpa until middle control raw material disappears.Pad diatomite filtering, filtrate concentration；It is dense
Contracting liquid is poured slowly into petroleum ether (1.4kg), the crystallization at 10 DEG C, obtains white solid wet product, drying white solid
Close object 5, yield 71%, GC=95%, ee%=99.0%.
Embodiment 4
It is prepared by compound 2
At room temperature, it is passed through nitrogen into 50L double-layer glass reaction kettles, n,N-Dimethylformamide (31.2kg) is added and changes
Object 1 (3.0kg, 18.22mol) is closed, after the dissolving of compound 1, potassium carbonate (7.55kg, 54.66mol) is added portionwise；By system
After being cooled to 10 DEG C, start that benzyl bromide (3.428kg, 20.042mol) is added dropwise, after completion of dropwise addition, temperature controls at 10-20 DEG C
React 18h.
Reaction solution is poured into ice water (75.0kg), stirs 1h, the crude product of white solid is obtained by filtration in centrifuge；Crude product is with two
Chloromethanes (12.0kg) is extracted, and organic phase dries 1h with anhydrous sodium sulfate (2.0kg)；Precipitation is depressurized, until solvent-free distillation
Out, concentrate is poured slowly into petroleum ether (5.0kg) and stirs 1h；Filtering, obtains white solid wet product, subtracts for 50 DEG C in baking oven
Pressure drying, obtains off-white powder compound 2, yield 54.2%, HPLC=96.2%.
It is prepared by compound 3
It is passed through nitrogen into 50L double-layer glass reaction kettles, after tetrahydrofuran (10.7kg) is added, lithium aluminium hydride reduction is added portionwise
(0.52kg, 13.6mol) is warming up to 40 DEG C after charging；To be dissolved in tetrahydrofuran (3.6kg) compound 2 (2.0kg,
It 9.16mol) is slowly dropped into reaction system, control temperature is at 40-55 DEG C.Control raw material ＜ 0.2% in HPLC detections, reaction knot
Beam；Tetrahydrofuran (2.7kg) is added in water (0.52kg) and is slowly dropped into reaction kettle, pad diatomite filtering is washed with tetrahydrofuran
It washs twice, filtrate is concentrated under reduced pressure, and yellow oily compounds 3, yield 80%, HPLC=94.0% are obtained.
The preparation of compound 4
At room temperature, to 50L double-layer glass reaction kettles injection water (15.0kg), be added portionwise potassium carbonate (1.31kg,
9.48mol), compound 3 (1.5kg, 7.34mol) is cooled to 15 DEG C, and two carbonic acid of di-t-butyl (1.59kg, 7.28mol) is molten
It is slowly dropped into reaction kettle in ethyl alcohol (2.5kg), control temperature at 10-20 DEG C, react by system.Control raw material ＜ in HPLC detections
0.2%；After reaction, wet product is directly obtained by filtration in reaction solution, is purified with petroleum ether (7.0kg), obtains white solid
4 yield of compound is 86%, HPLC=98.9%.
The preparation of compound 5
It is passed through nitrogen into 20L autoclaves, methanol (13.6kg), raw material (1.96kg), 5% palladium/carbon (0.2kg) is added,
Close kettle cover.4-6h are reacted at 20-25 DEG C, under 0.5Mpa until middle control raw material disappears.Pad diatomite filtering, filtrate concentration；It is dense
Contracting liquid is poured slowly into petroleum ether (1.4kg), the crystallization at 10 DEG C, obtains white solid wet product, drying white solid
Close object 5, yield 73%, GC=96.1%, ee%=98.9%.
Embodiment 5
The preparation of compound 6
At room temperature, it is passed through nitrogen into 100mL there-necked flasks, tetrahydrofuran (30mL), N- carbobenzyloxy-L-prolines is added
(3.5g), N-methylmorpholine (2.1g), 0 DEG C is cooled to cryosel, is started that ethyl chloroformate (1.6g) is added dropwise, is added dropwise, stirs
30min is mixed, control is to the reaction was complete in TLC；Then start that compound 5 (3g) is added dropwise, be added dropwise, rise again reaction 12h naturally,
Reaction solution is added into 50mL ice water and is quenched, be extracted twice with ethyl acetate (50ml) to the reaction was complete by control in TLC, is saturated
Brine It is primary, and anhydrous sodium sulfate drying is filtered, and concentration crosses silicagel column, obtains off-white powder, yield 85%,
Ee%=99.6%, HPLC=99.4%.
Compound 6 is occurred prepared by derivatization reaction using compound 5 and N- carbobenzyloxy-L-prolines as raw material, right
Compound 6 does single crystal diffraction test, as a result shows as follows：
By structural confirmation to N- carbobenzyloxy-L-prolines and the single crystal diffraction collection of illustrative plates of compound 6 is analyzed,
Obtain compound 5 is configured as (S) -3-Boc- aminomethylpiperidines, and the new method for further demonstrating synthesis compound 5 is feasible
's.
Configuration concentration be 1g/100mL methanol solution, measure its optical value, know its optical value 589nm at for-
8.98。
The invention is not limited in specific implementation modes 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 (11)
- The novel preparation method of (1. S) -3-Boc- aminomethylpiperidines, which is characterized in that synthetic route is as follows：Wherein, the benzylic halides include benzyl bromide, one kind in benzyl chloride and benzyl iodide；The reducing agent includes aluminum hydride One kind in lithium, diborane, sodium borohydride, aluminum hydride, amino lithium borohydride and sodium borohydride-titanium chloride；The weak base includes One kind in triethylamine and potassium carbonate；The catalyst includes one kind in palladium/carbon, platinum/carbon, rhodium/carbon and ruthenium/carbon.
- 2. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as described in claim 1, which is characterized in that the compound 2 specific preparation process is：At room temperature, compound 1 is dissolved in n,N-Dimethylformamide, potassium carbonate is added portionwise, cooled down To 8-12 DEG C, benzylic halides are added dropwise, for temperature control at 10-20 DEG C, system reacts 18-22h；Reaction solution is poured into ice water, stirring, from Gains in depth of comprehension crude product；By crude product extraction, concentration, purification, drying compound 2.
- 3. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as claimed in claim 2, which is characterized in that the compound Compound 1 described in 2 specific preparation processes and the molar ratio of benzylic halides are 1：1.0-1：1.1；The compound 1 and carbonic acid The molar ratio of potassium is 1：2.5ˉ1：3.0；The mass ratio of the compound 1 and N,N-dimethylformamide is 1：10.6-1：10.8.
- 4. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as described in claim 1, which is characterized in that the compound 3 specific preparation processes are：At room temperature, reducing agent is added in tetrahydrofuran in batches, system is warming up to 40 after charging ℃；The compound 2 for being dissolved in tetrahydrofuran that mass percent is 50%-55% is added in reaction system, 40-55 DEG C of temperature control Lower reaction；After reaction, reaction system is added in the tetrahydrofuran aqueous solution that mass percent is 500%-520%, pads silicon Diatomaceous earth is filtered, washed, concentrates, drying to get yellow oily compound 3.
- 5. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as claimed in claim 4, which is characterized in that the compound Compound 2 described in 3 specific preparation processes and the molar ratio of reducing agent are 1：1.4ˉ1：1.6；The tetrahydrofuran and reducing agent Mass ratio be 20：1-21：1.
- 6. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as described in claim 1, which is characterized in that the compound 4 specific preparation processes are：At room temperature, weak base is added to the water in batches, compound 3 is added after dissolving, is cooled to 15 DEG C；By matter Measure the Boc that percentage is 62%-67%2O- ethanol solutions are slowly dropped into, 10-20 DEG C of reaction of temperature control；Reaction terminates, and filters, carries Pure compound 4 to obtain the final product.
- 7. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as claimed in claim 6, which is characterized in that the compound Weak acid, compound 3, Boc described in 4 specific preparation processes2The molar ratio of O is 1.30-1.35：1.01-1.06：1.00-1.05； The mass ratio of the water and weak acid is 11：1-13：1.
- 8. the novel preparation method of (S) -3-Boc- aminomethylpiperidines as described in claim 1, which is characterized in that the compound 5 specific preparation processes are：By compound 4,5%-8% catalyst is dissolved in methanol, and 3-5h is reacted at 20-25 DEG C, pads diatomite Filtering, concentration, purification, drying compound 5；The methanol, compound 4, catalyst mass ratio be 65-68：9.60- 10.00：1.00ˉ1.05.
- 9. the novel preparation method of (S)-3-Boc- aminomethylpiperidines as described in any one of claim 1-8, feature exist In it is dichloromethane, methyl tertiary butyl ether(MTBE) and ethyl tert-butyl ether (ETBE) to extract extractant used described in the specific preparation process In one kind, preferred dichloromethane；The purification solvent for use is one kind in petroleum ether, normal heptane and ether, preferably oil Ether；The drier be anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and at least one of, it is preferably anhydrous Sodium sulphate.
- The structural confirmation new method of (10. S) -3-Boc- aminomethylpiperidines, which is characterized in that specifically derivatization reaction formula is：Reacting concrete operation method is：By N- carbobenzyloxy-L-prolines, N-methylmorpholine is dissolved in tetrahydrofuran, cryosel drop Temperature is added dropwise ethyl chloroformate, is added dropwise, is stirred to react to-5-0 DEG C；After reaction, compound 5 is added dropwise, is added dropwise, Naturally rise again 12-15h of reaction；Reaction is quenched with ice water, extraction, dry, filtering, concentration, crosses silicagel column at washing, and it is white to obtain class Color solid is compound 5.
- 11. the structural confirmation new method of (S) -3-Boc- aminomethylpiperidines as claimed in claim 10, which is characterized in that described N- carbobenzyloxy-L-prolines, N-methylmorpholine, ethyl chloroformate mass ratio be 2.2-2.5：1.3ˉ1.5：0.8ˉ1.0；Institute The mass ratio for stating compound 5 and N- carbobenzyloxy-L-prolines is 1：1.15ˉ1：1.18；Extractant used in the extraction is second At least one of acetoacetic ester, butyl acetate and butanone, ethyl acetate；The drier is anhydrous sodium sulfate, anhydrous sulphur Sour magnesium, activated carbon, anhydrous calcium chloride and at least one of, preferred anhydrous sodium sulfate.
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| WO2012104866A1 (en) * | 2011-01-31 | 2012-08-09 | Council Of Scientific & Industrial Research | Chiral 1-(4-methylphenylmethyl)-5-oxo-{n-[(3-t-butoxycarbonyl- aminomethyl)]-piperidin-1-yl}-pyrrolidine-2-carboxamides as inhibitors of collagen induced platelet activation and adhesion |
| CN103435538A (en) * | 2013-08-08 | 2013-12-11 | 爱斯特（成都）医药技术有限公司 | (R)-3-amino piperidine hydrochloride preparation method |
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| WO2012104866A1 (en) * | 2011-01-31 | 2012-08-09 | Council Of Scientific & Industrial Research | Chiral 1-(4-methylphenylmethyl)-5-oxo-{n-[(3-t-butoxycarbonyl- aminomethyl)]-piperidin-1-yl}-pyrrolidine-2-carboxamides as inhibitors of collagen induced platelet activation and adhesion |
| CN103435538A (en) * | 2013-08-08 | 2013-12-11 | 爱斯特（成都）医药技术有限公司 | (R)-3-amino piperidine hydrochloride preparation method |
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| Title |
|---|
| URBAN KOSAK，等: "N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer’s agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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