CN104710347B - (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 - Google Patents
(R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 Download PDFInfo
- Publication number
- CN104710347B CN104710347B CN201510019575.2A CN201510019575A CN104710347B CN 104710347 B CN104710347 B CN 104710347B CN 201510019575 A CN201510019575 A CN 201510019575A CN 104710347 B CN104710347 B CN 104710347B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- benzyl
- methyl isophthalic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention proposes a kind of synthetic method of the tetrahydrochysene piperidines of 3 methyl of (R) 1 benzyl 1,2,3,6, comprises the following steps：(a) material shown in formula (I) reacts the compound of production (II) expression with phosphate through Horner Wadsworth Emmons；(b) compound that formula (II) obtained by step (a) represents reduces to obtain alcohol through diisobutyl aluminium hydride, then obtains the compound of formula (III) expression through concentrated hydrochloric acid ethanol deprotection reaction；(c) compound that formula (III) obtained by step (b) represents reacts to obtain sulphonic acid ester or p-methyl benzenesulfonic acid ester through mesyl chloride or paratoluensulfonyl chloride, then obtains the compound shown in formula (IV) through benzylamine ring-closure reaction in alcohol.The preparation method of the present invention is different from initiation material, process route, last handling process, and raw material of the invention is simple and easy to get, and cost is cheap, simple to operate.
Description
Technical field
The present invention relates to organic synthesis technical field, one kind (R) -1- benzyl -3- methyl isophthalic acids are particularly related to, 2,3,6- tetra-
The synthetic method of hydrogen piperidines.
Background technology
(R) -1- benzyls -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines can be as the intermediates or work of synthesis kinase inhibitor
For chiral source be used for organic compound or medicine synthesis (WO2005077932A, US2010056576A1,
US2012225062A1 etc.).For (R) -1- benzyl -3- methyl isophthalic acids, the preparation of 2,3,6- tetrahydrochysene piperidines, data at home and abroad is had no
Report.
In view of this, one kind (R) -1- benzyl -3- methyl isophthalic acids, the appearance of the synthetic method of 2,3,6- tetrahydrochysene piperidines just have very much
It is necessary.
The content of the invention
The invention provides one kind (R) -1- benzyl -3- methyl isophthalic acids, the synthetic method of 2,3,6- tetrahydrochysene piperidines, this method from
Initiation material, process route, last handling process are different, and its raw material is simple and easy to get, and cost is cheap, simple to operate.
The technical proposal of the invention is realized in this way：
One kind (R) -1- benzyl -3- methyl isophthalic acids, the synthetic method of 2,3,6- tetrahydrochysene piperidines, comprise the following steps：
(a) material shown in formula (I) reacts production (II) through Horner-Wadsworth-Emmons with phosphate and represented
Compound；Wherein reaction temperature is -78 DEG C~0 DEG C；
(b) compound that formula (II) obtained by step (a) represents obtains alcohol through diisobutyl aluminium hydride (DIBAL-H) reduction,
Again the compound of formula (III) expression is obtained through concentrated hydrochloric acid-ethanol deprotection reaction；Wherein reaction temperature is -78 DEG C~0 DEG C；
(c) compound that formula (III) obtained by step (b) represents reacts to obtain sulfonic acid through mesyl chloride or paratoluensulfonyl chloride
Ester or p-methyl benzenesulfonic acid ester, then obtain the compound shown in formula (IV) through benzylamine ring-closure reaction in alcohol；Wherein reaction temperature for-
5 DEG C~0 DEG C.
It is described to comprise the following steps that as preferable technical scheme：
The phosphate is dissolved in tetrahydrofuran, potassium tert-butoxide is added when temperature is -78 DEG C~0 DEG C, after reaction,
The tetrahydrofuran solution of the material shown in formula (I) is added, reacts the compound of the formula of producing (II) expression；
The compound that formula (II) represents is dissolved in dichloromethane, when temperature is -78 DEG C~0 DEG C, adds diisobutyl
Aluminum hydride, then obtain the compound of formula (III) expression through concentrated hydrochloric acid-ethanol deprotection reaction；
The compound that formula (III) represents is dissolved in dichloromethane, adds triethylamine, is added when temperature is -5 DEG C~0 DEG C
Mesyl chloride or paratoluensulfonyl chloride, insulation reaction, produce crude product；The crude product is dissolved in ethanol, benzylamine is added, is warming up to
Backflow, afterwards insulation reaction, reaction terminate to produce (R) -1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysene piperidines.
As preferable technical scheme, the aftertreatment technology of the step (c) is：Shown in the formula (IV) that reaction is obtained
Compound is through extracting, dry and filtering, is evaporated under reduced pressure and produces after precipitation.
As preferable technical scheme, phosphonate ester used is selected from the Horner-Wadsworth-Emmons reactions
Two oxy-o-cresyl phosphinylidyne ethyls, di-o-tolyl phosphinylidyne ethyl, two o-tert-butyl diphenylphosphoryl acetic acid second
One kind in ester, phosphonoacetate.
As preferable technical scheme, the mol ratio of material, phosphonate ester and potassium tert-butoxide shown in the formula (I) is 1：
1.2~1.4：1.2~1.4.
As preferable technical scheme, per in 100mL tetrahydrofurans, 10~20g phosphonate ester is added.
As preferable technical scheme, the mass percent concentration of the tetrahydrofuran solution of the material shown in formula (I) is
20%~50%.
The compound and the mol ratio of diisobutyl aluminium hydride represented as preferable technical scheme, formula (II) is 1：2.5
~3.0；Per in 100mL dichloromethane, the compound of 2~10g formulas (II) expression is added.
As preferable technical scheme, the equivalent concentration of the concentrated hydrochloric acid-ethanol is 1N, wherein concentrated hydrochloric acid-ethanol matter
Amount is than being 1：25~40.
The compound represented as preferable technical scheme, formula (III), mesyl chloride or paratoluensulfonyl chloride, triethylamine,
The mol ratio of benzylamine is 1：3.0~3.5：3.0~3.5：8.0~10.0, per in 100mL dichloromethane, add 2~10g formulas
(III) compound represented.
The compound and the mass ratio of ethanol represented as preferable technical scheme, formula (III) is 1：16~50.
Beneficial effect
(1) preparation method of the invention raw material different from initiation material, process route, last handling process, of the invention
Simple and easy to get, cost is cheap, simple to operate.
(2) post processing of the invention is without using column chromatography purification ＆ isolation product because the raw material of the present invention with
And the selection of process route make it that the comparision contents of the other materials in product are few, so post processing is simpler, has saved production
Cost, at the same the time greatly shorten, be suitable for industrial-scale production, be also applied for laboratory and prepare in a small amount.
Brief description of the drawings
, below will be to embodiment in order to illustrate more clearly of embodiment of the present invention or technical scheme of the prior art
Or the required accompanying drawing used is briefly described in description of the prior art, it should be apparent that, drawings in the following description are only
It is some embodiments of the present invention, for those of ordinary skill in the art, is not paying the premise of creative labor
Under, other accompanying drawings can also be obtained according to these accompanying drawings.
Fig. 1 is the synthesis route figure of the present invention；
(R) -1- benzyl -3- methyl isophthalic acids that Fig. 2 is prepared for the present invention according to the method for embodiment 1,2,3,6- tetrahydrochysene piperidines
's1HNMR collection of illustrative plates；
Fig. 3 is according to (R) -1- benzyl -3- methyl isophthalic acids of the method preparation of embodiment 1, the LCMS of 2,3,6- tetrahydrochysene piperidines
Collection of illustrative plates.
Embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example only part of the embodiment of the present invention, rather than whole embodiments.It is common based on the embodiment in the present invention, this area
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belong to the model that the present invention protects
Enclose.
Embodiment 1
Two oxy-o-cresyl phosphinylidyne ethyls (4.29g, 12.3mmol) are dissolved in 40mL THF, protected in nitrogen
Under be cooled to -10 DEG C of potassium tert-butoxide (1.52g, 13.5mmol) be added portionwise.After adding, insulation reaction 2 hours.By (2S)-
3- tertiary butyl dimethyl Sis base -2 methyl propanal (I) (2g, 9.9mmol) is configured to the THF that mass percent concentration is 50%
Solution, and be slowly dropped in reaction solution.After dripping off, insulation reaction 2 hours.GC is detected, and reaction terminates, and adds water saturation ammonium chloride
The aqueous solution is quenched.Organic phase is separated, sloughs solvent, adds petroleum ether and water, is extracted, layering.Aqueous phase petroleum ether extraction two
It is secondary, merge organic phase, washed with saturated brine, add anhydrous sodium sulfate drying.Silica gel on toward sand core funnel middle berth, will be dried
Solution is filtered, and filter cake is rinsed with petroleum ether, filtrate be concentrated to give 3g formulas (II) expression compound (it is Z that reaction, which obtains product,
Type, the wherein mixture of E types, Z：E relative scale is 87:13).
The compound (5.2g, 20mmol) that formula (II) represents is dissolved in 260mL dichloromethane, cooled down under nitrogen protection
To -78 DEG C.1M DIBAH hexane solution (60mL) is added dropwise.After dripping off, continue insulation reaction 1 hour.GC is detected, reaction
Terminate.14.5mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains slightly
Product.130g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add semi-saturation
Salt solution and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, with unsaturated carbonate hydrogen
Sodium water solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 2.1g formulas (III) expression.
The compound (1.4g, 12mmol) that formula (III) represents is dissolved in 70mL dichloromethane, under nitrogen protection, adds three
Ethamine (4.2g, 41.5mmol) is simultaneously cooled to -5 DEG C.Methylsufonyl chloride (4.14g, 36.1mmol) is added dropwise, drips off rear insulation reaction
1.5 hour.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, and aqueous phase is stripped with dichloromethane, closes
And organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.Crude product is dissolved in the anhydrous second of 35g
In alcohol, benzylamine (10.3g, 96mmol) is added, and reaction solution is to slowly warm up to flow back.After insulation reaction 3 hours, GC detections,
Reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Separate organic phase, aqueous phase EA
Back extraction, merge organic phase, after acid-alkali washing, add anhydrous sodium sulfate drying, filter, be evaporated under reduced pressure to after precipitation 1.8g (R)-
1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：7.28-7.39(m,
5H), 5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H), 3.09-3.12 (m,
1H), 2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H), 0.96 (d, J=
7.0Hz,1H).LCMS(ESI):188.1[M+H]+。
Embodiment 2
Two o-tert-butyl diphenylphosphoryl ethyls (23.3g, 53.9mmol) are dissolved in 117mL THF, in nitrogen
- 15 DEG C of are cooled under protection potassium tert-butoxide (6.05g, 53.9mmol) is added portionwise.After adding, insulation reaction 1 hour.Will
(2S) -3- tertiary butyl dimethyl Sis base -2 methyl propanal (I) (8.4g, 41.5mmol) is configured to mass percent concentration and is
20% THF solution, and be slowly dropped in reaction solution.After dripping off, insulation reaction 3 hours.GC is detected, and reaction terminates, and adds water
Saturated aqueous ammonium chloride is quenched.Organic phase is separated, sloughs solvent, adds and adds petroleum ether and water, is extracted, layering.Aqueous phase
With petroleum ether extraction twice, merge organic phase, washed with saturated brine, add anhydrous sodium sulfate drying.Toward on sand core funnel middle berth
Silica gel, dried solution is filtered, filter cake is rinsed with petroleum ether, and filtrate is concentrated to give the compound of 8.3g formulas (II) expression
(it is Z-type that reaction, which obtains product, the mixture of E types, wherein Z：E relative scale is 90:10).
The compound (8.2g, 30mmol) that formula (II) represents is dissolved in 310mL dichloromethane, cooled down under nitrogen protection
To -60 DEG C.1M DIBAH hexane solution (75mL) is added dropwise.After dripping off, continue insulation reaction 1 hour.GC is detected, reaction
Terminate.18mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains crude product.
205g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add semi-saturation salt
Water and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, use saturated sodium bicarbonate
The aqueous solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 3.2g formulas (III) expression.
The compound (3.2g, 27.5mmol) that formula (III) represents is dissolved in 80mL dichloromethane, under nitrogen protection, added
Triethylamine (9.75g, 96.3mmol) is simultaneously cooled to 0 DEG C.Paratoluensulfonyl chloride (16.8g, 88.1mmol) is added dropwise, is incubated after dripping off
Reaction 2 hours.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, and aqueous phase is stripped with dichloromethane,
Merge organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.It is anhydrous that crude product is dissolved in 160g
In ethanol, benzylamine (29.5g, 275mmol) is added, and reaction solution is to slowly warm up to flow back.After insulation reaction 3 hours, GC inspections
Survey, reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Organic phase is separated, aqueous phase is used
EA is stripped, and is merged organic phase, after acid-alkali washing, is added anhydrous sodium sulfate drying, is filtered, be evaporated under reduced pressure to after precipitation 4.3g (R)-
1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：7.28-7.39(m,
5H), 5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H), 3.09-3.12 (m,
1H), 2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H), 0.96 (d, J=
7.0Hz,1H).LCMS(ESI):188.1[M+H]+。
Embodiment 3
Phosphonoacetate (13.95g, 62.2mmol) is dissolved in 100mL THF, cooled under nitrogen protection
Potassium tert-butoxide (1.52g, 13.5mmol) is added portionwise to -5 DEG C of.After adding, insulation reaction 2 hours.By (2S) -3- tert-butyl groups
Dimethylsilyl bis -2 methyl propanal (I) (9g, 44.5mmol) is configured to the THF solution that mass percent concentration is 30%, and
It is slowly dropped in reaction solution.After dripping off, insulation reaction 2 hours.GC is detected, and reaction terminates, and adds water saturation aqueous ammonium chloride solution
It is quenched.Organic phase is separated, sloughs solvent, adds petroleum ether and water, is extracted, layering.Aqueous phase twice, is merged with petroleum ether extraction
Organic phase, washed with saturated brine, add anhydrous sodium sulfate drying.Silica gel on toward sand core funnel middle berth, dried solution is entered
Row is filtered, and filter cake is rinsed with petroleum ether, and filtrate is concentrated to give the compound of 9.6g formulas (II) expression, and (it is Z-type that reaction, which obtains product, E
The mixture of type, wherein Z：E relative scale is 14:86).
The compound (9.6g, 35.2mmol) that formula (II) represents is dissolved in 240mL dichloromethane, it is cold under nitrogen protection
But to -45 DEG C.1M DIBAH hexane solution (105mL) is added dropwise.After dripping off, continue insulation reaction 1 hour.GC is detected, instead
It should terminate.25.5mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains
Crude product.384g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add half-full
With salt solution and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, use unsaturated carbonate
Hydrogen sodium water solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 3.5g formulas (III) expression.
The compound (3.5g, 30.1mmol) that formula (III) represents is dissolved in 70mL dichloromethane, under nitrogen protection, added
Triethylamine (10.3g, 101.8mmol) is simultaneously cooled to -5 DEG C.Methylsufonyl chloride (11g, 96mmol) is added dropwise, drips off rear insulation reaction
1.5 hour.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, and aqueous phase is stripped with dichloromethane, closes
And organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.Crude product is dissolved in the anhydrous second of 70g
In alcohol, benzylamine (25.8g, 240mmol) is added, and reaction solution is to slowly warm up to flow back.After insulation reaction 3 hours, GC detections,
Reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Separate organic phase, aqueous phase EA
Back extraction, merge organic phase, after acid-alkali washing, add anhydrous sodium sulfate drying, filter, 4.5g (R) -1- is evaporated under reduced pressure to after precipitation
Benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：7.28-7.39(m,5H),
5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H), 3.09-3.12 (m, 1H),
2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H), 0.96 (d, J=7.0Hz,
1H).LCMS(ESI):188.1[M+H]+。
Embodiment 4
Two o-tert-butyl diphenylphosphoryl ethyls (47.5g, 110mmol) are dissolved in 238mL THF, protected in nitrogen
- 78 DEG C of are cooled under shield potassium tert-butoxide (12.8g, 114mmol) is added portionwise.After adding, insulation reaction 1 hour.By (2S)-
3- tertiary butyl dimethyl Sis base -2 methyl propanal (I) (17.1g, 84.5mmol) is configured to mass percent concentration as 20%
THF solution, and be slowly dropped in reaction solution.After dripping off, insulation reaction 2 hours.GC is detected, and reaction terminates, and adds water saturation
Aqueous ammonium chloride solution is quenched.Organic phase is separated, sloughs solvent, adds and adds petroleum ether and water, is extracted, layering.Aqueous phase stone
Oily ether is extracted twice, and is merged organic phase, is washed with saturated brine, add anhydrous sodium sulfate drying.Silica gel on toward sand core funnel middle berth,
Dried solution is filtered, filter cake is rinsed with petroleum ether, and the compound that filtrate is concentrated to give 17.7g formulas (II) expression is (anti-
It is Z-type that product, which should be obtained, the mixture of E types, wherein Z：E relative scale is 97:3).
The compound (17.7g, 65mmol) that formula (II) represents is dissolved in 530mL dichloromethane, it is cold under nitrogen protection
But to -20 DEG C.1M DIBAH hexane solution (192mL) is added dropwise.After dripping off, continue insulation reaction 1 hour.GC is detected, instead
It should terminate.46.6mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains
Crude product.530g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add half-full
With salt solution and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, use unsaturated carbonate
Hydrogen sodium water solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 7.1g formulas (III) expression.
The compound (7.1g, 61.1mmol) that formula (III) represents is dissolved in 110mL dichloromethane, under nitrogen protection, added
Enter triethylamine (21.6g, 213.4mmol) and be cooled to -5 DEG C.Methylsufonyl chloride (9.45g, 82.5mmol) is added dropwise, is protected after dripping off
Temperature reaction 1.5 hours.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, aqueous phase dichloromethane is anti-
Extraction, merge organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.Crude product is dissolved in 284g
In absolute ethyl alcohol, benzylamine (59g, 550.6mmol) is added, and reaction solution is to slowly warm up to flow back.After insulation reaction 3 hours,
GC is detected, and reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Separate organic phase, water
Mutually it is stripped with EA, merges organic phase, after acid-alkali washing, add anhydrous sodium sulfate drying, filtered, is evaporated under reduced pressure to after precipitation
10.1g (R) -1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：7.28-
7.39 (m, 5H), 5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H), 3.09-
3.12 (m, 1H), 2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H), 0.96 (d,
J=7.0Hz, 1H) .LCMS (ESI):188.1[M+H]+.
Embodiment 5
Phosphonoacetate (38.7g, 172.6mmol) is dissolved in 387mL THF, cooled under nitrogen protection
Potassium tert-butoxide (1.52g, 123.5mmol) is added portionwise to -5 DEG C of.After adding, insulation reaction 1 hour.By (2S) -3- tert-butyl groups
Dimethylsilyl bis -2 methyl propanal (I) (25g, 123.5mmol) is configured to the THF solution that mass percent concentration is 40%,
And it is slowly dropped in reaction solution.After dripping off, insulation reaction 2 hours.GC is detected, and reaction terminates, and adds water saturation ammonium chloride solution
Liquid is quenched.Organic phase is separated, sloughs solvent, adds petroleum ether and water, is extracted, layering.Aqueous phase twice, is closed with petroleum ether extraction
And organic phase, washed with saturated brine, add anhydrous sodium sulfate drying.Silica gel on toward sand core funnel middle berth, by dried solution
Filtered, filter cake is rinsed with petroleum ether, filtrate be concentrated to give 27.9g formulas (II) expression compound (it is Z that reaction, which obtains product,
Type, the wherein mixture of E types, Z：E relative scale is 11:89).
The compound (27g, 99mmol) that formula (II) represents is dissolved in 530mL dichloromethane, cooled down under nitrogen protection
To -10 DEG C.1M DIBAH hexane solution (278mL) is added dropwise.After dripping off, continue insulation reaction 2 hours.GC is detected, reaction
Terminate.68.5mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains slightly
Product.945 g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add half-full
With salt solution and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, use unsaturated carbonate
Hydrogen sodium water solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 9.8g formulas (III) expression.
The compound (9.8g, 84.4mmol) that formula (III) represents is dissolved in 300mL dichloromethane, under nitrogen protection, added
Enter triethylamine (28.2g, 278.7mmol) and be cooled to 0 DEG C.Paratoluensulfonyl chloride (49.8g, 261.2mmol) is added dropwise, after dripping off
Insulation reaction 2 hours.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, aqueous phase dichloromethane is anti-
Extraction, merge organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.Crude product is dissolved in 440g
In absolute ethyl alcohol, benzylamine (76.8g, 716.6mmol) is added, and reaction solution is to slowly warm up to flow back.Insulation reaction 3 hours
Afterwards, GC is detected, and reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Separate organic
Phase, aqueous phase are stripped with EA, are merged organic phase, after acid-alkali washing, are added anhydrous sodium sulfate drying, are filtered, and are evaporated under reduced pressure after precipitation
Obtain 13g (R) -1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：7.28-
7.39 (m, 5H), 5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H), 3.09-
3.12 (m, 1H), 2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H), 0.96 (d,
J=7.0Hz, 1H) .LCMS (ESI):188.1[M+H]+.
Embodiment 6
Phosphonoacetate (59.8g, 266.7mmol) is dissolved in 540mL THF, is cooled under nitrogen protection
Potassium tert-butoxide (30g, 267.3mmol) is added portionwise in 0 DEG C of.After adding, insulation reaction 1 hour.By (2S) -3- tert-butyl group diformazans
Base siloxy -2 methyl propanal (I) (45g, 222.3mmol) is configured to mass percent concentration and is 20% THF solution, and delays
Slowly it is added drop-wise in reaction solution.After dripping off, insulation reaction 2 hours.GC is detected, and reaction terminates, and adds water saturation aqueous ammonium chloride solution to quench
Go out.Organic phase is separated, sloughs solvent, adds petroleum ether and water, is extracted, layering.Aqueous phase twice, is merged with petroleum ether extraction
Organic phase, washed with saturated brine, add anhydrous sodium sulfate drying.Silica gel on toward sand core funnel middle berth, dried solution is entered
Row is filtered, and filter cake is rinsed with petroleum ether, and filtrate is concentrated to give the compound of 47.2g formulas (II) expression, and (it is Z-type that reaction, which obtains product, E
The mixture of type, wherein Z：E relative scale is 10:90).
The compound (47g, 172.5mmol) that formula (II) represents is dissolved in 1175mL dichloromethane, under nitrogen protection
It is cooled to 0 DEG C.1M DIBAH hexane solution (432mL) is added dropwise.After dripping off, continue insulation reaction 2 hours.GC is detected, instead
It should terminate.105mL methanol is slowly added dropwise to be quenched, is warmed to room temperature, continues stirring 1~2 hour.Reaction solution decompression precipitation obtains slightly
Product.1880g 1N concentrated hydrochloric acids-ethanol solution is added into crude product, is stirred overnight at room temperature.GC is detected, and reaction terminates.Add half-full
With salt solution and dichloromethane extracting and demixing.Organic phase is separated, aqueous phase is stripped with dichloromethane.Merge organic phase, use unsaturated carbonate
Hydrogen sodium water solution washs, and saturated brine washing, adds sodium sulphate to dry, filters, be concentrated to give the compound of 16.8g formulas (III) expression.
The compound (16.8g, 144.6mmol) that formula (III) represents is dissolved in 168mL dichloromethane, under nitrogen protection,
Add triethylamine (51.2g, 506mmol) and be cooled to -2 DEG C.Methylsufonyl chloride (57.9g, 505.4mmol) is added dropwise, after dripping off
Insulation reaction 1.5 hours.GC is detected, and reaction terminates.Reaction solution adds water quenching to go out, and layering, separates organic phase, aqueous phase dichloromethane
Back extraction, merge organic phase.Organic phase is washed with saturated brine, and sodium sulphate is dried, and filtering, is concentrated to give crude product.Crude product is dissolved in
In 270g absolute ethyl alcohols, benzylamine (124g, 1157mmol) is added, and reaction solution is to slowly warm up to flow back.Insulation reaction 3 hours
Afterwards, GC is detected, and reaction terminates.After reaction solution precipitation is removed into ethanol, ethyl acetate and water extracting and demixing are added.Separate organic
Phase, aqueous phase are stripped with EA, are merged organic phase, after acid-alkali washing, are added anhydrous sodium sulfate drying, are filtered, and are evaporated under reduced pressure after precipitation
Obtain 21.6g (R) -1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysenes piperidines (IV).1H-NMR (500MHz, CDCl3) δ (ppm)：
7.28-7.39 (m, 5H), 5.62-5.66 (m, 2H), 3.62 (d, J=13.0Hz, 1H), 3.58 (d, J=13.0Hz, 1H),
3.09-3.12 (m, 1H), 2.79-2.85 (m, 2H), 2.44-2.45 (m, 1H), 2.0 (dd, J=8.0Hz, 11.0Hz, 1H),
0.96 (d, J=7.0Hz, 1H) .LCMS (ESI):188.1[M+H]+.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.
Claims (9)
1. one kind (R) -1- benzyl -3- methyl isophthalic acids, the synthetic method of 2,3,6- tetrahydrochysene piperidines, it is characterised in that including following step
Suddenly：
(a) material shown in formula (I) reacts the change of production (II) expression with phosphate through Horner-Wadsworth-Emmons
Compound；Wherein reaction temperature is -78 DEG C~0 DEG C；
(b) compound that formula (II) obtained by step (a) represents obtains alcohol through diisobutyl aluminium hydride (DIBAL-H) reduction, then passes through
Concentrated hydrochloric acid-ethanol deprotection reaction obtains the compound of formula (III) expression；Wherein reaction temperature is -78 DEG C~0 DEG C；
(c) compound that formula (III) obtained by step (b) represents through mesyl chloride or paratoluensulfonyl chloride react to obtain sulphonic acid ester or
P-methyl benzenesulfonic acid ester, then obtain the compound shown in formula (IV) through benzylamine ring-closure reaction in alcohol；Wherein reaction temperature is -5 DEG C
~0 DEG C；
The aftertreatment technology of the step (c) is：The compound shown in formula (IV) that reaction is obtained is through extracting, dry and mistake
Filter, be evaporated under reduced pressure and produce after precipitation.
2. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 1, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, it is described to comprise the following steps that：
The phosphate is dissolved in tetrahydrofuran, potassium tert-butoxide is added when temperature is -78 DEG C~0 DEG C, reacts and then adds
Enter the tetrahydrofuran solution of the material shown in formula (I), react the compound of the formula of producing (II) expression；
The compound that formula (II) represents is dissolved in dichloromethane, when temperature is -78 DEG C~0 DEG C, adds diisobutyl hydrogenation
Aluminium, then obtain the compound of formula (III) expression through concentrated hydrochloric acid-ethanol deprotection reaction；
The compound that formula (III) represents is dissolved in dichloromethane, adds triethylamine, first sulphur is added when temperature is -5 DEG C~0 DEG C
Acyl chlorides or paratoluensulfonyl chloride, insulation reaction, produce crude product；The crude product is dissolved in ethanol, benzylamine is added, is warming up to back
Stream, afterwards insulation reaction, reaction terminate to produce (R) -1- benzyl -3- methyl isophthalic acids, 2,3,6- tetrahydrochysene piperidines.
3. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 1 or 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines,
Characterized in that, phosphonate ester used in the Horner-Wadsworth-Emmons reactions is selected from two oxy-o-cresyl phosphinylidynes
Ethyl, di-o-tolyl phosphinylidyne ethyl, two o-tert-butyl diphenylphosphoryl ethyl acetate, the second of phosphinylidyne guanidine-acetic acid three
One kind in ester.
4. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, the mol ratio of material, phosphonate ester and potassium tert-butoxide shown in the formula (I) is 1：1.2~1.4：1.2~1.4.
5. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, per in 100mL tetrahydrofurans, adds 10~20g phosphonate ester；The tetrahydrofuran solution of material shown in formula (I)
Mass percent concentration be 20%~50%.
6. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 1, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, the compound and the mol ratio of diisobutyl aluminium hydride that formula (II) represents are 1：2.5~3.0；Per 100mL dichloromethanes
In alkane, the compound that 2~10g formulas (II) represent is added.
7. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, the equivalent concentration of the concentrated hydrochloric acid-ethanol is 1N, and wherein the mass ratio of concentrated hydrochloric acid-ethanol is 1：25~40.
8. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, the compound that formula (III) represents, mesyl chloride or paratoluensulfonyl chloride, triethylamine, the mol ratio of benzylamine is 1：3.0
~3.5：3.0~3.5：8.0~10.0, per in 100mL dichloromethane, add the compound of 2~10g formulas (III) expression.
9. one kind (R) -1- benzyl -3- methyl isophthalic acids according to claim 2, the synthetic method of 2,3,6- tetrahydrochysene piperidines, its
It is characterised by, the compound and the mass ratio of ethanol that formula (III) represents are 1：16~50.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510019575.2A CN104710347B (en) | 2015-01-14 | 2015-01-14 | (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510019575.2A CN104710347B (en) | 2015-01-14 | 2015-01-14 | (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104710347A CN104710347A (en) | 2015-06-17 |
| CN104710347B true CN104710347B (en) | 2018-01-16 |
Family
ID=53410137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510019575.2A Active CN104710347B (en) | 2015-01-14 | 2015-01-14 | (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104710347B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577974B (en) * | 2019-09-10 | 2021-07-20 | 杭州澳赛诺生物科技有限公司 | Synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine |
| BR112022019536A2 (en) * | 2020-03-31 | 2022-11-16 | Dsm Ip Assets Bv | PROCESS FOR THE PRODUCTION OF TERPENOID INTERMEDIATES |
| CN112110879B (en) * | 2020-10-21 | 2022-07-26 | 扬州中宝药业股份有限公司 | Preparation method of sulcardine free alkali |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101955457A (en) * | 2010-09-21 | 2011-01-26 | 海门慧聚药业有限公司 | General preparation method of optical-activity 3-aminopyrrolidine, 3-alkyl amino piperidine and derivatives thereof |
| CN102391251A (en) * | 2004-02-11 | 2012-03-28 | 诺瓦提斯公司 | Chemokine receptor antagonists |
| CN103980186A (en) * | 2013-02-07 | 2014-08-13 | 上海威智医药科技有限公司 | Preparation method of amino protection (R)-3-amino piperidine |
-
2015
- 2015-01-14 CN CN201510019575.2A patent/CN104710347B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391251A (en) * | 2004-02-11 | 2012-03-28 | 诺瓦提斯公司 | Chemokine receptor antagonists |
| CN101955457A (en) * | 2010-09-21 | 2011-01-26 | 海门慧聚药业有限公司 | General preparation method of optical-activity 3-aminopyrrolidine, 3-alkyl amino piperidine and derivatives thereof |
| CN103980186A (en) * | 2013-02-07 | 2014-08-13 | 上海威智医药科技有限公司 | Preparation method of amino protection (R)-3-amino piperidine |
Non-Patent Citations (2)
| Title |
|---|
| An Approach to the Synthesis of a C9-C15 Fragment of Discodermolide;Julian M. C. Golec，等;《Tetrahedron Letters》;19931231;第34卷(第50期);第8167-8168页 * |
| Ferric Chloride Hexahydrate: A Mild Hydrolytic Agent for the Deprotection of Acetals;Stephanie E. Sen，等;《J. Org. Chem.》;19971231;第62卷(第19期);第6684-6686页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104710347A (en) | 2015-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106748950B (en) | A kind of preparation method of Bu Waxitan and its intermediate | |
| CN108314639B (en) | Compound (E) -3-(1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride and synthetic method | |
| CN105037363B (en) | A kind of entecavir compound prepared novel synthesis | |
| CN104710347B (en) | (R) synthetic method of the tetrahydrochysene piperidines of 1 benzyl, 3 methyl 1,2,3,6 | |
| CN105829284B (en) | The method for preparing adamantane Carbox amide | |
| CN101845017A (en) | Preparation method of atracurium besilate intermediates | |
| CN107540574A (en) | The preparation method of R biphenyl Propanolamines | |
| CN102167654A (en) | Preparation method of trans-4-substituted cyclohexyl olefin compound | |
| CN105237411A (en) | Preparation method for sarpogrelate hydrochloride photodegradable impurity III | |
| CN105218329A (en) | Clean analogue intermediate of a kind of row and preparation method thereof | |
| CN102070469B (en) | Resolution method for preparing optically pure metoprolol | |
| CN102408442B (en) | Synthesis method for calix [4] arenes substituted by 2-diphenylphosphine benzoyl and application | |
| CN104557583A (en) | Method for synthesizing gamma-aminobutyric acid chiral compound | |
| CN107021886A (en) | One class quaternary amines chiral ionic liquid and preparation method thereof | |
| CN104193638A (en) | Method for preparing (S)-2',6'-dimethyl tyrosine and derivative of (S)-2',6'-dimethyl tyrosine, and derivative | |
| CN104974051A (en) | Synthetic method for (1S,4R)-cis-4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
| CN112430208A (en) | Preparation method of PF-06651600 intermediate | |
| CN103373956B (en) | Method for preparing clevidipine butyrate | |
| CN105175364A (en) | Method for preparing amprenavir midbody serving as anti-AIDS medicine | |
| CN104610037A (en) | Preparation method of beta-trifluoromethyl-beta-hydroxyketone | |
| CN103044467A (en) | Method for preparing intermediate used for synthesizing bortezomib | |
| CN104072407B (en) | A kind of preparation method of Rho kinase inhibitor Y27632 compound | |
| CN102584512A (en) | Method for synthesizing benzofuran derivatives in one pot process | |
| CN104844495A (en) | Synthesis method of (2S,4S)-4-thiophenyl-L-proline hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wen Jianming Inventor after: Fang Weiguo Inventor after: Hu Jianfeng Inventor after: Shi Guoqiang Inventor before: Wen Jianming Inventor before: Fang Weiguo Inventor before: Hu Jianfeng |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |