CN108101860B - Preparation method of cis-2, 6-dimethyl morpholine - Google Patents
Preparation method of cis-2, 6-dimethyl morpholine Download PDFInfo
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- CN108101860B CN108101860B CN201810130007.3A CN201810130007A CN108101860B CN 108101860 B CN108101860 B CN 108101860B CN 201810130007 A CN201810130007 A CN 201810130007A CN 108101860 B CN108101860 B CN 108101860B
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Abstract
The invention discloses a preparation method of cis-2, 6-dimethylmorpholine, which is characterized by comprising the following steps: (1) benzylamine and chiral epoxypropane are used as raw materials, and N-benzyl-diisopropanolamine is obtained through condensation; (2) dehydrating and cyclizing the N-benzyl-diisopropanolamine obtained in the step (1) by using sulfuric acid to obtain N-benzyl-cis-2, 6-dimethylmorpholine; (3) and (3) carrying out hydrogenation debenzylation on the product obtained in the step (2) to obtain cis-2, 6-dimethylmorpholine. The invention takes benzylamine and chiral epoxypropane as raw materials, the raw materials are low in price and easy to obtain, the reaction condition is mild, and the reaction yield is high; the cis-isomer content in the product is high, and the product can completely meet the requirement of medicine.
Description
Technical Field
The invention relates to a synthetic method of a heterocyclic compound used as a medical intermediate, in particular to a preparation method of cis-2, 6-dimethylmorpholine.
Background
Cis-2, 6-dimethylmorpholine is an important intermediate of the antineoplastic drug Sonidegibb (Sonidegib).
In the prior art, one method for synthesizing cis-2, 6-dimethylmorpholine is to dehydrate and cyclize with diisopropanolamine at high temperature in the presence of concentrated sulfuric acid, and then fractionate cis-trans isomer under high vacuum [ DE2822326(1979) ]; as shown in the following reaction scheme.
The problems of the method are as follows: the proportion of cis-isomer produced by condensation is less than 80% (cis-trans isomer ratio = 78: 22); the purity of the separated product of high vacuum fractionation is difficult to meet the medicinal requirements.
The other method is as follows: the imine Schiff base generated by condensation of chiral isopropanolamine and benzaldehyde is reduced by sodium borohydride to generate N-benzyl-isopropanolamine; then catalytically condensing the alpha-bromopropionic acid and cyclizing to obtain N-benzyl-2, 6-dimethyl-3-oxo-morpholine, finally reducing lithium aluminum hydrogen to obtain cis-2, 6-dimethyl morpholine [ JACS,2009,131,11: 3991-7 ] through debenzylation;
further, directly condensing chiral isopropanolamine and alpha-chloropropionic acid to generate chiral amide, and cyclizing the chiral amide in the presence of potassium tert-butoxide to obtain 2, 6-dimethyl-3-oxo-morpholine; finally, reducing by lithium aluminum hydrogen in tetrahydrofuran solvent to obtain cis-2, 6-dimethylmorpholine [ Synthesis (Germany), 2014, vol.46, art No.46 ];
the method adopts lithium aluminum hydrogen reduction, the reaction condition requirement is higher, and the requirement on safety protection in the production process is particularly high.
Therefore, a new method for producing cis-2, 6-dimethylmorpholine has been desired.
Disclosure of Invention
The invention aims to provide a method for preparing cis-2, 6-dimethylmorpholine, which is used for improving the content of cis-isomer in a product and simultaneously enabling reaction conditions to be mild.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a preparation method of cis-2, 6-dimethylmorpholine comprises the following steps:
(1) benzylamine and chiral epoxypropane are used as raw materials, and N-benzyl-diisopropanolamine is obtained through condensation; the reaction formula is as follows:
(2) dehydrating and cyclizing the N-benzyl-diisopropanolamine obtained in the step (1) by using sulfuric acid to obtain N-benzyl-cis-2, 6-dimethylmorpholine;
(3) and (3) carrying out hydrogenation debenzylation on the product obtained in the step (2) to obtain cis-2, 6-dimethyl morpholine, wherein the reaction formula is as follows:
in the above technical scheme, in the step (1), the chiral epoxypropane is in an R configuration or an S configuration; the molar ratio of benzylamine to chiral epoxypropane is 1: 1.8-2.5; the reaction is carried out in a polar solvent, the reaction temperature is between room temperature and 100 ℃, and the reaction time is 1-18 hours.
Preferably, the molar ratio of benzylamine to chiral epoxypropane is 1: 2.0-2.4; the reaction temperature is 40-80 ℃, and the reaction time is 4-10 hours.
More preferably, the molar ratio of benzylamine to chiral epoxypropane is 1: 2.3-2.4; the reaction temperature is 60-80 ℃, and the reaction time is 6-8 hours.
Wherein the polar solvent is DMF, DMSO or aliphatic alcohol.
Preferably, the aliphatic alcohol is methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol. Methanol, ethanol or isopropanol are most preferably selected.
In the step (2), heating, dehydrating and cyclizing chiral N-benzyl-diisopropanolamine in the presence of concentrated sulfuric acid, wherein the molar ratio of the chiral N-benzyl-diisopropanolamine to the concentrated sulfuric acid is 1: 1-5, preferably 1: 1.5-2.5, and most preferably 1: 1.8-2.0; the reaction temperature is controlled to be between room temperature and 230 ℃, the preferable temperature is 40-180 ℃, and the optimal temperature is 60-130 ℃; the reaction time is 1 to 18 hours, preferably 3 to 10 hours, and most preferably 5 to 8 hours.
As can be seen from the examples, the product of step (2) is predominantly N-benzyl-cis-2, 6-dimethylmorpholine, with a cis/trans ratio of about 92: 2.
in the step (3), the N-benzyl-2, 6-dimethyl morpholine is debenzylated by a catalytic method, and the used catalyst is palladium-carbon; the weight ratio of the substrate to the catalyst is 1-10%; the reaction solvent is fatty alcohol; the hydrogenation pressure is 1.0-4.5 MPa; the reaction temperature is between room temperature and 100 ℃; the reaction time is 1-18 hours.
Preferably, the catalyst is 5-10% of palladium-carbon; the weight ratio of the substrate to the catalyst is 3-8%; the aliphatic alcohol is methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; the hydrogenation pressure is 1.2-3.0 MPa; the reaction temperature is 40-80 ℃; the reaction time is 4-10 hours.
More preferably, the catalyst is 5% palladium on carbon; the weight ratio of the substrate to the catalyst is 4-5%; the aliphatic alcohol is methanol, ethanol or isopropanol; the hydrogenation pressure is 1.5-2.0 MPa; the reaction temperature is 60-80 ℃; the reaction time is 5-7 hours.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention takes benzylamine and chiral epoxypropane as raw materials, the raw materials are low in price and easy to obtain, the reaction condition is mild, and the reaction yield is high;
2. the product of the invention has high cis-isomer content and can completely meet the requirement of medical use.
Detailed Description
The invention is further described below with reference to the following examples:
example 1: preparing chiral N-benzyl-diisopropanolamine;
80.2g (0.75mol) of benzylamine, 103.0g (1.78mol) of (S) -propylene oxide and 600ml of methanol were put into a 1000ml four-necked flask, heated to reflux, and after the reaction was completed by GC analysis and the content of the adduct was 0.5% or less at the end of the reaction, the reaction was refluxed for about 8 hours, and the solvent methanol was removed under reduced pressure to obtain 168.2g of a condensate. The yield was determined and the content was 97% or more (GC).
The nuclear magnetic data are as follows, indicating that the product was obtained.
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; N-CH2Ph)，3.51 (d, J=13.6 Hz, 1H; N-CH2Ph)，2.65(br, 2H; OH)， 2.45 (d, J=6.1 Hz, 4H; N-CH2)，1.10(d, J=6.1 Hz, 6H; CH3) ppm。
EXAMPLE 2 preparation of N-benzyl-cis-2, 6-dimethylmorpholine
168.2g (0.75mol) of the adduct was charged into a 1000ml four-necked flask, heated to 60 ℃ and then gradually dropped therein 133g of concentrated sulfuric acid (98% strength) while controlling the liquid temperature at 100 ℃ or lower. After the dropwise addition is finished, heating to 118 ℃, carrying out heat preservation reaction for 5-6 hrs at 118-122 ℃, and carrying out HPLC monitoring, wherein the reaction end point is that the content of the raw material is less than or equal to 1.0%. After the reaction, the reaction mixture was cooled to 70 ℃ and 250ml of water was slowly added thereto at about 70 ℃. After the water addition is finished, 400g of 30% liquid alkali is dropwise added at the temperature of about 50 ℃,200 ml of toluene is added, and the mixture is stirred and layered. The aqueous layer was extracted once with 150ml of toluene. The organic phases were combined, 300ml of water and a small amount of activated carbon were added and stirred for decolorization for 1 hr. Suction filtration and washing with 100ml of toluene. The toluene layer was washed once with 300ml of water, and toluene was removed under reduced pressure to obtain 146.0g of N-benzyl-cis-2, 6-dimethylmorpholine, with a yield of about 95%. The content was about 95% (HPLC).
The detected nuclear magnetic data are as follows:
1H NMR (CDCl3): δ7.32 ~7.21 (m, 5H; ArH)，3.72~3.63(m, 2H; 2CH)，3.45 (s, 2H; CH2)， 2.70~2.67 (d, J=15 Hz, 2H; N-CH2Ph)，1.77~1.70 (dd, J=15 Hz, 2H; N-CH2Ph )， 1.13,1.11(d, J=10 Hz, 6H; CH3) ppm。
EXAMPLE 3 preparation of cis-2, 6-dimethylmorpholine hydrochloride
146.0g of N-benzyl-cis-2, 6-dimethylmorpholine and 1020ml of methanol are placed in a 2000ml pressure cooker, the lid is closed and replaced three times with hydrogen. Starting a stirring and heating system, controlling the temperature to be 65-75 ℃, and hydrogenating for 5hrs under the pressure of 1.5-2.0 MPa until hydrogen is not absorbed basically (GC monitors the reaction end point, and the ratio of cis-trans isomers measured in the reaction liquid is about 92: 2). Cooling to room temperature. And (5) pressure relief. Filtering, washing, mixing the filtrate and washing solution, adding 100g concentrated hydrochloric acid (36%), stirring for 1hr to form salt. Methanol was removed under reduced pressure, 250ml of toluene was added, heated to reflux and azeotropically dehydrated. Then, the toluene is removed under reduced pressure, and the residual liquid is cooled and solidified. 1300ml of acetone was added to the solid, and dissolved by heating. Cooling, cooling to below 5 deg.C, and stirring for 2 hrs. Suction filtration was carried out and washed with 200ml of cold acetone. Drying to obtain 76.6g of solid (white). The yield is about 71 percent. The filtrate and the washing liquid are combined, and acetone is distilled off to about 150ml under normal pressure. Cooling, cooling to below 5 deg.C, and stirring for 2 hrs. And (3) carrying out suction filtration, washing a small amount of acetone to obtain a solid, adding 120ml of acetone into the solid, heating to dissolve the acetone, and cooling to separate out the solid. Cooled to below 5 ℃ and stirred for 2 hrs. Suction filtration, washing with a little acetone, drying to obtain solid 8.3g, yield about 7.7%. 84.9g of cis-2, 6-dimethylmorpholine hydrochloride is obtained in 78.7% yield.
Example 4 preparation of cis-2, 6-dimethylmorpholine
84.9g of cis-2, 6-dimethylmorpholine hydrochloride and 320g of 30% aqueous alkali are added to a 500ml four-necked flask and stirred for 1 hr. Layering, adding 120g 50% liquid alkali into the organic layer, stirring for 1hr, and layering to obtain organic phase. The product was distilled under reduced pressure to give 58.1 g. The cis content was 99.41% and the trans isomer was 0.23% by GC. The yield is about 90 percent.
1HNMR (CDCl3): 1.12 (d, methyl), 3.57 (m, CH), 2.496 (NH); 2.80,2.40 (t, CH)2）。
The separated alkali liquor is combined and distilled under reduced pressure, and the distillate is about 50 g. After drying with alkaline solution, more than 4.0g of 99.0% of product can be recovered, and the yield is about 6%.
Claims (11)
1. A preparation method of cis-2, 6-dimethylmorpholine is characterized by comprising the following steps:
(1) benzylamine and chiral epoxypropane are used as raw materials, and N-benzyl-diisopropanolamine is obtained through condensation;
(2) dehydrating and cyclizing the N-benzyl-diisopropanolamine obtained in the step (1) by using sulfuric acid to obtain N-benzyl-cis-2, 6-dimethylmorpholine;
(3) carrying out hydrogenation debenzylation on the product obtained in the step (2) to obtain cis-2, 6-dimethyl morpholine, and specifically carrying out debenzylation by a catalytic method, wherein the catalyst is palladium-carbon; the weight ratio of the substrate to the catalyst is 1-10%; the reaction solvent is fatty alcohol; the hydrogenation pressure is 1.0-4.5 MPa; the reaction temperature is between room temperature and 100 ℃; the reaction time is 1-18 hours.
2. The process according to claim 1, wherein the reaction mixture comprises: in the step (1), the chiral epoxypropane is in an R configuration or an S configuration; the molar ratio of benzylamine to chiral epoxypropane is 1: 1.8-2.5; the reaction is carried out in a polar solvent, the reaction temperature is between room temperature and 100 ℃, and the reaction time is 1-18 hours.
3. The process according to claim 2, wherein: the molar ratio of benzylamine to chiral epoxypropane is 1: 2.0-2.4; the reaction temperature is 40-80 ℃, and the reaction time is 4-10 hours.
4. The process according to claim 3, wherein the reaction mixture comprises: the molar ratio of benzylamine to chiral epoxypropane is 1: 2.3-2.4; the reaction temperature is 60-80 ℃, and the reaction time is 6-8 hours.
5. The process according to claim 2, wherein: the polar solvent is DMF, DMSO or aliphatic alcohol.
6. The process according to claim 5, wherein the reaction mixture comprises: the aliphatic alcohol is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or tert-butanol.
7. The process according to claim 1, wherein the reaction mixture comprises: in the step (2), heating, dehydrating and cyclizing chiral N-benzyl-diisopropanolamine in the presence of concentrated sulfuric acid, wherein the molar ratio of the chiral N-benzyl-diisopropanolamine to the concentrated sulfuric acid is 1: 1-5; the reaction temperature is controlled between room temperature and 230 ℃; the reaction time is 1-18 hours.
8. The process according to claim 7, wherein the reaction mixture comprises: the molar ratio of the chiral N-benzyl-diisopropanolamine to the concentrated sulfuric acid is 1: 1.5-2.5, the reaction temperature is 40-180 ℃, and the reaction time is 3-10 hours.
9. The process according to claim 8, wherein the reaction mixture comprises: the molar ratio of the chiral N-benzyl-diisopropanolamine to the concentrated sulfuric acid is 1: 1.8-2.0, the reaction temperature is 60-130 ℃, and the reaction time is 5-8 hours.
10. The process according to claim 1, wherein the reaction mixture comprises: the catalyst is 5-10% of palladium-carbon; the weight ratio of the substrate to the catalyst is 3-8%; the aliphatic alcohol is methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert-butanol; the hydrogenation pressure is 1.2-3.0 MPa; the reaction temperature is 40-80 ℃; the reaction time is 4-10 hours.
11. The process according to claim 10, wherein the reaction mixture comprises: the catalyst is 5% palladium-carbon; the weight ratio of the substrate to the catalyst is 4-5%; the aliphatic alcohol is methanol, ethanol or isopropanol; the hydrogenation pressure is 1.5-2.0 MPa; the reaction temperature is 60-80 ℃; the reaction time is 5-7 hours.
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