CN108101860A - The preparation method of cis -2,6- thebaines - Google Patents
The preparation method of cis -2,6- thebaines Download PDFInfo
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- CN108101860A CN108101860A CN201810130007.3A CN201810130007A CN108101860A CN 108101860 A CN108101860 A CN 108101860A CN 201810130007 A CN201810130007 A CN 201810130007A CN 108101860 A CN108101860 A CN 108101860A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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Abstract
The invention discloses a kind of preparation methods of cis 2,6 thebaine, which is characterized in that comprises the following steps：(1) using benzylamine and chiral epoxy propane as raw material, through being condensed to yield N benzyl diisopropanolamine (DIPA)s；(2) N benzyls cis 2,6 thebaines are obtained with sulfuric acid dehydration condensation to the N benzyls diisopropanolamine (DIPA) that step (1) obtains；(3) hydrogenation debenzylation is carried out to the product of step (2) and obtains cis 2,6 thebaines.The present invention is using benzylamine and chiral epoxy propane as raw material, and low in raw material price is easy to get, and reaction condition is mild, and reaction yield is high；Cis-isomer content is high in product, fully achieves medicinal requirement.
Description
Technical field
The present invention relates to a kind of synthetic methods of the heterocyclic compound for medicine intermediate, and in particular to it is a kind of it is cis-
The preparation method of 2,6- thebaines.
Background technology
Cis -2,6- thebaines are the important intermediates of antitumor drug Sony Ji cloth (Sonidegib).
In the prior art, a kind of method of synthesizing cis -2,6- thebaine is to be deposited with diisopropanolamine (DIPA) in the concentrated sulfuric acid
In lower high temperature dehydration cyclization, then high-vacuum fractionation cis-trans isomer [DE2822326 (1979)]；Such as formulas below institute
Show.
The above method there are the problem of be：The ratio of the cis-isomer of generation is condensed less than 80%（Cis-trans-isomer ratio=
78：22）；The purity of the separation product of high-vacuum fractionation is difficult to reach medicinal requirements.
Another method is：Chiral isopropanolamine and the imines Xi Fushi alkali that benzaldehyde generates are also primary with sodium borohydride
Into N- benzyls-isopropanolamine；Then become with alpha-brominated propionic acid catalyzing and condensing and cyclization N- benzyl -2,6- dimethyl -3- oxos -
Morpholine, last Li-Al hydrogen reduces to obtain and debenzylation obtain cis -2,6- thebaines [JACS, 2009,131,11:
3991~7]；
Further, directly it is condensed with chiral isopropanolamine with alpha-chloro propionic acid, the chiral amides of generation are in the presence of butyl alcohol-tert potassium
Cyclization obtains 2,6- dimethyl -3- oxo-morpholins；It is finally reduced in tetrahydrofuran solvent with Li-Al hydrogen, obtains cis -2,
6- thebaines [Synthesis (Germany), 2014, vol.46, art. no.46]；
This kind of method is reduced using Li-Al hydrogen, and reaction condition is more demanding, and the requirement in production process to security protection is especially high.
Therefore, it is necessary to seek the preparation method of new cis -2,6- thebaines.
The content of the invention
The goal of the invention of the present invention is to provide a kind of preparation method of cis -2,6- thebaines, to improve in product
The content of cis-isomer, while make reaction condition mild.
To achieve the above object of the invention, the technical solution adopted by the present invention is：A kind of system of cis -2,6- thebaines
Preparation Method comprises the following steps：
(1) using benzylamine and chiral epoxy propane as raw material, through being condensed to yield N- benzyls-diisopropanolamine (DIPA)；Reaction equation is as follows：
(2) N- benzyls-cis -2,6- bis- is obtained with sulfuric acid dehydration condensation to N- benzyls-diisopropanolamine (DIPA) that step (1) obtains
Methyl morpholine；
(3) hydrogenation debenzylation is carried out to the product of step (2) and obtains cis -2,6- thebaines, reaction equation is as follows：
In above-mentioned technical proposal, in step (1), the chiral epoxy propane is R configurations or S configurations；Benzylamine and chiral epoxy
The molar filling ratios of propane are 1: 1.8~2.5；Reaction carried out in polar solvent, reaction temperature for room temperature to 100 DEG C, reaction
When time is 1~18 small.
Preferably, the molar filling ratios of benzylamine and chiral epoxy propane are 1: 2.0~2.4；Reaction temperature is 40~80 DEG C,
When reaction time is 4~10 small.
It is furthermore preferred that the molar filling ratios of benzylamine and chiral epoxy propane are 1: 2.3~2.4；Reaction temperature is 60~80
DEG C, when the reaction time is 6~8 small.
Wherein, the polar solvent is DMF, DMSO or fatty alcohol.
Preferably, the fatty alcohol is methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, isobutanol or the tert-butyl alcohol.Optimal selection
Methanol, ethyl alcohol or isopropanol.
In step (2), chiral N- benzyls-diisopropanolamine (DIPA) thermal dehydration cyclization in the presence of the concentrated sulfuric acid, chiral N- benzyls-
The molar filling ratios of diisopropanolamine (DIPA) and the concentrated sulfuric acid are 1: 1~5, preferably 1: 1.5~2.5, most preferably 1: 1.8~2.0；Reaction temperature
Degree control is in room temperature to 230 DEG C, and preferable temperature is 40~180 DEG C, 60~130 DEG C of optimal selection；Reaction time is small for 1~18
When, preferably 3~10 it is small when, most preferably 5~8 it is small when.
From embodiment, the product of step (2) is mainly N- benzyls-cis -2,6- thebaines, cis-trans-isomer
Ratio be about 92：2.
In step (3), N- benzyls -2,6- thebaine use catalysis process debenzylation, used catalyst for palladium -
Carbon；The weight proportion of substrate and catalyst is 1~10%；Reaction dissolvent is fatty alcohol；Hydrogenation pressure is 1.0~4.5MPa；Reaction
Temperature is room temperature to 100 DEG C；When reaction time 1~18 is small.
Preferably, the catalyst is 5~10% palladium-carbon；The weight proportion of substrate and catalyst is 3~8%；The fat
Fat alcohol is methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, isobutanol or the tert-butyl alcohol；Hydrogenation pressure is 1.2~3.0MPa；Reaction temperature
It spends for 40~80 DEG C；When reaction time 4~10 is small.
It is furthermore preferred that the catalyst is 5% palladium-carbon；The weight proportion of substrate and catalyst is 4~5%；The fat
Alcohol is methanol, ethyl alcohol or isopropanol；Hydrogenation pressure is 1.5~2.0MPa；Reaction temperature is 60~80 DEG C；Reaction time 5~7 is small
When.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：
1st, the present invention is using benzylamine and chiral epoxy propane as raw material, and low in raw material price is easy to get, and reaction condition is mild, reaction yield
It is high；
2nd, in product of the invention, cis-isomer content is high, fully achieves medicinal requirement.
Specific embodiment
With reference to embodiment, the invention will be further described：
Embodiment 1：The preparation of chiral N- benzyls-diisopropanolamine (DIPA)；
80.2g (0.75mol) benzylamine, 103.0g (1.78mol) are added in 1000ml four-hole bottles（S）- propylene oxide and 600ml
Methanol is heated to flowing back, and GC research and applications are reaction end with adduct content≤0.5%, reacts and terminates when about reflux 8 is small,
Removed under reduced pressure solvent methanol obtains 168.2g condensation products.Quantitative yield, content more than 97% (GC).
Nuclear magnetic data is as follows, shows to have obtained the product.
1H NMR (CDCl3): δ7.35 ~7.28 (m, 5H;ArH), 3.94 ~ 3.78 (m, 2H;CH2), 3.89
(d, J=13.6 Hz, 1H;), 3.51 N-CH2Ph (d, J=13.6 Hz, 1H;N-CH2Ph), 2.65 (br, 2H;
), 2.45 OH (d, J=6.1 Hz, 4H;), 1.10 N-CH2 (d, J=6.1 Hz, 6H; CH3) ppm。
Embodiment 2, the preparation of N- benzyls-cis -2,6- thebaines
Addition compound product 168.2g is added in 1000ml four-hole bottles（0.75mol）, be heated to 60 DEG C, control liquid temperature 100 DEG C with
Under, the 133g concentrated sulfuric acids are slowly added dropwise（98% concentration）.After completion of dropwise addition, 118 DEG C are heated to, and under the conditions of 118 ~ 122 DEG C
Insulation reaction 5 ~ 6hrs, HPLC monitoring, material content≤1.0% are reaction end.After reaction, 70 DEG C are cooled to, control
250ml water is slowly added at 70 DEG C or so.After adding water, 30% liquid caustic soda 400g is added dropwise at 50 DEG C or so for control temperature, adds in
200ml toluene, stirring layering.Water layer is extracted once with 150ml toluene.Merge organic phase, add in 300ml water and a small amount of activated carbon
Stirring decoloration 1hr.It filters, the washing of 100ml toluene.Toluene layer uses 300ml water washings once again, and removed under reduced pressure toluene obtains N- benzyls
Base-cis -2,6- thebaine 146.0g, yield 95% or so.Content 95% or so（HPLC）.
It is as follows to detect nuclear magnetic data：
1H NMR (CDCl3): δ7.32 ~7.21 (m, 5H;ArH), 3.72 ~ 3.63 (m, 2H;2CH), 3.45 (s,
2H;), 2.70 ~ 2.67 CH2 (d, J=15 Hz, 2H; N-CH2), 1.77 ~ 1.70 Ph (dd, J=15 Hz, 2H; N-
CH2Ph), 1.13,1.11 (d, J=10 Hz, 6H; CH3) ppm。
Embodiment 3, the preparation of cis -2,6- thebaine hydrochlorides
N- benzyls-cis -2,6- thebaines of 146.0g and 1020ml methanol are put into 2000ml pressure cookers, covers pot
Lid, with hydrogen displacement three times.Stirring and heating system are opened, control temperature is at 65 ~ 75 DEG C, and pressure is under the conditions of 1.5 ~ 2.0MPa
5hrs is hydrogenated, until hydrogen is not inhaled substantially（GC monitors reaction end, and reaction solution measures the ratio about 92 of cis-trans-isomer：2）.
It is cooled to room temperature.Pressure release.It filters, washing, merging filtrate and washing lotion add in 100g concentrated hydrochloric acids（36%）, 1hr is stirred into salt.Decompression is de-
Except methanol, 250ml toluene is added in, is heated to flowing back, azeotropic dehydration.Then removed under reduced pressure toluene, raffinate cooling and solidifying.In solid
1300ml acetone is added in, is dissolved by heating.Cooling is cooled to less than 5 DEG C, stirs 2hrs.It filters, is washed with 200ml cold acetones.It is dry
Obtain solid（White）76.6g.Yield 71% or so.Filtrate and washing lotion merge, and air-distillation removes acetone to 150ml or so.Cooling,
It is cooled to less than 5 DEG C, stirs 2hrs.It filters, a small amount of acetone washs to obtain solid, adds in 120ml acetone in solid, dissolves by heating, cold
But solid is precipitated.It is cooled to less than 5 DEG C, stirs 2hrs.It filters, the washing of a small amount of acetone, dry solid 8.3g, yield about 7.7%.
Merge must cis -2,6- thebaine hydrochloride 84.9g, yield 78.7%.
Embodiment 4, the preparation of cis -2,6- thebaines
Added in 500ml four-hole bottles 84.9g it is cis-liquid caustic soda of 2,6- thebaines hydrochloride and 320g 30%, stirring
1hr.It is layered, the liquid caustic soda of 120g 50% is added in organic layer, stir 1hr, be layered to obtain organic phase.It is evaporated under reduced pressure to product 58.1g.
GC measures cis-content 99.41%, transisomer 0.23%.Yield 90% or so.
1HNMR (CDCl3)：1.12（D, methyl）, 3.57（m,CH）,2.496(NH)；2.80,2.40（T, CH2）.
Merge the lye separated, vacuum distillation, distillate 50g or so.After being dried with lye recyclable 4.0g 99.0% with
On product, yield about 6%.
Claims (10)
1. a kind of preparation method of cis -2,6- thebaines, which is characterized in that comprise the following steps：
(1) using benzylamine and chiral epoxy propane as raw material, through being condensed to yield N- benzyls-diisopropanolamine (DIPA)；
(2) N- benzyls-cis -2,6- bis- is obtained with sulfuric acid dehydration condensation to N- benzyls-diisopropanolamine (DIPA) that step (1) obtains
Methyl morpholine；
(3) hydrogenation debenzylation is carried out to the product of step (2) and obtains cis -2,6- thebaines.
2. the preparation method of cis -2,6- thebaines according to claim 1, it is characterised in that：In step (1),
The chiral epoxy propane is R configurations or S configurations；The molar filling ratios of benzylamine and chiral epoxy propane are 1: 1.8~2.5；
Reaction carries out in polar solvent, and reaction temperature is room temperature to 100 DEG C, the reaction time for 1~18 it is small when.
3. the preparation method of cis -2,6- thebaines according to claim 2, it is characterised in that：Benzylamine and chirality
The molar filling ratios of propylene oxide are 1: 2.0~2.4；Reaction temperature is 40~80 DEG C, when the reaction time is 4~10 small.
4. the preparation method of cis -2,6- thebaines according to claim 3, it is characterised in that：Benzylamine and chirality
The molar filling ratios of propylene oxide are 1: 2.3~2.4；Reaction temperature is 60~80 DEG C, when the reaction time is 6~8 small.
5. the preparation method of cis -2,6- thebaines according to claim 2, it is characterised in that：The polarity is molten
Agent is DMF, DMSO or fatty alcohol.
6. the preparation method of cis -2,6- thebaines according to claim 5, it is characterised in that：The fatty alcohol
It is methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, isobutanol or the tert-butyl alcohol.
7. the preparation method of cis -2,6- thebaines according to claim 1, it is characterised in that：In step (2),
Chiral N- benzyls-diisopropanolamine (DIPA) thermal dehydration cyclization in the presence of the concentrated sulfuric acid, chiral N- benzyls-diisopropanolamine (DIPA) and the concentrated sulfuric acid
Molar filling ratios for 1: 1~5, preferably 1: 1.5~2.5, most preferably 1: 1.8~2.0；Reaction temperature is controlled in room temperature to 230
DEG C, preferable temperature is 40~180 DEG C, 60~130 DEG C of optimal selection；Reaction time for 1~18 it is small when, preferably 3~10 it is small when, most
It is preferred that 5~8 it is small when.
8. the preparation method of cis -2,6- thebaines according to claim 1, it is characterised in that：In step (3),
N- benzyls -2,6- thebaine uses catalysis process debenzylation, and used catalyst is palladium-carbon；Substrate and catalyst
Weight proportion is 1~10%；Reaction dissolvent is fatty alcohol；Hydrogenation pressure is 1.0~4.5MPa；Reaction temperature is room temperature to 100
℃；When reaction time 1~18 is small.
9. the preparation method of cis -2,6- thebaines according to claim 8, it is characterised in that：The catalyst
For 5~10% palladium-carbon；The weight proportion of substrate and catalyst is 3~8%；The fatty alcohol is methanol, ethyl alcohol, propyl alcohol, isopropyl
Alcohol, butanol, isobutanol or the tert-butyl alcohol；Hydrogenation pressure is 1.2~3.0MPa；Reaction temperature is 40~80 DEG C；Reaction time 4~10
Hour.
10. the preparation method of cis -2,6- thebaines according to claim 9, it is characterised in that：The catalyst
For 5% palladium-carbon；The weight proportion of substrate and catalyst is 4~5%；The fatty alcohol is methanol, ethyl alcohol or isopropanol；Hydrogenation
Pressure is 1.5~2.0MPa；Reaction temperature is 60~80 DEG C；When reaction time 5~7 is small.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293649A (en) * | 2018-11-12 | 2019-02-01 | 新发药业有限公司 | A kind of preparation method of Sony's Ji cloth intermediate and Sony's Ji cloth |
| CN115583923A (en) * | 2022-10-19 | 2023-01-10 | 枣庄市润安制药新材料有限公司 | Preparation method of cis-2,6-dimethylmorpholine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293649A (en) * | 2018-11-12 | 2019-02-01 | 新发药业有限公司 | A kind of preparation method of Sony's Ji cloth intermediate and Sony's Ji cloth |
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| CN115583923A (en) * | 2022-10-19 | 2023-01-10 | 枣庄市润安制药新材料有限公司 | Preparation method of cis-2,6-dimethylmorpholine |
| CN115583923B (en) * | 2022-10-19 | 2023-10-17 | 枣庄市润安制药新材料有限公司 | Preparation method of cis-2, 6-dimethyl morpholine |
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