CN102180821A - Tamiflu intermediate and synthesis method thereof - Google Patents
Tamiflu intermediate and synthesis method thereof Download PDFInfo
- Publication number
- CN102180821A CN102180821A CN2011100572539A CN201110057253A CN102180821A CN 102180821 A CN102180821 A CN 102180821A CN 2011100572539 A CN2011100572539 A CN 2011100572539A CN 201110057253 A CN201110057253 A CN 201110057253A CN 102180821 A CN102180821 A CN 102180821A
- Authority
- CN
- China
- Prior art keywords
- reaction
- tamiflu
- molar ratio
- catalyzer
- ethyl propenoate
- 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.)
- Pending
Links
Images
Abstract
The invention relates to a Tamiflu intermediate and a synthesis method thereof, solving the technical problems of effectively reducing the production cost of the Tamiflu intermediate and effectively improving the yield of the Tamiflu intermediate and the content of the Tamiflu intermediate in a product. The method comprises the following steps: 1) catalytic reaction: in an organic solvent, reacting 3-pentyloxy acetaldehyde (1) and 3-nitro ethyl acrylate (2) in a molar ratio of 2: (1-2) in the presence of salt which is prepared by premixing (R)-N,N-dimethlbenzylamine prolinol silicon ether (3) with Bronzed acid in a molar ratio of 1: (1-8), so as to obtain an addition product (4); 2) carrying out reaction on the addition product (4) and 2-(diethoxy, phosphoryl) ethyl acrylate (5) in a molar ratio of 1: (1-2) and carrying out a reaction on cesium carbonate and the 2-(diethoxy, phosphoryl) ethyl acrylate (5) in a molar ratio of 2:1, so as to produce a produce (6); and 3) carrying out michael addition on the product (6) and p-methylthiophenol in a molar ratio of 1: (2-10), so as to obtain cyclohexane derivative, namely Tamiflu intermediate.
Description
Technical field
The invention belongs to chemosynthesis, high-activity biological pharmaceutical intermediate study on the synthesis technical field.Specifically be a kind of Tamiflu intermediate and synthetic method thereof.
Background technology
The H5N1 influenza virus wreaked havoc the whole world in 2009, nowadays the hidden danger of this viroid still exists, Oseltamivir phosphoric acid salt (Tamiflu) can be treated A type and Type B human influenza effectively as a kind of neuraminidase inhibitor, and many countries all plan this medicine of mass production in case the influenza great outburst.Developing this type of specifics and intermediate thereof becomes the research focus in the whole world.
People such as Hayashi (Angew.Chem.Int.Ed., 2009,48,1-5) reported the method for utilization (R)-hexichol dried meat ammonia alcohol silicon ether (8) catalysis tamiflu synthesis intermediate (12) in 2009:
Intermediate (12) passes through deprotection again; the acid azid nitrogenize; simple reactions such as rearrangement and Michael obtain the finished product Tamiflu; this building-up process step is simple; intermediate productive rate height is a kind of ideal Tamiflu intermediate synthetic method, but catalyzer (8) price height; and can not recycle, become the major obstacle of its low-cost industrialization utilization.If can find a kind of callable effective catalyst will make whole synthetic route more economically.
Solid phase, ionic liquid, fluorine-containing reagent etc. often are used as the carrier of organic catalyst, thereby catalyzer is recycled, but these methods but make original activity of such catalysts and stereoselectivity reduce greatly, (J.Am.Chem.Soc. such as Bukuo Ni, 2010,132,50-51) reported (R)-N in 2010, behind N-dimethyl benzylamine dried meat ammonia alcohol silicon ether and the bronsted sour salify, at catalysis aldehyde during to the Michael reaction of nitroolefin, the high reaction activity that plays, stereoselectivity (〉 99%ee) and the effect of recyclable utilization, this catalyzed reaction can be applied in fragrance or the Michael reaction of aliphatic nitroolefin to aldehyde, can recycle more than six times behind catalyzer and the bronsted sour salify, and do not reduce catalytic activity, and stereoselectivity, thereby can be used in large scale experiment research and the suitability for industrialized production.
Summary of the invention
The order technical issues that need to address of the present invention are, effectively reduce Tamiflu intermediate production cost, effectively improve the productive rate of Tamiflu intermediate and the content in the product.And provide new synthetic method for the similar reaction in the other medicines intermediate.
Tamiflu intermediate of the present invention has following structural formula:
The synthetic method of Tamiflu intermediate of the present invention, its synthetic line is as follows:
As follows:
1) catalyzed reaction: catalyzer (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) stirs salify in 1:1～8 in molar ratio in advance with bronsted acid earlier; Described bronsted acid is selected from Mono Chloro Acetic Acid or o-Carboxynitrobenzene;
In organic solvent, 3-pentyloxy acetaldehyde (1) and 3-nitro ethyl propenoate (2) in molar ratio 2:1～2 under the catalysis of the salt that catalyzer stirs in advance, reaction times 30min ~ 48h, 0 ℃ ~ 25 ℃ of temperature, obtain adduct (4), removal of solvent under reduced pressure, the n-hexane dissolution after-filtration, filtrate is directly used in down step 2) reaction; The consumption of the salt that described catalyzer stirs in advance makes catalyzer (R)-N, and N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) consumption is 1～10mol% of 3-nitro ethyl propenoate (2) consumption;
Described organic solvent is selected from methylene dichloride, chloroform, acetonitrile, toluene, N, dinethylformamide, dimethyl sulfoxide (DMSO);
2) Michael addition and Huo Naer-Wordsworth-Ai Mengsi reaction: adduct (4) and 2-(diethoxy, phosphoryl) ethyl propenoate (5) 1:1～2 in molar ratio, and cesium carbonate and 2-(diethoxy, phosphoryl) ethyl propenoate (5) 2:1 reaction in molar ratio, reaction times 1～5h, temperature-5 ℃～25 ℃, the back adds excess ethyl alcohol down with the generation that prevents side reaction and stir 10～30min and generate product (6) in 0 ℃～25 ℃;
3) Michael reaction: with product (6) with to methylbenzene thiophenol 1:2～10 Michael additions in molar ratio, reaction times 24h～48h, after the temperature-20 ℃ ~ 0 ℃, with 1N～4N hydrochloric acid cancellation, obtaining cyclohexane derivant is the Tamiflu intermediate.
Catalyzer of the present invention can also reclaim,
4) reclaim reaction: the solid matter of the filtration gained in the step 1) is added bronsted acid (the mol ratio 1:1 of two materials～8) again, and all the other steps are with 1), 2), 3).
The present invention selects for use cheap raw material 3-nitro ethyl propenoate (2) as the 3-nitro propylene butyl carboxylate (9) in the alternative former document of reactant; catalyzer (3) stirs earlier the Michael reaction of catalysis 3-pentyloxy acetaldehyde (1) and 3-nitro ethyl propenoate (2) behind the salify in advance with bronsted acid; obtain the adduct (4) of high yield and highly-solid selectively; product (4) and 2-(diethoxy, phosphoryl) ethyl propenoate (5) passes through Michael addition and intramolecular nail (unit of length)-Wordsworth suddenly-Ai Mengsi reaction generates product (6).Dibasic acid esters (6) is the mixture of diastereomer, with mixture (6) and the cyclohexene derivative that is configured as (5S)-7 that methylbenzene thiophenol Michael addition is obtained high yield.
Intermediate (12) structural similitude in intermediate (7) that generates and the document in the report can pass through deprotection equally, the acid azid nitrogenize, and simple reactions such as rearrangement and Michael obtain the finished product Tamiflu.The present invention has contrasted two kinds of catalyzer (3) respectively, and (8) catalytic effect in reaction system is found that catalyzer (3) reactive behavior and stereoselectivity all are better than the catalyzer (8) in the former report, and can be recycled.Below be to use the not comparative example of catalyzer of the same race, concrete synthetic route is respectively:
Catalyzer of the present invention can repeat to reclaim, and production cost reduces; The productive rate height (can reach 75%) that also has the Tamiflu intermediate, reaction has good stereoselectivity, target compound content height advantages such as (can reach 94%).
Description of drawings
Fig. 1 is the hydrogen spectrum nuclear-magnetism figure of Tamiflu intermediate of the present invention (7).
Fig. 2 is the carbon spectrum nuclear-magnetism figure of Tamiflu intermediate of the present invention (7).
Fig. 3 is the infrared figure of Tamiflu intermediate of the present invention (7).
Fig. 4 is the mass spectrum of Tamiflu intermediate of the present invention (7).
Embodiment
Embodiment 1: synthetic line sees before and states comparative example 2.
Step 1): 25 ° of C, with o-Carboxynitrobenzene (38.6g, 0.231mol) and (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) (25.4g, 0.058mol) stirred in advance 30 minutes, add 3-pentyloxy acetaldehyde (1) (225g behind the salify, 1.73 mol) with 3-nitro ethyl propenoate (2) (168g, 1.16mol) methylene dichloride (2L) solution in, reactant after stirring 24h under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, solids can be used for catalyzed reaction once more, and filtrate contains product (4) and is directly used in the next step.
Step 2): filtrate adds the 2-(diethoxy under 0 ° of C; phosphoryl) ethyl propenoate (5) (409.2g; 1.73mol) and cesium carbonate (1.13Kg; 3.47mol) and under 0 ° of C, stir 3h; removal of solvent under reduced pressure; ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down.
Step 3): (716.7g 5.78mol) and under-15 ° of C reacts 36h, uses the cancellation of 2N hydrochloric acid again to the methylbenzene thiophenol in-15 ° of C addings.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (418.5g, 94%ee, 75%yield).
1HNMR (400 MHz, CDCl
3) δ 7.38(d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 4.61-4.68 (m, 1H), 4.20-4.28 (m, 1H), 4.06-4.17 (m, 2H), 3.98-4.00 (t, J=7.2Hz, 1H), 3.84-3.90 (m, 1H), 3.77-3.81 (dd, J
1=3.6Hz, J
2=10.8Hz, 1H), 3.38-3.44 (t, J=10.8Hz, 1H), 3.12-3.18 (m, 1H), 2.74-2.79 (dt, J
1=3.2Hz, J
2=13.2Hz, 1H), 2.60-2.65 (dt, J
1=3.6z, J
2=13.6z, 1H), 2.30-2.36 (m, 4H), 1.25-1.30 (m, 6H), 1.16-1.20 (t, J=7.2Hz, 4H), 0.72-0.76 (t, J=7.2Hz, 3H), 0.62-0.65 (t, J=7.2Hz, 3H) (see figure 1);
13CNMR (100MHz, CDCl
3) δ 172.0,170.1,137.7,133.0(2C), 131.4,129.6 (2C), 83.4,80.4,76.8,61.8,61.6,52.8,49.2,43.5,27.0,25.1,23.7,21.2,14.2,9.0,8.5(sees Fig. 2); IR (film) ν
Max2965,2937,2878,1733,1557,1493,1463,1376,1290,1260,1197,1033,953,810 cm
-1(see figure 3); ESI calculated for[C
24H
35NO
7S]: 481.21, found:481.38(sees Fig. 4).
Step 4): in the solid filtering thing of step 1) gained, add o-Carboxynitrobenzene (38.6g again, 0.231mol), (1) (225g, 1.73 mol), (2) (168g, 1.16mol) and methylene dichloride (2L), reactant after stirring 24h under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, (filtrate can be used for catalyzed reaction once more), filtrate under 0 ° of C, add (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg 3.47mol) and under 0 ° of C stirs 3h, removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down, and-15 ° of C add methylbenzene thiophenol (716.7g, 5.78mol) and under-15 ° of C, react 36h, use the cancellation of 2N hydrochloric acid again.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (400g, 94%ee, 72%yield).
Embodiment 2: synthetic line is as follows,
Step 1): 25 ° of C, with Mono Chloro Acetic Acid (21.8g, 0.231mol) and (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) (25.4g, 0.058mol) stir 30min in advance, add 3-pentyloxy acetaldehyde (1) (225g behind the salify, 1.73 mol) with 3-nitro ethyl propenoate (2) (168g, 1.16mol) methylene dichloride (2L) solution in, reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, solids can be used for catalyzed reaction once more, and filtrate contains product (4) and is directly used in the next step.
Step 2): filtrate adds the 2-(diethoxy under 0 ° of C; phosphoryl) ethyl propenoate (5) (409.2g; 1.73mol) and cesium carbonate (1.13Kg; 3.47mol); and under 0 ° of C, stir 3h; removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down.
Step 3): (716.7g 5.78mol) and under-15 ° of C reacts 36h, uses the cancellation of 2N hydrochloric acid again to the methylbenzene thiophenol in-15 ° of C addings.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (418g, 94%ee, 75%yield).
1HNMR (400 MHz, CDCl
3) δ 7.38(d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 4.61-4.68 (m, 1H), 4.20-4.28 (m, 1H), 4.06-4.17 (m, 2H), 3.98-4.00 (t, J=7.2Hz, 1H), 3.84-3.90 (m, 1H), 3.77-3.81 (dd, J
1=3.6Hz, J
2=10.8Hz, 1H), 3.38-3.44 (t, J=10.8Hz, 1H), 3.12-3.18 (m, 1H), 2.74-2.79 (dt, J
1=3.2Hz, J
2=13.2Hz, 1H), 2.60-2.65 (dt, J
1=3.6z, J
2=13.6z, 1H), 2.30-2.36 (m, 4H), 1.25-1.30 (m, 6H), 1.16-1.20 (t, J=7.2Hz, 4H), 0.72-0.76 (t, J=7.2Hz, 3H), 0.62-0.65 (t, J=7.2Hz, 3H) (see figure 1);
13CNMR (100MHz, CDCl
3) δ 172.0,170.1,137.7,133.0(2C), 131.4,129.6 (2C), 83.4,80.4,76.8,61.8,61.6,52.8,49.2,43.5,27.0,25.1,23.7,21.2,14.2,9.0,8.5(sees Fig. 2); IR (film) ν
Max2965,2937,2878,1733,1557,1493,1463,1376,1290,1260,1197,1033,953,810 cm
-1(see figure 3); ESI calculated for[C
24H
35NO
7S]: 481.21, found:481.38(sees Fig. 4).
Step 4): in the solid filtering thing of step 1) gained, add Mono Chloro Acetic Acid (21.8g again, 0.231mol), (1) (225g, 1.73 mol), (2) (168g, 1.16mol) and methylene dichloride (2L), reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, (filtrate can be used for catalyzed reaction once more), filtrate under 0 ° of C, add (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg 3.47mol) and under 0 ° of C stirs 3h, removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down, and-15 ° of C add methylbenzene thiophenol (716.7g, 5.78mol) and under-15 ° of C, react 36h, use the cancellation of 2N hydrochloric acid again.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (407g, 94%ee, 73%yield).
Embodiment 3: synthetic line is as follows,
Step 1): 25 ° of C, with Mono Chloro Acetic Acid (21.8g, 0.231mol) and (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) (35.1g, 0.058mol) stirred in advance 30 minutes, add 3-pentyloxy acetaldehyde (1) (225g behind the salify, 1.73 mol) with 3-nitro ethyl propenoate (2) (168g, 1.16mol) methylene dichloride (2L) solution in, reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, solids can be used for catalyzed reaction once more, and filtrate contains product (4) and is directly used in the next step.
Step 2): filtrate adds the 2-(diethoxy under 0 ° of C; phosphoryl) ethyl propenoate (5) (409.2g; 1.73mol) and cesium carbonate (1.13Kg; 3.47mol) and under 0 ° of C, stir 3h; removal of solvent under reduced pressure; ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down.
Step 3): (716.7g 5.78mol) and under-15 ° of C reacts 36h, uses the cancellation of 2N hydrochloric acid again to the methylbenzene thiophenol in-15 ° of C addings.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (390.6g, 90%ee, 70%yield).
1HNMR (400 MHz, CDCl
3) δ 7.38(d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 4.61-4.68 (m, 1H), 4.20-4.28 (m, 1H), 4.06-4.17 (m, 2H), 3.98-4.00 (t, J=7.2Hz, 1H), 3.84-3.90 (m, 1H), 3.77-3.81 (dd, J
1=3.6Hz, J
2=10.8Hz, 1H), 3.38-3.44 (t, J=10.8Hz, 1H), 3.12-3.18 (m, 1H), 2.74-2.79 (dt, J
1=3.2Hz, J
2=13.2Hz, 1H), 2.60-2.65 (dt, J
1=3.6z, J
2=13.6z, 1H), 2.30-2.36 (m, 4H), 1.25-1.30 (m, 6H), 1.16-1.20 (t, J=7.2Hz, 4H), 0.72-0.76 (t, J=7.2Hz, 3H), 0.62-0.65 (t, J=7.2Hz, 3H) (see figure 1);
13CNMR (100MHz, CDCl
3) δ 172.0,170.1,137.7,133.0(2C), 131.4,129.6 (2C), 83.4,80.4,76.8,61.8,61.6,52.8,49.2,43.5,27.0,25.1,23.7,21.2,14.2,9.0,8.5(sees Fig. 2); IR (film) ν
Max2965,2937,2878,1733,1557,1493,1463,1376,1290,1260,1197,1033,953,810 cm
-1(Fig. 3); ESI calculated for[C
24H
35NO
7S]: 481.21, found:481.38(Fig. 4).
Step 4): in the solid filtering thing of step 1) gained, add Mono Chloro Acetic Acid (21.8g again, 0.231mol), (1) (225g, 1.73 mol), (2) (168g, 1.16mol) and methylene dichloride (2L), reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, (filtrate can be used for catalyzed reaction once more), filtrate under 0 ° of C, add (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg 3.47mol) and under 0 ° of C stirs 3h, removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down, and-15 ° of C add methylbenzene thiophenol (716.7g, 5.78mol) and under-15 ° of C, react 36h, use the cancellation of 2N hydrochloric acid again.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (384.4g, 90%ee, 68.9%yield).
Embodiment 4: synthetic line is as follows,
Step 1): 25 ° of C, with Mono Chloro Acetic Acid (21.8g, 0.231mol) and (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) (27.9g, 0.058mol) stir 30min in advance, add 3-pentyloxy acetaldehyde (1) (225g behind the salify, 1.73 mol) with 3-nitro ethyl propenoate (2) (168g, 1.16mol) methylene dichloride (2L) solution in, reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, solids can be used for catalyzed reaction once more, and filtrate contains product (4) and is directly used in the next step.
Step 2): filtrate adds the 2-(diethoxy under 0 ° of C; phosphoryl) ethyl propenoate (5) (409.2g; 1.73mol) and cesium carbonate (1.13Kg; 3.47mol); and under 0 ° of C, stir 3h; removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down.
Step 3): (716.7g 5.78mol) and under-15 ° of C reacts 36h, uses the cancellation of 2N hydrochloric acid again to the methylbenzene thiophenol in-15 ° of C addings.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (389g, 92%ee, 70%yield).
1HNMR (400 MHz, CDCl
3) δ 7.38(d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 4.61-4.68 (m, 1H), 4.20-4.28 (m, 1H), 4.06-4.17 (m, 2H), 3.98-4.00 (t, J=7.2Hz, 1H), 3.84-3.90 (m, 1H), 3.77-3.81 (dd, J
1=3.6Hz, J
2=10.8Hz, 1H), 3.38-3.44 (t, J=10.8Hz, 1H), 3.12-3.18 (m, 1H), 2.74-2.79 (dt, J
1=3.2Hz, J
2=13.2Hz, 1H), 2.60-2.65 (dt, J
1=3.6z, J
2=13.6z, 1H), 2.30-2.36 (m, 4H), 1.25-1.30 (m, 6H), 1.16-1.20 (t, J=7.2Hz, 4H), 0.72-0.76 (t, J=7.2Hz, 3H), 0.62-0.65 (t, J=7.2Hz, 3H) (see figure 1);
13CNMR (100MHz, CDCl
3) δ 172.0,170.1,137.7,133.0(2C), 131.4,129.6 (2C), 83.4,80.4,76.8,61.8,61.6,52.8,49.2,43.5,27.0,25.1,23.7,21.2,14.2,9.0,8.5(sees Fig. 2); IR (film) ν
Max2965,2937,2878,1733,1557,1493,1463,1376,1290,1260,1197,1033,953,810 cm
-1(see figure 3); ESI calculated for[C
24H
35NO
7S]: 481.21, found:481.38(sees Fig. 4).
Step 4): in the solid filtering thing of step 1) gained, add Mono Chloro Acetic Acid (21.8g again, 0.231mol), (1) (225g, 1.73 mol), (2) (168g, 1.16mol) and methylene dichloride (2L), reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, (filtrate can be used for catalyzed reaction once more), filtrate under 0 ° of C, add (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg 3.47mol) and under 0 ° of C stirs 3h, removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down, and-15 ° of C add methylbenzene thiophenol (716.7g, 5.78mol) and under-15 ° of C, react 36h, use the cancellation of 2N hydrochloric acid again.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (381.6g, 90%ee, 68%yield).
Embodiment 5: synthetic line is as follows,
Step 1): 25 ° of C, with Mono Chloro Acetic Acid (21.8g, 0.231mol) and (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) (27.9g, 0.058mol) stir 30min in advance, add 3-pentyloxy acetaldehyde (1) (225g behind the salify, 1.73 mol) with 3-nitro ethyl propenoate (2) (168g, 1.16mol) methylene dichloride (2L) solution in, reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, solids can be used for catalyzed reaction once more, and filtrate is directly used in the next step.
Step 2): filtrate adds the 2-(diethoxy under 0 ° of C; phosphoryl) ethyl propenoate (5) (409.2g; 1.73mol) and cesium carbonate (1.13Kg; 3.47mol); and under 0 ° of C, stir 3h; removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down.
Step 3): (716.7g 5.78mol) and under-15 ° of C reacts 36h, uses the cancellation of 2N hydrochloric acid again to the methylbenzene thiophenol in-15 ° of C addings.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (390g, 94%ee, 70%yield).
1HNMR (400 MHz, CDCl
3) δ 7.38(d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 4.61-4.68 (m, 1H), 4.20-4.28 (m, 1H), 4.06-4.17 (m, 2H), 3.98-4.00 (t, J=7.2Hz, 1H), 3.84-3.90 (m, 1H), 3.77-3.81 (dd, J
1=3.6Hz, J
2=10.8Hz, 1H), 3.38-3.44 (t, J=10.8Hz, 1H), 3.12-3.18 (m, 1H), 2.74-2.79 (dt, J
1=3.2Hz, J
2=13.2Hz, 1H), 2.60-2.65 (dt, J
1=3.6z, J
2=13.6z, 1H), 2.30-2.36 (m, 4H), 1.25-1.30 (m, 6H), 1.16-1.20 (t, J=7.2Hz, 4H), 0.72-0.76 (t, J=7.2Hz, 3H), 0.62-0.65 (t, J=7.2Hz, 3H) (see figure 1);
13CNMR (100MHz, CDCl
3) δ 172.0,170.1,137.7,133.0(2C), 131.4,129.6 (2C), 83.4,80.4,76.8,61.8,61.6,52.8,49.2,43.5,27.0,25.1,23.7,21.2,14.2,9.0,8.5(sees Fig. 2); IR (film) ν
Max2965,2937,2878,1733,1557,1493,1463,1376,1290,1260,1197,1033,953,810 cm
-1(see figure 3); ESI calculated for[C
24H
35NO
7S]: 481.21, found:481.38(sees Fig. 4).
Step 4): in the solid filtering thing of step 1) gained, add Mono Chloro Acetic Acid (21.8g again, 0.231mol), (1) (225g, 1.73 mol), (2) (168g, 1.16mol) and methylene dichloride (2L), reactant after stirring 40min under 25 ° of C, removal of solvent under reduced pressure, normal hexane (2L) dissolving after-filtration, (filtrate can be used for catalyzed reaction once more), filtrate under 0 ° of C, add (5) (409.2g, 1.73mol) and cesium carbonate (1.13Kg 3.47mol) and under 0 ° of C stirs 3h, removal of solvent under reduced pressure, ethanol (3L) is added in the above crude product, and 25 ° of C stir 15min down, and-15 ° of C add methylbenzene thiophenol (716.7g, 5.78mol) and under-15 ° of C, react 36h, use the cancellation of 2N hydrochloric acid again.Chloroform extraction three times merges organic phase, and saturated sodium bicarbonate is washed, and anhydrous magnesium sulfate drying is spin-dried for.Cross the post gradient elution, (SiO
2, 5% ethyl acetate/normal hexane-10% ethyl acetate/normal hexane), colorless oil (7) (373g, 92%ee, 67%yield).
Claims (2)
1. Tamiflu intermediate is characterized in that having following structural formula:
2. the synthetic method of a Tamiflu intermediate as claimed in claim 1 is characterized in that as follows:
1) catalyzed reaction: catalyzer (R)-N, N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) stirs salify in 1:1～8 in molar ratio in advance with bronsted acid earlier; Described bronsted acid is selected from Mono Chloro Acetic Acid or o-Carboxynitrobenzene;
In organic solvent, 3-pentyloxy acetaldehyde (1) and 3-nitro ethyl propenoate (2) in molar ratio 2:1～2 under the catalysis of the salt that catalyzer stirs in advance, reaction times 30min ~ 48h, 0 ℃ ~ 25 ℃ of temperature, obtain adduct (4), removal of solvent under reduced pressure, the n-hexane dissolution after-filtration, filtrate is directly used in down step 2) reaction; The consumption of the salt that described catalyzer stirs in advance makes catalyzer (R)-N, and N-dimethyl benzylamine dried meat ammonia alcohol silicon ether (3) consumption is 1～10mol% of 3-nitro ethyl propenoate (2) consumption;
Described organic solvent is selected from methylene dichloride, chloroform, acetonitrile, toluene, N, dinethylformamide, dimethyl sulfoxide (DMSO);
2) Michael addition and Huo Naer-Wordsworth-Ai Mengsi reaction: adduct (4) and 2-(diethoxy, phosphoryl) ethyl propenoate (5) 1:1～2 in molar ratio, and cesium carbonate and 2-(diethoxy, phosphoryl) ethyl propenoate (5) 2:1 reaction in molar ratio, reaction times 1～5h, temperature-5 ℃～25 ℃, the back adds excess ethyl alcohol down with the generation that prevents side reaction and stir 10～30min and generate product (6) in 0 ℃～25 ℃;
3) Michael reaction: with product (6) with to methylbenzene thiophenol 1:2～10 Michael additions in molar ratio, reaction times 24h～48h, after the temperature-20 ℃ ~ 0 ℃, with 1N～4N hydrochloric acid cancellation, obtaining cyclohexane derivant is the Tamiflu intermediate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100572539A CN102180821A (en) | 2011-03-10 | 2011-03-10 | Tamiflu intermediate and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100572539A CN102180821A (en) | 2011-03-10 | 2011-03-10 | Tamiflu intermediate and synthesis method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102180821A true CN102180821A (en) | 2011-09-14 |
Family
ID=44567137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100572539A Pending CN102180821A (en) | 2011-03-10 | 2011-03-10 | Tamiflu intermediate and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102180821A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107304171A (en) * | 2017-05-05 | 2017-10-31 | 杭州师范大学 | A kind of synthetic method of Oseltamivir |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009145263A1 (en) * | 2008-05-30 | 2009-12-03 | 学校法人東京理科大学 | Process for producing oseltamivir phosphate and intermediate compound |
| CN101735140A (en) * | 2009-12-23 | 2010-06-16 | 中国科学院上海有机化学研究所 | Chiral amino compound, method for synthesizing same and application of anti-flu medicament tamifiu intermediate thereof |
-
2011
- 2011-03-10 CN CN2011100572539A patent/CN102180821A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009145263A1 (en) * | 2008-05-30 | 2009-12-03 | 学校法人東京理科大学 | Process for producing oseltamivir phosphate and intermediate compound |
| CN101735140A (en) * | 2009-12-23 | 2010-06-16 | 中国科学院上海有机化学研究所 | Chiral amino compound, method for synthesizing same and application of anti-flu medicament tamifiu intermediate thereof |
Non-Patent Citations (2)
| Title |
|---|
| HAYATO ISHIKAWA等: "High-Yielding Synthesis of the Anti-Influenza Neuramidase Inhibitor", 《ANGEW.CHEM.INT.ED.》, vol. 48, no. 1, 31 December 2009 (2009-12-31), pages 1305 - 1307 * |
| ZILONG ZHENG等: "Diarylprolinol Silyl Eher Salts as New,Efficient,Water-Soluable,and Recyclable organocatalysts for the asymmetric Michael addition on water", 《J.AM.CHEM.SOC.》, vol. 132, no. 1, 15 December 2009 (2009-12-15) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107304171A (en) * | 2017-05-05 | 2017-10-31 | 杭州师范大学 | A kind of synthetic method of Oseltamivir |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111732509B (en) | Synthesis method of cyclopropane compound | |
| CN103833570B (en) | Synthesis method of oseltamivir | |
| JP2012106982A (en) | Method of producing ester | |
| CN102276463A (en) | Process for producing ethyl trifluoroacetate | |
| CN103864618A (en) | Synthetic process of 1, 1-cyclopropane dicarboxylic acid dimethyl ester | |
| CN103396330A (en) | Preparation method of N,N-dimethyl glycine ester based on silica gel sulfonic acid serving as catalyst | |
| CN101845006B (en) | Beta-alkyl sulfide substituted vinyl propionate sulfur compound and preparation method thereof | |
| Oe et al. | Addition reaction of 2-phenylbenzoic acid onto unactivated olefins catalyzed by Ru (II)–xantphos catalysis | |
| CN102180821A (en) | Tamiflu intermediate and synthesis method thereof | |
| CN104624231A (en) | Catalyst for synthesizing propylene carbonate and preparation method of catalyst | |
| CN110615811B (en) | Method for preparing chiral sulfinamide monophosphine ligand in large scale | |
| CN105618143A (en) | Seven-member aza-magnesium metal catalyst and preparation method and application thereof | |
| Kiasat et al. | Al (HSO4) 3/silica gel as a novel catalytic system for the ring opening of epoxides with thiocyanate anion under solvent-free conditions | |
| Wen et al. | Perfectly green organocatalysis: quaternary ammonium base triggered cyanosilylation of aldehydes | |
| CN103665036B (en) | Chiral sulfoxide-phosphine compound, preparations and applicatio | |
| CN106365962A (en) | 1,3-dihydroxy-3,7-dimethyl-6-octen-2-one synthesis method | |
| CN111039783A (en) | Method for synthesizing ethyl laurate by taking eutectic solvent based on benzyltrimethylammonium chloride as catalyst | |
| CN1315874C (en) | Process for synthesizing alpha-Schiff base derivatized beta-cyclodextrin | |
| CN115353449B (en) | Bivalent samarium single-electron reducing reagent, preparation method and application thereof | |
| CN104230880A (en) | Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate | |
| CN101830823A (en) | Chemical synthesis method of N-butoxyoxalyl amino acid butyl ester | |
| CN103435535A (en) | Preparation method of R-proline having cyclopropane structure | |
| CN101857627A (en) | Synthesis method for ciclesonide | |
| CN109721491B (en) | Application and method of immobilized ionic liquid in catalytic synthesis of n-butyl carboxylate | |
| CN103242157A (en) | Method for catalytically synthesizing acetyl tributyl citrate (ATBC) by utilizing solid superacid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110914 |