CN107840798A - A kind of preparation method of the oxoheptanoate of 7 chlorine 2 - Google Patents
A kind of preparation method of the oxoheptanoate of 7 chlorine 2 Download PDFInfo
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- CN107840798A CN107840798A CN201610840347.6A CN201610840347A CN107840798A CN 107840798 A CN107840798 A CN 107840798A CN 201610840347 A CN201610840347 A CN 201610840347A CN 107840798 A CN107840798 A CN 107840798A
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- CSUBTPQOZXSPAV-UHFFFAOYSA-N CCCCCCCC(C#N)O Chemical compound CCCCCCCC(C#N)O CSUBTPQOZXSPAV-UHFFFAOYSA-N 0.000 description 1
- GVIQYWPEJQUXLX-UHFFFAOYSA-N O=CCCCCCCl Chemical compound O=CCCCCCCl GVIQYWPEJQUXLX-UHFFFAOYSA-N 0.000 description 1
- BXTNCYYMUQUDBH-UHFFFAOYSA-N OC(CCCCCCl)C(O)=O Chemical compound OC(CCCCCCl)C(O)=O BXTNCYYMUQUDBH-UHFFFAOYSA-N 0.000 description 1
- JNTPTNNCGDAGEJ-UHFFFAOYSA-N OCCCCCCCl Chemical compound OCCCCCCCl JNTPTNNCGDAGEJ-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
The invention discloses a kind of preparation method of the oxoheptanoate of 7 chlorine 2, belong to pharmaceutical chemical synthesis field.Using the chloracetyl chloride of formula (I) compound 6 be initiation material in condensing agent, P2O5In the presence of, nucleophilic substitution occurs with the first nucleopilic reagent, obtains the chloracetyl cyanogen of formula (II) 6；After the chloracetyl cyanogen of formula (II) 6 hydrolyzes under the action of an acid, nucleophilic substitution occurs with the second nucleopilic reagent, obtains the oxoheptanoate of 7 chlorine of target formula (III) compound 2.Methods described need to only be synthesized by two steps and can obtain target product, and methods described condition is easily-controllable, cost is relatively low, post processing is simple, side reaction is few, high income, meets the requirement of industrialized production.
Description
Technical field
The invention belongs to the synthesis of the pharmaceutical chemistry of organic chemistry filed, and in particular to a kind of 7- chloro-2-oxoheptanoates
Preparation method.
Background technology
Statins is the general name of 3-hydroxyl-3-methylglutaryl coenzyme A A (HM G-CoA) reductase inhibitor, from
Since 1987 come out, as maximally effective lipid-regulation medicine, the firsts and seconds prevention of coronary heart disease has clinically been widely used in.
In recent years, some basic and clinic studies are found, statins in addition to traditional lipid-reducing function, its non-effect for reducing fat (including
It is anti-oxidant, improve endothelial function, anti-inflammatory, regulation neuroendocrine, suppress remodeling ventricle etc.) have to the preventing and treating of heart failure
Benefit.7- chloro-2-oxoheptanoates are the important intermediates for synthesizing statins, and its structural formula is：
At present, the synthetic method of 7- chloro-2-oxoheptanoates includes：
1)Banyu Pharmaceutical Co.,Ltd.Patent:EP2065354A1,2009 discloses one kind and prepared
7- chloro-2-oxoheptanoate methods.Using the bromo- 5- chloropentanes of 1- as initiation material, react to obtain target product 7- through 3 steps chloro-
2- oxoheptanoates, the synthetic route yield is higher, but cost is higher, for the synthesis price for simple compounds not
Meet the needs of industrialized production.Its reaction equation is as follows：
2) it also reported in the prior art and carry out grignard reaction as initiation material and magnesium powder by the bromo- 5- chloropentanes of 1-, close
Into 7- chloro-2-oxoheptanoates, some side reactions may be produced in course of reaction, such as chlorine and bromine both ends may all be sent out
Raw grignard reaction, makes impurity caused by reaction more, and purifying is cumbersome, and the solvent selected by synthetic route is entirely tetrahydrochysene furan
Mutter, bad recovery, and costly, based on above-mentioned deficiency, the unsuitable industrialized production requirement of this route.
3)Zhejiang Hisun Pharmaceutical Co.Ltd.Patent:EP2394979A1,2011 is disclosed
One kind prepares 7- chloro-2-oxoheptanoate methods.Using 1- chlorine amylalcohol as initiation material, react to obtain target product 7- through 5 steps
Chloro-2-oxoheptanoate (III), although the synthetic method overcomes the financial cost on the above method, but route is too superfluous
It is long, the characteristics of total recovery is low, the requirement of industrialized production is not met, its chemical equation is as follows：
The content of the invention
In order to overcome drawbacks described above of the prior art, it is chloro- that the present invention proposes 7- shown in a kind of two steps synthesis formula (III)
The method of 2- oxoheptanoates, methods described accessory substance is few, and raw material is cheap and easily-available, and cost is relatively low, and post processing is simple, yield compared with
Height, two-step reaction total recovery can reach 60%-80%, more meet industrialized production requirement.
The preparation method of the 7- chloro-2-oxoheptanoates of the present invention, comprises the following steps：
(a) in the first solvent, formula (I) 6- chloracetyl chlorides are in condensing agent and P2O5In the presence of, and the first nucleopilic reagent hair
Nucleophilic substitution is given birth in hair tonic, obtains formula (II) 6- chloracetyl cyanogen；
(b) in the second solvent, formula (II) 6- chloracetyls cyanogen reacts with acid and the second nucleopilic reagent, obtains formula
(III) compound 7- chloro-2-oxoheptanoates.
In particular：
(a) in the first solvent, condensing agent and P2O5In the presence of, the carbonyl of first nucleopilic reagent attack formula (I) 6- chloracetyl chlorides
Base carbon, nucleophilic substitution occurs, obtains formula (II) 6- chloracetyl cyanogen；
(b) in the second solvent and acid, the cyano group in formula (II) 6- chloracetyl cyanogen hydrolyzes under the action of an acid first
Reaction, intermediate 7- chloro-2-oxo-heptanoic acids are generated, then intermediate 7- chloro-2-oxo-heptanoic acids and the second nucleopilic reagent are in formula
(II) nucleophilic substitution occurs in the carbonyl carbon of 6- chloracetyls cyanogen side chain, obtains formula (III) compound 7- chloro-2-oxo-heptanoic acids
Ethyl ester.
Shown in course of reaction such as route (1)：
Wherein, in step a),
First nucleopilic reagent is Cymag (NaCN), cuprous cyanide (CuCN), is cuprous cyanide more preferably
(CuCN)。CN-As the carbonyl carbon of nucleopilic reagent attack formula (I) 6- chloracetyl chlorides, Cl-Left away as leaving group, nucleophilic occurs
Substitution reaction.
The temperature of the reaction is 80 DEG C -150 DEG C, and more preferably, reaction temperature is 120 DEG C.
The time of the reaction is 2-8 hours, and more preferably, the reaction time is 5 hours.
Described condensing agent is DMAP (DMAP), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkane
Base (PyBOP), (dimethylamino) phosphorus (AOP) of hexafluorophosphoric acid 7- azepine BTA -1- epoxides three or 2- (7- azos benzos three
Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU)；More preferably, it is DMAP.
The P2O5Effect be that dehydration is played in reaction system, if can occur with the presence of water, acyl chlorides in reaction system
Hydrolysis, carboxylic acid corresponding to generation.
First solvent is acetonitrile, 1-Methyl-2-Pyrrolidone, tetrahydronaphthalene, toluene or dimethylbenzene；More preferably, it is
Tetrahydronaphthalene.
Formula (I) the 6- chloracetyl chlorides and the first nucleopilic reagent, P2O5And the mol ratio of condensing agent is 1.0:1.3‐2.0:
0.05‐0.10:0.01‐0.1.More preferably 1.0:1.5:0.07:0.1.
After the completion of the electrophilic substitution reaction, step a ' can also be included)：Solvent under reduced pressure in reaction system is spin-dried for,
Then extracted with a certain amount of ethyl acetate, then washed successively with the sodium bicarbonate solution of saturation, sodium chloride solution, finally with nothing
Aqueous sodium persulfate is dried, and is evaporated, is passed through column chromatography (PE:EA=10：1) purified, obtain formula (II) compound (6- chloracetyls
Cyanogen).
Wherein, in step b),
The acid is the concentrated sulfuric acid, concentrated hydrochloric acid, is the concentrated sulfuric acid more preferably.
Second nucleopilic reagent is ethanol, chloroacetic chloride.More preferably, it is ethanol.Because ethanol can both make solvent, reaction
Gently, small toxicity, industrialized production control well.Chloroacetic chloride excitant is larger.
Second solvent is absolute ethyl alcohol.
The temperature of the reaction is 80 DEG C~100 DEG C, is 90 DEG C more preferably.
The time of the reaction is 3-5 hours, is 3.5 hours more preferably.
Formula (II) the 6- chloracetyls cyanogen is 1.0 with the mol ratio of acid and the second nucleopilic reagent:0.5-1.0:1.1-1.5
More preferably, it is 1.0:0.5:1.3.
In the present invention, it is preferable that in step b), after the completion of described nucleophilic substitution, step b ' can also be included)：
A certain amount of ethyl acetate extraction is added, successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate
Dry, be evaporated, by column chromatography (PE:EA=1:40-1:30) purification obtains formula (III) compound 7- chloro-2-oxo-heptanoic acid second
Ester.
Raw material formula (I) compound used in the present invention is easily prepared reagent (Phosphorus, Sulfur and
Silicon and Related Elements,1999,vol.149,p.137–14)
The present invention reaction mechanism be：
Step (a)
CN- attack carbonyl carbons are formed, and the pair of electrons on carbon transmits oxygen supply and forms negative oxygen ion, and then a pair on oxygen are lonely
Electronics is given and forms C=O bond, chlorion is left away as leaving group, obtains formula (II) 6- chloracetyl cyanogen.
Step (b)
First, a pair of lone pair electrons on oxygen form a positive oxygen ion with hydrogen ion, then ethanol attack carbonyl carbon, hair
Raw Hydrogen Proton transfer, sloughs a molecular water, then sloughs a Hydrogen Proton, obtain formula (III) compound 7- chloro-2-oxo-heptanoic acids
Ethyl ester.
The beneficial effects of the present invention are, the present invention using formula (I) compound be initiation material in the presence of condensing agent
Target compounds of formula (III) 7- chloro-2-oxoheptanoates are obtained through nucleophilic substitution twice.The inventive method synthetic route
Briefly, cost is relatively low, and condition is easily-controllable, and post processing is simple, and accessory substance is few, and purity is higher, and yield is higher, can reach 60%-80%,
The feasibility of the route is stronger, is easy to industrialized production.
Embodiment
With reference to specific examples below, the present invention is described in further detail.Implement the present invention process, condition,
Experimental method etc., it is the universal knowledege and common knowledge of this area in addition to the following content specially referred to, the present invention does not have
Especially limitation content.
Embodiment 1
The preparation of 1.1 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
30mg phosphorus pentoxide, 36mg DMAP；Then after being gradually heating to 120 DEG C of reaction 5 hours.TLC detection raw materials are complete
After disappearance, stopping reaction, first oil pump decompression steams tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then successively with saturation
Sodium bicarbonate solution, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, are evaporated, pass through column chromatography (PE：EA=10：1)
Purified, obtain product 0.37g yields as 79%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.2 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL 1-Methyl-2-Pyrrolidone, the cyaniding for sequentially adding 0.4g is sub-
Copper, 30mg phosphorus pentoxide, 36mg DMAP；Then after being gradually heating to 120 DEG C of reaction 5 hours.TLC detection raw materials are complete
After totally disappeared mistake, stop reaction, first oil pump decompression steams tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then use saturation successively
Sodium bicarbonate solution, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, be evaporated, pass through column chromatography (PE：EA=10：
1) purified, obtain product 0.35g.Yield is 74.7%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.3 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
36mg DMAP；Then after being gradually heating to 120 DEG C of reaction 5 hours.After TLC detection raw materials are wholly absent, stop reaction, first
Oil pump decompression steams tetrahydronaphthalene, is then extracted with 20mL ethyl acetate, then uses sodium bicarbonate solution, the sodium chloride of saturation successively
Solution washs, and finally with anhydrous sodium sulfate drying, is evaporated, passes through column chromatography (PE：EA=10：1) purified, obtain product
0.31g, yield 65%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.4 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
30mg phosphorus pentoxide；Then after being gradually heating to 120 DEG C of reaction 5 hours.After TLC detection raw materials are wholly absent, stop
Reaction, first oil pump decompression steam tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then molten with the sodium acid carbonate of saturation successively
Liquid, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, are evaporated, pass through column chromatography (PE：EA=10：1) purified,
Obtain product 0.29g, yield 62%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.5 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
30mg phosphorus pentoxide, 36mg DMAP；Then after being gradually heating to 150 DEG C of reaction 5 hours.TLC detection raw materials are complete
After disappearance, stopping reaction, first oil pump decompression steams tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then successively with saturation
Sodium bicarbonate solution, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, are evaporated, pass through column chromatography (PE：EA=10：1)
Purified, obtain product 0.36g, yield 76.9%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.6 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
30mg phosphorus pentoxide, 36mg DMAP；Then after being gradually heating to 80 DEG C of reaction 5 hours.TLC detection raw materials disappear completely
After mistake, stop reaction, first oil pump decompression steams tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then use the carbon of saturation successively
Sour hydrogen sodium solution, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, are evaporated, pass through column chromatography (PE：EA=10：1) enter
Row purification, obtains product 0.32, yield 68%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
The preparation of 1.7 compound 6- chloracetyl cyanogen
0.5g 6- chloracetyl chlorides are dissolved in 5mL anhydrous tetrahydronaphthalene, sequentially add 0.4g cuprous cyanide,
30mg phosphorus pentoxide, 36mg DMAP；Then after being gradually heating to 120 DEG C of reaction 8 hours.TLC detection raw materials are complete
After disappearance, stopping reaction, first oil pump decompression steams tetrahydronaphthalene, then extracted with 20mL ethyl acetate, then successively with saturation
Sodium bicarbonate solution, sodium chloride solution washing, finally with anhydrous sodium sulfate drying, are evaporated, pass through column chromatography (PE：EA=10：1)
Purified, obtain product 0.35g, yield 74.7%.
1H-NMR(CDCl3, 400M) and δ=1.35 (2H, J=48Hz, m), 1.57 (2H, J=40Hz, m), 1.77 (2H, J=
48, q), 2.8 (2H, J=16Hz, t), 3.62 (2H, J=24Hz, t)
MS(EI):M/e=159
Embodiment 2：
The preparation of 2.1 compound 7- chloro-2-oxoheptanoates
0.5g 6- chloracetyl cyanogen is dissolved in 5mL absolute ethyl alcohols, the 5 drop concentrated sulfuric acids is added, is warming up to 90 DEG C, reaction 3.5
Hour, TLC detections, raw material disappears, and generates the product point that a polarity reduces.After reaction stops, 20mL ethyl acetate is added
Extraction, successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate drying, it is evaporated, by column chromatography
(PE:EA=1：40-1:30) purification obtains compound III (7- chloro-2-oxoheptanoates).0.51g products are obtained, yield is
78%.
H-NMR (400M) δ=1.2 (5H, J=64Hz, m), 1.6 (2H, J=40Hz, m), 1.77 (2H, J=48Hz, m),
3.33 (2H, J=16Hz, t), 3.60 (2H, J=24Hz, t), 4.16 (2H, J=32Hz, q).
MS(EI):M/e=206
The preparation of 2.2 compound 7- chloro-2-oxoheptanoates
0.5g 6- chloracetyl cyanogen is dissolved in 5mL absolute ethyl alcohols, the 5 drop concentrated sulfuric acids is added, is warming up to 90 DEG C, reaction 5 is small
When, TLC detections, raw material disappears, and generates the product point that a polarity reduces.After reaction stops, 20mL ethyl acetate extraction is added
Take, successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate drying, be evaporated, by column chromatography
(PE:EA=1：40-1:30) purification obtains compound III (7- chloro-2-oxoheptanoates).0.48g products are obtained, yield is
73.4%.
H-NMR (400M) δ=1.2 (5H, J=64Hz, m), 1.6 (2H, J=40Hz, m), 1.77 (2H, J=48Hz, m),
3.33 (2H, J=16Hz, t), 3.60 (2H, J=24Hz, t), 4.16 (2H, J=32Hz, q).
MS(EI):M/e=206
2.3 the preparation of compound 7- chloro-2-oxoheptanoates
0.5g 6- chloracetyl cyanogen is dissolved in 5mL absolute ethyl alcohols, sequentially adds 0.32g chloroacetic chloride, 5 drip the concentrated sulfuric acids,
90 DEG C are warming up to, is reacted 3.5 hours, TLC detections, raw material disappears, and generates the product point that a polarity reduces.After reaction stops,
20mL ethyl acetate extraction is added, is done successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate
It is dry, it is evaporated, by column chromatography (PE:EA=1：40-1:30) purification obtains compound III (7- chloro-2-oxoheptanoates).
0.50g products, yield 76.47%.
H-NMR (400M) δ=1.2 (5H, J=64Hz, m), 1.6 (2H, J=40Hz, m), 1.77 (2H, J=48Hz, m),
3.33 (2H, J=16Hz, t), 3.60 (2H, J=24Hz, t), 4.16 (2H, J=32Hz, q).
MS(EI):M/e=206
The preparation of 2.4 compound 7- chloro-2-oxoheptanoates
0.5g 6- chloracetyl cyanogen is dissolved in 5mL absolute ethyl alcohols, the 5 drop concentrated sulfuric acids is added, is warming up to 100 DEG C, reaction 3.5
Hour, TLC detections, raw material disappears, and generates the product point that a polarity reduces.After reaction stops, 20mL ethyl acetate is added
Extraction, successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate drying, it is evaporated, by column chromatography
(PE:EA=1：40-1:30) purification obtains compound III (7- chloro-2-oxoheptanoates).0.48g products are obtained, yield is
73.4%.
H-NMR (400M) δ=1.2 (5H, J=64Hz, m), 1.6 (2H, J=40Hz, m), 1.77 (2H, J=48Hz, m),
3.33 (2H, J=16Hz, t), 3.60 (2H, J=24Hz, t), 4.16 (2H, J=32Hz, q).
MS(EI):M/e=206
The preparation of 2.5 compound 7- chloro-2-oxoheptanoates
0.5g 6- chloracetyl cyanogen is dissolved in 5mL absolute ethyl alcohols, sequentially adds 0.37g chloroacetic chloride, 5 drip the concentrated sulfuric acids,
90 DEG C are warming up to, is reacted 3.5 hours, TLC detections, raw material disappears, and generates the product point that a polarity reduces.After reaction stops,
20mL ethyl acetate extraction is added, is done successively with saturated sodium bicarbonate solution, the washing of the saturated common salt aqueous solution, anhydrous sodium sulfate
It is dry, it is evaporated, by column chromatography (PE:EA=1：40-1:30) purification obtains compound III (7- chloro-2-oxoheptanoates).
0.49g products, yield 74.9%.
H-NMR (400M) δ=1.2 (5H, J=64Hz, m), 1.6 (2H, J=40Hz, m), 1.77 (2H, J=48Hz, m),
3.33 (2H, J=16Hz, t), 3.60 (2H, J=24Hz, t), 4.16 (2H, J=32Hz, q).
MS(EI):M/e=206
In summary, the method for present invention synthesis compound 7- chloro-2-oxoheptanoates has that synthetic line is brief, into
This is relatively low, easy to operate, and yield is high, the advantages of being easy to industrialized production.
The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this
Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect
Protect scope.
Claims (11)
1. a kind of preparation method of 7- chloro-2-oxoheptanoates, it is characterised in that comprise the following steps：
(a) in the first solvent, formula (I) 6- chloracetyl chlorides are in condensing agent and P2O5In the presence of, and the first nucleopilic reagent generation parent
Core substitution reaction, obtain formula (II) 6- chloracetyl cyanogen；
(b) in the second solvent, formula (II) 6- chloracetyls cyanogen reacts with acid and the second nucleopilic reagent, obtains formula (III) change
Compound 7- chloro-2-oxoheptanoates；
Shown in course of reaction such as route (1)：
Route 1.
2. according to the method for claim 1, it is characterised in that in step a), first nucleopilic reagent is Cymag, cyanogen
Change cuprous.
3. according to the method for claim 1, it is characterised in that in step a), the temperature of the reaction is 80 DEG C -150 DEG C；
The time of the reaction is 2-8 hours.
4. according to the method for claim 1, it is characterised in that in step a), the condensing agent is DMAP, PyBOP, AOP
Or HATU.
5. according to the method for claim 1, it is characterised in that in step a), first solvent be acetonitrile, 1- methyl-
2-Pyrrolidone, tetrahydronaphthalene, toluene or dimethylbenzene.
6. according to the method for claim 1, it is characterised in that in step a), formula (I) the 6- chloracetyl chlorides and the first parent
Core reagent, P2O5And the mol ratio 1 of condensing agent:1.3‐2.0:0.05‐0.10:0.01‐0.1.
7. according to the method for claim 1, it is characterised in that in step b), the acid is the concentrated sulfuric acid, concentrated hydrochloric acid.
8. according to the method for claim 1, second nucleopilic reagent is ethanol, chloroacetic chloride.
9. according to the method for claim 1, it is characterised in that in step b), the temperature of the reaction is 80 DEG C~100
DEG C, the time of the reaction is 3-5 hours.
10. according to the method for claim 1, it is characterised in that in step b), formula (II) the 6- chloracetyls cyanogen with acid and
The mol ratio of second nucleopilic reagent is 1.0:0.5‐1.0:1.1‐1.5.
11. according to the method for claim 1, it is characterised in that in step b), second solvent is absolute ethyl alcohol.
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