CN104860870A - Preparation method of piperidine with different substituents - Google Patents
Preparation method of piperidine with different substituents Download PDFInfo
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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
- C07D211/02—Preparation by ring-closure or hydrogenation
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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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a preparation method of piperidine with different substituents. The piperidine is shown in the formula 1. The preparation method comprises a compound shown in the formula 2 undergoes a hydrogenation reaction, wherein R represents COOR1 or R2-OH, R1 represents CnH2n+1, R2 represents CnH2n and n is an integer of 1-6.
Description
Technical field
The invention provides a kind of preparation method with the piperidines of different substituents, it provides piperidines method for making tool security more in the past and falls oligosaprobic method and obtains piperidines.
Background technology
Piperidines (piperidine), its chemistry hexahydropyridine by name, is colourless fuming liquid under room temperature, has the irritating smell of similar ammonia, pepper, be widely used in organic synthesis, especially in pharmaceutical synthesis.Therefore piperidines is a very important intermediate in medical applications, and being successfully applied to medical composition at present has: Antiemetics, antihistaminic, mental medication or anticancer medication.
But at present for the preparation method of piperidines, people (the Continuous FlowHydrogenation of Functionalized Pyridines such as Muhammed Irfan, European Journal of OrganicChemistry, Vol.2009, Issue9, pages1327 – 1334) to disclose a kind of be starting raw material by isonicotine acid methyl esters (methyl isonicotinate), hydrogenation is carried out under 30 bar (bar) pressure, the catalyzer used is palladium-carbon catalyst (Pd/C), platinum C catalyst (Pt/C) or rhodium C catalyst (Rh/C), and use solvent for acetic acid (HOAC), use temperature is 80 DEG C simultaneously, and therefore the method must be carried out under high temperature and high pressure, therefore has considering of security, used acetic acid does solvent contamination comparatively greatly in addition, and utilizes expensive platinum C catalyst not meet economic benefit.
Separately there is document (Josue Alfaro-Lopez et al., Journal of Medicinal Chemistry, 1999, Vol.42, p5359-5368) also point out with isonipecotic acid (isonipecotic acid) for starting raw material is dissolved in methyl alcohol, and add sulfur oxychloride (SOCl
2) react under normal temperature, isonipecotic acid methyl esters (methyl isonipecotate, MINP) can be obtained.But the starting raw material price of this preparation method costly, therefore do not meet economic benefit.Separately there is research (C.A.Grob and E.Renk, Helvetica Chimica Acta, 1954, Vol.37, pages1672-1680) be for starting raw material with isonicotine acid (isonicotinic acid), with Raney's nickel (Raney nickel) for catalyzer, react under 180 DEG C and pressure 116 normal atmosphere (atm), finally obtain isonipecotic acid methyl esters with methyl alcohol and concentrated hydrochloric acid; Right aforesaid method need carry out hydrogenation under high temperature and high pressure, based on the unsuitable commercialization of safety grounds.
In addition, also research (ROBERT E.LYLE et al. is had, Journal of Organic Chemistry, 1955, Vol.20, pages1761-1765) be utilize isonicotine acid methyl esters (methyl isonicotinate) to be starting raw material, under Adams'catalyst (Adam ' s catalyst), carry out hydrogenation, to prepare isonipecotic acid methyl esters, but it uses platinum dioxide (PtO
2) expensive, do not meet economic benefit yet.
Be with, to prepare in the process of piperidines or derivatives thereof the unavoidable starting raw material etc. using organic solvent that the reactions steps of High Temperature High Pressure, contaminative are high or costliness at present, therefore also exist prepare that production cost is high, the problem such as the security of preparation process and environmental pollution.Therefore how effectively to prepare piperidines or derivatives thereof, and overcome the problems referred to above, be the difficult problem of current related industries for solving.
Summary of the invention
The present invention discloses the preparation method of the piperidines (piperidine) of two kinds of different substituents, comprise: the preparation of (1) isonipecotic acid methyl esters: by isonicotine acid methyl esters (methyl isonicotinate) be starting raw material, its price inexpensively, carry out reacting to obtain a pyridinium salt (compd B) with cylite, then with sodium borohydride (NaBH
4) destroy its aromatic nucleus, to obtain methyl 1-benzyl-3,6-dihydro-2 hydrogen-pyridine-3-carboxylic acid, finally can complete isonipecotic acid methyl esters (methyl isonipecotate with hydrogenation, MINP) prepare, and the present invention premised on security is considered under, be with 10% palladium-carbon catalyst (Pd/c) when carrying out hydrogenation, under methanol aqueous solution, and the environment of normal temperature and pressure reacts; And (2) 4-piperidine carbinols (4-piperidine methanol, preparation 4-PM): with isonicotine acid alcohol (isopyridiol) for starting raw material, and react with cylite, be reacted into a pyridinium compound (compd E), its aromatic nucleus is destroyed again with sodium borohydride, to obtain (1-benzyl-3,6-dihydro-2 pyridinium hydroxide-4-base) methyl alcohol, finally 4-piperidine carbinols can be obtained with hydrogenation.Above-mentioned preparation method can avoid as in prior document use High Temperature High Pressure, expensive platinum dioxide (PtO
2) as catalyzer, or use acetic acid as problems such as solvents
In addition, above-mentioned two kinds have in the preparation method of the croak pyridine of different substituents, and this isonicotine acid alcohol can be obtained by this isonicotine acid methyl esters and sodium borohydride reaction under methanol solvate; And be somebody's turn to do (1-benzyl-1,2,3,6-tetrahydropyridine-4-base) methyl alcohol ((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl) methanol) also can by this 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate methyl ester (methyl1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate) carry out reacting and obtaining with red aluminium.Therefore, in the preparation process of this isonipecotic acid methyl esters, compound can be converted into compound in the preparation process of 4-piperidine carbinols, continues and carries out the reactions steps of follow-up 4-piperidine carbinols.Therefore the present invention just can obtain the derivative of the important intermediate piperidines in current medical composition with three steps, and via the production method of industry member, comprise extraction, to be separated and purifying can obtain on a small quantity, its productive rate about 60%.Isonipecotic acid methyl esters (MINP) prepared by the present invention meets the specification of medicine intermediate, and its outward appearance is white powder, and purity is 99%.Therefore the piperidines prepared by the present invention with different substituents can be applied to medical composition further, the preparation of animal-feed or food, wherein this medical composition comprises Antiemetics (as metopimazine (metopimazine), croak horse piperazine (pipamazine)), antihistaminic (ketotifen (ketotifen), saturating non-Nutting (terfenadine), azatadine (azatadine), fexofenadine (fexofenadine)), mental medication is (as Zomaril (iloperidone), ritanserin (ritanserin), Li Sipei ketone (risperidone), E2020 (donepezil)), anticancer medication (ZD6474 (vandetanib)) or other take piperidines as compound or the medicine of intermediate.
Term used herein " one ", " one " and " being somebody's turn to do " mean " one or more ", and this term is only in order to describe convenient and give basic concepts of the present invention.This describe should be understood to include one or at least one, unless and refer else significantly, represent odd number time also comprise plural number.
Term "or" herein its meaning with " and/or ".
The invention provides a kind of method of preparation formula 1 compound
Comprise: by formula 2 compound
Carry out hydrogenation, wherein R is COOR
1or R
2-OH, wherein this R
1for C
nh
2n+1, and R
2for C
nh
2n, and n is the integer of 1 to 6.In a preferred embodiment, this n is the integer of 1 to 3.
In one embodiment, this R is 3-COOR
1or 4-COOR
1.In another specific embodiment, this R is 3-R
2-OH or 4-R
2-OH.
" Ph " herein in carried various compound refers to phenyl (phenyl).
In one embodiment, this hydrogenation comprises a catalyzer further, and wherein this catalyzer is including but not limited to having the reagent impelling organic compound and hydrogen to react.In one preferably specific embodiment, this hydrogenation comprises a catalyzer further, and wherein this catalyzer is palladium-carbon catalyst (Pd/C).In addition, this formula 2 compound carry out hydrogenation be in an organic solvent reaction and must this formula 1 compound.In one embodiment, this organic solvent is methyl alcohol.
In another specific embodiment, this formula 2 converting compounds is the hydrogenation condition of this formula 1 compound is in passing into hydrogen (H
2) under and react under normal temperature and pressure environment.In a preferred embodiment, this normal pressure is 0.5-10kg/cm
2.In a better specific embodiment, this normal pressure is 1-3kg/cm
2.And to carry out the reaction times under above-mentioned normal temperature and pressure environment be 10-60 hour, preferably the reaction times is 23-50 hour.
This formula 2 converting compounds is after the reaction of this formula 1 compound terminates, can by filtering, the mode of concentrated, extraction and drying gets the solids of this formula 1 compound.In addition, if the R of this formula 1 compound is COOR
1time, can by methyl alcohol and this formula 1 compound of ethyl acetate process before enrichment step, in order to carrying out subsequent step.In one embodiment, this time of drying is 10-20 hour; Be preferably 16 hours.
This formula 2 compound is by formula 3 compound
React with reductive agent and obtain.
In one embodiment, this reductive agent is including but not limited in a redox reaction, and Oxidation Number is by the low material uprising (namely losing electronics).In a preferred embodiment, this reductive agent is sodium borohydride (NaBH
4).
This formula 3 compound and this reductive agent to react in an organic solvent and must this formula 2 compound.In one embodiment, this organic solvent is methyl alcohol.In another specific embodiment, this formula 3 converting compounds is this formula 2 compound is react under low temperature environment; Wherein the preferred temperature scope of this low temperature environment is-30 DEG C to 0 DEG C; Be more preferred from-20 DEG C to-10 DEG C.In addition, if the R of formula 3 compound is R
2during-OH, then need pass into nitrogen (N under this low temperature environment
2), carry out in order to reaction.
This formula 3 converting compounds is after the reaction of this formula 2 compound terminates, and can get the liquids of this formula 2 compound by extraction, concentrated and dry mode; Wherein this extraction step processes with ethyl acetate.
This formula 3 compound is by formula 4 compound
React with bromizating agent and obtain.
In one embodiment, this bromizating agent is including but not limited to the reagent that can cause bromination reaction.In a preferred embodiment, this bromizating agent is cylite (benzyl bromride, PhCH
2br).
This formula 4 compound and this bromizating agent to react in an organic solvent and must this formula 3 compound.In one embodiment, if the R of this formula 4 compound is COOR
1time, then this organic solvent is methyl alcohol, and if the R of this formula 4 compound is R
2during-OH, then this organic solvent is acetone.In another specific embodiment, this formula 4 converting compounds is this formula 3 compound is react under passing into normal temperature and pressure environment.In a preferred embodiment, the reaction times under this normal temperature environment is 10 to 20 hours; Be more preferred from 14 to 16 hours.
In addition, this has R is COOR
1formula 4 compound further can by the R of formula 4 compound be COOH compound via esterification transform obtain.
The contained 2-1 compound of this formula 2 compound or formula 2-2 compound,
Wherein this formula 2-2 compound is reacted by this formula 2-1 compound and hydride reducer and obtained.
In one embodiment, this hydride reducer is two (2-methoxy ethoxy) sodium aluminate (sodium bis (2-methoxyethoxy) aluminumhydride is called for short red aluminium (Red-Al)) of dihydro.
This formula 2-1 compound and this hydride reducer to react in an organic solvent and must this formula 2-2 compound.In one embodiment, this organic solvent is toluene.In another specific embodiment, this formula 2-1 converting compounds is this formula 2-2 compound is react under normal temperature and pressure environment, and the reaction times is 0.5 to 3 hour, is preferably 1 hour.
This formula 2-1 converting compounds is after the reaction of this formula 2-2 compound terminates, can by extraction, filter, liquids that concentrated and dry mode gets this formula 2-2 compound; Wherein this extraction step processes with ethyl acetate.In one embodiment, this time of drying is 10-20 hour; Be preferably 16 hours.
The contained 4-1 compound of this formula 4 compound and formula 4-2 compound,
Wherein this formula 4-2 compound is reacted by this formula 4-1 compound and reductive agent and obtained.
In one embodiment, this reductive agent is sodium borohydride (NaBH
4).
This formula 4-1 compound and this reductive agent to react in an organic solvent and must this formula 4-2 compound.In one embodiment, this organic solvent is methyl alcohol.
In another specific embodiment, this formula 4-1 converting compounds is this formula 4-2 compound is react under low temperature environment; Wherein the preferred temperature scope of this low temperature environment is-50 DEG C to 0 DEG C; Be more preferred from-20 DEG C to-10 DEG C.In a preferred embodiment, the reaction times under this low temperature environment is 1 to 4 hour; Be more preferred from 2 hours.
This formula 4-1 converting compounds is after the reaction of this formula 4-2 compound terminates, can by extraction, filter, liquids that concentrated and dry mode gets this formula 4-2 compound; Wherein this extraction step processes with ethyl acetate.
The method of preparation formula 1 compound provided by the present invention, when mutually comparing with other located by prior art, has more following advantages:
(1) piperidines that the present invention's preparation has a different substituents just can obtain by three steps, in the present invention simultaneously, the resultant of each reactions steps can continue and react in same container, therefore the step that synthesis has the piperidines of different substituents can be shortened, the intermediate pyridinium salt (pyridinium salt) produced in reaction process can be solved simultaneously, such as formula 3 compounds, the deliquescent problem when being separated, and operation when impact is produced.
(2) starting raw material of preparation method of the present invention, as isonicotine acid methyl esters (methyl nicotinate) or isonicotine acid alcohol (isopyridiol), its cost is low, and the step that preparation has the piperidines of different substituents can operate under the environment of normal temperature and pressure, the risk reducing High Temperature High Pressure exists.
Accompanying drawing explanation
Fig. 1 is the schema that preparation has the piperidines of different substituents.
Fig. 2 is the schematic flow sheet preparing isonipecotic acid methyl esters and 4-piperidine carbinols.
Embodiment
Following examples are used to present and unrestricted all respects of the present invention and characteristic.
Fig. 1 is the schema that preparation has the piperidines of different substituents.As shown in Figure 1, the basic preparation process of the piperidines of different substituents of the present invention, first be there is different substituents pyridine (I) as starting raw material, be translated into pyridinium salt (pyridinium salt) (II), an intermediate (III) is obtained again through reduction reaction (as with sodium borohydride reduction), finally utilize hydrogenation that the reduction on this intermediate is become singly-bound, the phenmethyl of cracking simultaneously can have the piperidines (IV) of different substituents.
Fig. 2 is the schematic flow sheet preparing isonipecotic acid methyl esters and 4-piperidine carbinols, and detailed preparation process is described as follows:
(1) preparation of isonipecotic acid methyl esters (MINP):
The preparation flow of isonipecotic acid methyl esters (MINP), comprises following steps:
Step (a):
Get compd A (isonicotine acid methyl esters, methyl isonicotinate, 10g, 72.9mmol) and be placed in 3L three-necked bottle, under room temperature, add 10mL methyl alcohol, more slowly instill cylite (benzylbromride, PhCH
2br, 10mL=11g, 86.9mmol), in normal-temperature reaction 15 hours, to obtain compd B.
Compd B
1h-NMR (DMSO): δ 3.98 (s, 3H), 6.02 (s, 2H), 7.45 (m, 3H).
After above-mentioned reaction terminates, contain in the three-necked bottle of compd B add 90mL methyl alcohol in this, and slowly add 3.3g sodium borohydride (sodium tetrahydridoborate, NaBH in ice bath in batches
4), then stir 1 hour, add 50mL water, again with 100mL extraction into ethyl acetate, after layering, organic layer cleans with 100mL sodium hydroxide (NaCl) again, getting organic layer is concentrated into dry, can obtain reddish-brown fluid cpds C (1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate methyl ester, methyl1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate) 15.9g.
Compound C
1h-NMR (CDCl
3): δ 2.41 (br.s, 2H), 2.61 (t, J=5.60Hz, 2H), 3.13 (br.s, 2H), 3.61 (s, 2H), 3.73 (s, 3H), 6.87 (s, 1H), 7.25 ~ 7.38 (m, 5H).
Step (b):
Take this Compound C (40g, 149.39mmol) be dissolved in 300ml methyl alcohol and be placed in hydrogenation apparatus, then 20g10% palladium-carbon catalyst (Pd/C)/100ml is slowly added in hydrogenation apparatus, logical hydrogen (H under room temperature
2), pressure-controlling is at 1kg/cm
2react 23 hours, to obtain compound isonipecotic acid methyl esters (methyl isonipecotate, MINP).
Compound MINP's
1h-NMR (CDCl
3): δ 1.57 ~ 1.65 (m, 2H), 1.86 ~ 1.90 (m, 2H), 2.40 ~ 2.45 (m, 1H), 2.60 ~ 2.66 (m, 2H), 3.06 ~ 3.11 (m, 2H), 3.68 (s, 3H).
(2) preparation of 4-piperidine carbinols (4-PM):
The preparation flow of 4-piperidine carbinols (4-piperidinemethanol, 4-PM), comprises following steps:
Step (a):
Get Compound D (isonicotine acid alcohol, isopyridiol, 1.01g, 9.3mmol) be placed in the mono-neck bottle of 100mL, under room temperature, add 10mL acetone (Acetone) dissolve and cylite (1.7mL=2.43g, 14.2mmol) react 2 hours, filter, solid 20mL ethyl acetate cleans 2 times, filter, dry 16 hours, 2.25g ivory buff solid chemical compound E can be obtained.
Weigh Compound E (2.1g, 7.5mmol) is placed in the mono-neck bottle of 100mL, under room temperature, adds 20mL dissolve with methanol, under ice bath, and logical nitrogen (N
2), slowly add sodium borohydride (1.3g, 34.4mmol) in batches, then stir 0.5 hour.
After above-mentioned reaction terminates, add 20mL water, with 20mL extraction into ethyl acetate 2 times, after layering, merge organic layer and add anhydrous magnesium sulfate (MgSO
4) dry, filter, be concentrated into dry, in oil free type pump (pump) drying 16 hours, orange-yellow fluid cpds F ((1-benzyl-1,2,3 can be obtained, 6-tetrahydropyridine-4-base) methyl alcohol, (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl) methanol, 1.36g).
Compound D
1h-NMR (CDCl
3): δ 4.69 (s, 2H), 7.25 (m, 2H), 8.40 (m, 2H).
Compd E
1h-NMR (DMSO): δ 4.77 (s, 2H), 5.81 (s, 2H), 5.90 (br.s, 1H), 7.38 ~ 7.50 (m, 5H), 8.02 (d, J=6.4Hz, 2H), 9.01 (d, J=6.8Hz, 2H).
Step (b):
Weigh Compound F (3.78g, 17.56mmol) is dissolved in 20ml methyl alcohol (CH
3oH) (faint yellow clear liquor) be placed in hydrogenation apparatus, then by 3.78g, 10% palladium-carbon catalyst (Pd/C) slowly adds in hydrogenation apparatus, logical hydrogen (H under room temperature
2), pressure-controlling is at 3kg/cm
2react 50 hours.After reaction terminates, filter, filtrate is concentrated into dry, within 16 hours, can obtain brown liquid compound 4-piperidine carbinols (4-PM) 1.67g with the drying of oil free type pump.
Compound F 17-hydroxy-corticosterone
1h-NMR (CDCl
3): δ 2.15 (br.s, 2H), 2.59 (t, J=5.6Hz, 2H), 2.98 (br.s, 2H), 3.58 (s, 2H), 3.99 (s, 2H), 5.61 (s, 1H), 7.23 ~ 7.35 (m, 5H).
Compound 4-PM's
1h-NMR (CD
3oD): δ 1.17 ~ 1.20 (m, 2H), 1.56 ~ 1.62 (m, 1H), 1.71 ~ 1.75 (m, 2H), 2.54 ~ 2.60 (m, 2H), 3.02 ~ 3.07 (m, 2H), 3.38 (d, 2H).
In addition, Compound D can obtain through following reaction conversions via compd A,
Compd A (isonicotine acid methyl esters, methyl isonicotinate, 10g, 72.9mmol) be placed in the mono-neck bottle of 1L, under room temperature, add 150mL methyl alcohol, slowly add sodium borohydride (sodium tetrahydridoborate, NaBH under ice bath in batches
4, 6.6g, 174.5mmol), in stirred at rt for another 2 hours.
Reaction terminates, and adds 500mL water, and with 200mL extraction into ethyl acetate 2 times, after layering, organic layer adds anhydrous magnesium sulfate (MgSO
4) dry, layering, organic layer is concentrated into dry, can obtain orange-yellow fluid cpds D (isonicotine acid alcohol, isonicotinatol) 9.0g.
And compound F 17-hydroxy-corticosterone also can obtain through following reaction via Compound C.
Weigh Compound C (1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate methyl ester, methyl1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate, 3g, 11.2mmol) add 20ml toluene, then (sodiumbis (2-methoxyethoxy) aluminumhydride, is called for short red aluminium (Red-Al) to take two (2-methoxy ethoxy) sodium aluminate of dihydro, 6.2g, 21.79mmol), under ice bath, instill above-mentioned solution, react 1 hour.
After reaction terminates, add 48ml, 0.5M Seignette salt (Rochelle salt), with 40ml extraction into ethyl acetate, organic layer cleans with full conjunction salt solution, gets organic layer and adds the dry behaviour of anhydrous magnesium sulfate, filter, concentrated, with oil free type pump drying 16 hours, obtain brown liquid compound F 17-hydroxy-corticosterone ((1-benzyl-1,2,3,6-tetrahydropyridine-4-base) methyl alcohol, 2.32 grams).
Therefore Compound D or compound F 17-hydroxy-corticosterone can be reacted conversion by compd A or Compound C and after obtaining, can be continued and carry out the preparation process of 4-piperidine carbinols (4-PM), to obtain 4-piperidine carbinols.
Above-listed detailed description is illustrating of a better embodiment of the present invention, so itself and be not used to limit the present invention, therefore anyly have the knack of this those skilled in the art, do a little equivalence without departing from the spirit and scope of the present invention and implement or change, all should comprise in right of the present invention.
Claims (12)
1. the method for preparation formula 1 compound
Comprise: by formula 2 compound
Carry out hydrogenation, wherein R is COOR
1or R
2-OH, wherein said R
1for C
nh
2n+1, and R
2for C
nh
2n, and n is the integer of 1 to 6.
2. method as claimed in claim 1, wherein said n is the integer of 1 to 3.
3. method as claimed in claim 1, wherein said R is 3-COOR
1or 4-COOR
1.
4. method as claimed in claim 1, wherein said R is 3-R
2-OH or 4-R
2-OH.
5. method as claimed in claim 1, wherein said hydrogenation comprises a catalyzer further, and wherein said catalyzer is palladium-carbon catalyst.
6. method as claimed in claim 1, wherein said formula 2 compound is by formula 3 compound
React with reductive agent and obtain.
7. method as claimed in claim 6, wherein said formula 3 compound is by formula 4 compound
React with bromizating agent and obtain.
8. method as claimed in claim 7, wherein said bromizating agent is cylite.
9. method as claimed in claim 1, the contained 2-1 compound of wherein said formula 2 compound or formula 2-2 compound,
Wherein said formula 2-2 compound is reacted by described formula 2-1 compound and hydride reducer and obtained.
10. method as claimed in claim 9, wherein said hydride reducer is two (2-methoxy ethoxy) sodium aluminate of dihydro.
11. methods as claimed in claim 7, the contained 4-1 compound of wherein said formula 4 compound and formula 4-2 compound,
Wherein said formula 4-2 compound is reacted by described formula 4-1 compound and reductive agent and obtained.
12. as the method for claim 6 or 11, and wherein said reductive agent is sodium borohydride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724070A (en) * | 2021-01-08 | 2021-04-30 | 南京方生和医药科技有限公司 | Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol |
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| CN112724070A (en) * | 2021-01-08 | 2021-04-30 | 南京方生和医药科技有限公司 | Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol |
| CN113717152A (en) * | 2021-09-08 | 2021-11-30 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
| CN113717152B (en) * | 2021-09-08 | 2022-06-17 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
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