CN104974153B - The synthetic method of 7 [1 (alkoxy carbonyl group) alkyl] 5 oxo, 1,2,3,5 indolizine, 8 carboxylic acid ester compound - Google Patents
The synthetic method of 7 [1 (alkoxy carbonyl group) alkyl] 5 oxo, 1,2,3,5 indolizine, 8 carboxylic acid ester compound Download PDFInfo
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- CN104974153B CN104974153B CN201510322414.0A CN201510322414A CN104974153B CN 104974153 B CN104974153 B CN 104974153B CN 201510322414 A CN201510322414 A CN 201510322414A CN 104974153 B CN104974153 B CN 104974153B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to organic chemistry filed, and in particular to a kind of synthetic method of 7 [1 (alkoxy carbonyl) alkyl] 51,2,3,5 indolizine of oxo, 8 carboxylic acid ester compound.The method be 7 alkoxycarbonylmethyl, 5 oxo, 1,2,3,5 indolizine, 8 carboxylic acid ester compound (II) withCAlkylating reagent adds phase transfer catalyst in the presence of an inorganic base or is not added with phase transfer catalyst and carries outCAlkylated reaction is obtained 7 [1 (alkoxy carbonyl) alkyl] 5 oxo, 1,2,3,5 indolizine, 8 carboxylic acid ester compound (I).These compounds can be used to synthesize camptothecin antitumor crude drug.Mild condition of the present invention, easy to operate, environmental friendliness, to production equipment without particular/special requirement, are suitable for extensive preparation.
Description
Technical field
The invention belongs to technical field of organic chemistry, and in particular to a kind of 7- [1- (alkoxy carbonyl group)-alkyl] -5- oxos -
The synthetic method of 1,2,3,5- indolizine -8- carboxylic acid ester compounds.
Background technology
7- [1- (alkoxy carbonyl)-alkyl] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid ester compounds
(I) it is Enantioselective total synthesis camptothecin antitumor crude drug such as irinotecan (Irinotecan), topotecan
(Topotecan), Belotecan (Belotecan), 10-hydroxycamptothecine (10-Hydroxycamptothecin) and its class
Like the important intermediate of thing.
United States Patent (USP) US5391745 is described with alkyl iodide as alkylating reagent, by 7- alkoxycarbonylmethyl -5-
Oxo -1,2,3,5- indolizines -8- carboxylic acid ester compounds (II) is carried out in organic solvent in the presence of organic baseC- alkylated reaction prepares 7- [1- (alkoxy carbonyl group)-alkyl] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid esters
The process of compound (I), but the alkylating reagent alkyl iodide used by the technique, it is expensive, and toxicity is larger, opposite
Produce labor protection infringement greatly, environmental pollution is extremely serious.A certain amount of pair of alkane is formed easily especially with the alkylating reagent
Base by-product, and the by-product cannot be effectively separated purification with required product, so that causing camptothecin raw material
Medicine is unable to reach drug quality requirement.
The content of the invention
It is an object of the invention to overcome the deficiencies in the prior art, there is provided a kind of solvent-free 7- [1- (alkane of high selectivity
Epoxide carbonyl)-alkyl] -5- oxos -1,2,3,5- indolizines -8- carboxylic acid ester compounds (I) synthetic method.
The synthetic method of compound (I) proposed by the present invention, is by 7- alkoxycarbonylmethyl -5- oxo -1 2,3,
5- indolizines -8- carboxylic acid ester compounds (II) withC- alkylating reagent add in inorganic base phase transfer catalyst or
Person is not added with phase transfer catalyst and carries out ethylation reaction, obtains final product 7- [1- (alkoxy carbonyl group)-alkyl] -5- oxos -1,2,3,5- four
Hydrogen indolizine -8- carboxylic acid ester compounds (I).Product purity is more than 99%, and the presence without any pair of ethylization by-product is sufficient
So that the complete synthesis camptothecin crude drug quality of chemistry meets all standard.Its synthetic route is as follows：
R in formula1, R2For same or different C1-5Straight or branched alkyl, C1-5Alkoxy methyl, C3-5Cycloalkyl
Methyl, benzyl or substituted benzyl, C1-5Alkylthiomethyl.
Concrete preparation condition is as follows：
(1) usedC- alkylating reagent is the alkyl carbonate esters (A) that are shown below:
R in formula2For C1-5Straight or branched alkyl, C1-5Alkoxy methyl, C3-5Methyl cycloalkyl, benzyl replace benzyl
Base, C1-5Alkylthiomethyl；
(2) inorganic base for being used is anhydrous alkali metal carbonate, one kind of anhydrous heavy carbonate；
(3) phase transfer catalyst for being used is be shown below quaternary ammonium salt (B) or polyethylene glycols (C)：
R in formula3, R4,R6For C1-12Identical alkyl or different alkyl, R5For C1-8Alcoxyl or benzyl：Y is Cl, Br；
(C): HO(CH2CH2O)nH, mean molecule quantity 400-1500；
(4) compound (II),CThe mol ratio of-alkylating reagent and inorganic base is 1:（1~30）:（0.1~5）；
(5) compound (II) and the weight ratio of phase transfer catalyst are 1:（0.01-0.1）；
(6) reaction temperature is 140 ~ 250 DEG C, and the response time is 1 ~ 24h.
In the present invention, compound (II),CThe mol ratio of-alkylating reagent and inorganic base is 1: (1~30): (0.1~
5) arbitrary proportion reaction can be smoothed out.Compound (II) is 1 with the weight ratio of phase transfer catalyst:(0.01-0.1) appoint
Meaning ratio, you can makeCCompleting for-alkylated reaction high selectivity, does not have the formation of any pair of alkyl by-product.Inorganic base can be with
It is anhydrous alkali metal carbonate, such as any one such as Anhydrous potassium carbonate, natrium carbonicum calcinatum, Carbon Dioxide caesium, or it is anhydrous heavy
Carbonate, such as potassium bicarbonate, sodium bicarbonate etc. any one, can promote the reaction to be smoothed out, and these inorganic bases are originated
Extensively, it is cheap and easy to get.Phase transfer catalyst is quaternary ammonium salt such as triethyl group Hydroxyethyl Ammonium Chloride, triethyl ammonium chloride, tetrabutyl phosphonium bromide
Ammonium etc. and different molecular weight Polyethylene Glycol are to thisC- alkylated reaction is effective catalyst.Reaction temperature control 140 ~
250 DEG C of scopes, suitable response time are 1 ~ 24 hour；
The present invention'sC- alkylated reaction optimum condition is：The inorganic base for being used is Anhydrous potassium carbonate；Compound
(II)、CThe mol ratio of-alkylating reagent and inorganic base is 1:（1~10）:（0.5~2）；Compound (II) and phase transfer catalysis
The weight ratio of agent is 1:（0.03-0.06）；Reaction temperature is 160 ~ 180 DEG C, and the response time is 8 ~ 10 h；
Present invention process reaction condition is gentle, easy to operate, environmental friendliness, it is with low cost, produce good quality and to production set
For without particular/special requirement, with industrial production value.
Specific embodiment
The present invention, but not limited to this are specifically described further below by embodiment.
Embodiment 1：7- [1- (methoxycarbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylate methyl esters
(I) preparation
By 7- Methoxycarbonylmethyl -5- oxo -1,2,3,5- indolizines -8- carboxylate methyl esters (II) (26.5 g,
0.1 mol), diethyl carbonate (177g, 1.5 mol) and Anhydrous potassium carbonate (2.76 g, 0.02 mol) are placed in pressure anti-
In answering device, stir 16 hours at 140 DEG C, reaction is finished, and is cooled to room temperature, filter, it is after the excessive diethyl carbonate of recovered under reduced pressure, cold
But to room temperature, solid is separated out, with re-crystallizing in ethyl acetate, activated carbon decolorizing, 23.4 g of off-white powder (I), yield is obtained
80%, chemical purity 99.1% (HPLC).
Embodiment 2：7- [1- (methoxycarbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylate methyl esters
(I) preparation
By 7- Methoxycarbonylmethyl -5- oxo -1,2,3,5- indolizines -8- carboxylate methyl esters (II) (26.5 g,
0.1 mol), diethyl carbonate (70.8 g, 0.6 mol), Anhydrous potassium carbonate (20.7 g, 0.15 mol) and Polyethylene Glycol-
600 (1.3 g) are placed in voltage-resistant reactor, are stirred 9 hours at 170 DEG C, and reaction is finished, and is cooled to room temperature, are filtered, recovered under reduced pressure
After excessive diethyl carbonate, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white color powder
End (I) 26.9g, yield 92%, chemical purity 99.8% (HPLC).
Embodiment 3：7- [1- (methoxycarbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylate methyl esters
(I) preparation
By 7- Methoxycarbonylmethyl -5- oxo -1,2,3,5- indolizines -8- carboxylate methyl esters (II) (26.5 g,
0.1 mol), diethyl carbonate (153.4 g, 1.3 mol), natrium carbonicum calcinatum (2.1 g, 0.02 mol) and Polyethylene Glycol-
800 (1.3 g) are placed in voltage-resistant reactor, are stirred 17 hours at 160 DEG C, and reaction is finished, and is cooled to room temperature, are filtered, are reduced pressure back
After receiving excessive diethyl carbonate, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white color
26.1 g of powder (I), yield 89%, chemical purity 99.3% (HPLC).
Embodiment 4：7- [1- (ethoxy carbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid, ethyl esters
(I) preparation
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3 g,
0.1 mol), diethyl carbonate (153.4g, 1.3 mol), Anhydrous potassium carbonate (2.76 g, 0.02mol) and Polyethylene Glycol-
600 (1.5 g) are placed in voltage-resistant reactor, are stirred 14 hours at 150 DEG C, and reaction is finished, and is cooled to room temperature, are filtered, are reduced pressure back
After receiving excessive diethyl carbonate, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white color
Powder (I) 28.2g, yield 88%, chemical purity 99.5% (HPLC).
Embodiment 5：7- [1- (ethoxy carbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid, ethyl esters
(I) preparation
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3g,
0.1 mol), diethyl carbonate (177 g, 1.5 mol), Anhydrous potassium carbonate (2.76 g, 0.02 mol) and triethyl group chlorination
Benzyl ammonium (1.5 g) is placed in voltage-resistant reactor, is stirred 16 hours at 140 DEG C, and reaction is finished, and is cooled to room temperature, is filtered, is reduced pressure back
After receiving excessive diethyl carbonate, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white color
26.3 g of powder (I), yield 82%, chemical purity 99.3% (HPLC).
Embodiment 6：7- [1- (ethoxy carbonyl)-propyl group] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid, ethyl esters
(I) preparation
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3 g,
0.1 mol), diethyl carbonate (70.8 g, 0.6 mol), Anhydrous potassium carbonate (20.7 g, 0.15 mol) and Polyethylene Glycol-
600 (1.5 g) are placed in voltage-resistant reactor, are stirred 9 hours at 175 DEG C, and reaction is finished, and is cooled to room temperature, are filtered, recovered under reduced pressure
After excessive diethyl carbonate, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white color powder
End (I) 29.9 g, yield 93%, chemical purity 99.9% (HPLC).
Embodiment 7：7- [1- (ethoxy carbonyl)-benzyl ethyl] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid second
The preparation of ester
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3g,
0.1 mol), dimethyl benzyl (290.4 g, 1.2 mol), Anhydrous potassium carbonate (4.14 g, 0.03 mol) and poly- second two
Alcohol -600 (1.5 g) is placed in voltage-resistant reactor, is stirred 15 hours at 150 DEG C, and reaction is finished, and is cooled to room temperature, is filtered, decompression
After reclaiming excessive dimethyl benzyl, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain class white
30.3 g of color powder (I), yield 78%, chemical purity 99.5% (HPLC).
Embodiment 8：7- [1- (ethoxy carbonyl)-benzyl ethyl] -5- oxo -1,2,3,5- indolizine -8- carboxylic acid second
The preparation of ester
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3g,
0.1 mol), dimethyl benzyl (145.2 g, 0.6 mol), Anhydrous potassium carbonate (20.7 g, 0.15 mol) and triethyl group chlorine
Change benzyl ammonium (1.5 g) to be placed in voltage-resistant reactor, stir 10 hours at 180 DEG C, reaction is finished, and is cooled to room temperature, filter, decompression
After reclaiming excessive dimethyl benzyl, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain class white
34.5 g of color powder (I), yield 90%, chemical purity 99.6% (HPLC).
Embodiment 9：7- [1- (ethoxy carbonyl)-methylmercaptoethyl] -5- oxo -1,2,3,5- indolizine -8- carboxylics
The preparation of acetoacetic ester (I)
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3 g,
0.1 mol), carbonic acid dimethyl sulfide methyl ester (109.2 g, 0.6 mol), Anhydrous potassium carbonate (20.7 g, 0.15 mol) and poly- second
Glycol -600 (1.3 g) is placed in voltage-resistant reactor, is stirred 10 hours at 180 DEG C, and reaction is finished, and is cooled to room temperature, is filtered, is subtracted
Push back after receiving excessive carbonic acid dimethyl sulfide methyl ester, be cooled to room temperature, separate out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing,
Obtain 31.7 g of off-white powder (I), yield 90%, chemical purity 99.8% (HPLC).
Embodiment 10：7- [1- (ethoxy carbonyl)-methylmercaptoethyl] -5- oxo -1,2,3,5- indolizine -8- carboxylics
The preparation of acetoacetic ester (I)
By 7- ethoxy carbonyl methyl -5- oxo -1,2,3,5- indolizines -8- carboxylic acid, ethyl esters (II) (29.3g,
0.1 mol), carbonic acid dimethyl sulfide methyl ester (218.4 g, 1.2 mol), Anhydrous potassium carbonate (20.7 g, 0.15mol) are placed in resistance to
In pressure reactor, stir 10 hours at 180 DEG C, reaction is finished, and is cooled to room temperature, filter, the excessive carbonic acid dimethyl sulfide of recovered under reduced pressure
After methyl ester, room temperature is cooled to, separates out solid, with re-crystallizing in ethyl acetate, activated carbon decolorizing, obtain off-white powder (I) 30.4
G, yield 86%, chemical purity 99.6% (HPLC).
Claims (4)
1. a kind of preparation method of compound (I),
In formula, R1, R2For same or different C1-5Straight or branched alkyl, C1-5Alkoxy methyl, C3-5Cycloalkyl first
Base, benzyl or substituted benzyl, C1-5Alkylthiomethyl；It is characterized in that：
7- alkoxycarbonylmethyls -5- oxos -1,2,3,5- indolizines -8- carboxylic acid ester compounds (II) withC- alkyl
Change reagent and add phase transfer catalyst in the presence of an inorganic base, carry outC- alkylated reaction, is obtained compound (I)；
In formula, R1For C1-5Straight or branched alkyl, C1-5Alkoxy methyl, C3-5Methyl cycloalkyl, benzyl or substituted benzyl,
C1-5Alkylthiomethyl；
Concrete preparation condition is as follows：
（1）UsedC- alkylating reagent is the alkyl carbonate esters (A) that are shown below:
In formula, R2For C1-5Straight or branched alkyl, C1-5Alkoxy methyl, C3-5Methyl cycloalkyl, benzyl or substituted benzyl,
C1-5Alkylthiomethyl；
（2）The inorganic base for being used is anhydrous alkali metal carbonate, one kind of anhydrous heavy carbonate；
（3）The phase transfer catalyst for being used is be shown below quaternary ammonium salt (B) or polyethylene glycols (C)：
In formula, R3, R4,R6For C1-12Identical alkyl or different alkyl, R5For C1-8Alcoxyl or benzyl：Y is Cl, Br；
(C): HO(CH2CH2O)nH, mean molecule quantity 400-1500；
（4）Compound (II),CThe mol ratio of-alkylating reagent and inorganic base is 1:（1~10）:（0.5~2）；
（5）Compound (II) is 1 with the weight ratio of phase transfer catalyst: 0.01-0.1；
（6）Reaction temperature is 160 ~ 180 DEG C, and the response time is 8 ~ 10h.
2. preparation method as claimed in claim 1, it is characterised in that：The inorganic base for being used is Anhydrous potassium carbonate.
3. preparation method as claimed in claim 1, it is characterised in that：The phase transfer catalyst for being used is Polyethylene Glycol, point
Son amount is 600.
4. preparation method as claimed in claim 1, it is characterised in that：The weight ratio of compound (II) and phase transfer catalyst
For 1:（ 0.03-0.06）.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69210323T3 (en) * | 1991-07-31 | 1999-06-02 | Tessenderlo Chem Nv | Process for the alpha monoalkyation of arylacetonitriles, arylacetooesters and arylacetic acids |
| US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
| CN101007807A (en) * | 2007-01-10 | 2007-08-01 | 复旦大学 | 6-cyano-1,1(1,3-subpropyldioxy)-7-[1'-(carbalkoxy)-propyl]-5-oxo-delta6(8)-tetrahydro indolizine compound preparation method |
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