CN107344916B - Prepare the intermediate and its preparation method and use of 7- halogen -2- oxoheptanoate - Google Patents
Prepare the intermediate and its preparation method and use of 7- halogen -2- oxoheptanoate Download PDFInfo
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- CN107344916B CN107344916B CN201710619142.XA CN201710619142A CN107344916B CN 107344916 B CN107344916 B CN 107344916B CN 201710619142 A CN201710619142 A CN 201710619142A CN 107344916 B CN107344916 B CN 107344916B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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Abstract
The present invention relates to the intermediate and its preparation method and use that prepare 7- halogen -2- oxoheptanoate, which is that the intermediate is used to prepare 7- halogen -2- oxoheptanoate.The present invention passes through new synthetic method; it is prepared for intermediate 7- halogen -2- hydroxyl heptamide; it is with good chemical stability and thermal stability; it is easy to purify; to make the technical process for preparing 7- halogen -2- oxoheptanoate simplify; cost reduces, and improves production environment, more conducively large-scale production.
Description
Technical field
The invention belongs to organic synthesis field, centre that is specific and preparing 7- halogen -2- oxoheptanoate (type I compound)
Body and its preparation method and use, the purposes are to be used to prepare 7- halogen -2- oxoheptanoate.
Background technique
7- halogen -2- oxoheptanoate is synthesis and the kidney peptase inhibition that carbapenem antibiotics imipenem 5 uses
The key intermediate of agent --- cilastatin, Imipenem/cilastatin composition are used as effective wide spectrum Hangzhoupro microbial inoculum.
United States Patent (USP) US5 discloses the synthesis of 7- chloro-2-oxoheptanoate in 147,868, using the bromo- 5- chlorine of 1- first
Pentane is reacted through grignard reaction with excessive diethy-aceto oxalate.The Chinese patent text in Publication No. CN1587248A such as Chen Xinzhi
The method is improved in offering, but yield only has 24~43%, obtained in 7- chloro-2-oxoheptanoate content only
30~40%, it is difficult to which separating-purifying goes out the 7- chloro-2-oxoheptanoate of high-purity.
Existing technical literature J.Med.Chem., 1987,30 (6): 1074-1090 and " Chinese Journal of Pharmaceuticals ",
2005,36 (9), 531 describe that use 1,5 1 dibromo pentanes, diethoxy acetic ether, dimercaptopropane etc. be raw material through ring
The method that the reactions such as conjunction, substitution, change prepare the bromo- 2- oxoheptanoate of 7-.But these method raw material are expensive, and use stench
Dimercaptopropane, be not suitable for industrialized production.
The PCT Application Publication that publication No. is WO98/15520 uses the bromo- 5- chloropentane of 1- and acetoacetate second vinegar for original
Material, after being substituted, with nitrosylsulfuric acid nitrosation, deacetylation, then reacts with formaldehyde and is changed into fat in acid condition
Ketone is most refining to obtain the preparation method of the 7- chloro-2-oxoheptanoate of higher degree through sub- hydrosulphuric acid sodium afterwards.But this method is still
Expensive raw material are used, and generate a large amount of spent acid when nitrosation, environmental pressure is big.
Publication number CN 101475481A application is disclosed with such as formula III, and compound represented is that intermediate synthesizes 7- halogen -2-
The route of oxoheptanoate:
Above-mentioned route Chinese style III, compound intermediate be it is thick, purification use benzene for solvent azeotropic dehydration after weigh
Crystallization, due to Chinese style III during this, compound is unstable, it is prone to formula III, the dehydration condensation between compound molecule,
Make to refine yield reduction, and more significant with the reduction of the amplification yield of scale.
And if the purification of intermediate is not directly used in the next step, the target product prepared is difficult to purify, product matter
Measure the problems such as not high, at high cost.
Summary of the invention
In order to solve the above technical problems existing in the prior art, the present invention provides a kind of thermal stability and chemical stabilization
Good, new intermediate for being used to prepare 7- halogen -2- oxoheptanoate for being easily isolated purifying of property and application thereof, and a kind of behaviour is provided
Make simplicity, Quality advance, cost reduction, large-scale production of being more convenient for the method for preparing 7- halogen -2- oxoheptanoate.
The present invention adopts the following technical scheme: preparing the intermediate of 7- halogen -2- oxoheptanoate, its chemical name is 7-
Halogen -2- hydroxyl heptamide, structural formula is as shown in following formula III:
The present invention also protects the synthetic method of the intermediate, comprising the following steps:
II compound of formula is dissolved in solvent, inorganic base is added, is hydrolyzed under the catalysis of hydrogen peroxide, obtains the change of formula III
Close object:
In the preferred embodiments of the present invention, the reaction temperature is controlled at 0-40 DEG C, and preferably 35 DEG C.
In the preferred embodiments of the present invention, the molar equivalent ratio of II compound of formula and inorganic base is 1:0.01-
0.10, preferably 1:0.05.
In the preferred embodiments of the present invention, the solvent is water, aqueous alcohol or aqueous dimethyl sulfoxide, wherein described
Alcohol is selected from C1-C4Alcohol, the inorganic base are potassium carbonate or sodium carbonate.
II compound of formula can using 6- halogen hexanal as starting material, by conventional method, first with sodium hydrogensulfite, again with
Cymag addition is made.This general common sense method is by reference and in into the application.
The present invention protects the method for preparing 7- halogen -2- oxoheptanoate, III compound conduct of applying equation in the method
Intermediate, comprising the following steps:
1) with ethyl alcohol IV compound of esterification preparation formula occurs for III compound of formula under acid catalysis:
2) IV compound of formula in the presence of a catalyst, obtains type I compound with oxidant reaction:
In the preferred embodiments of the present invention, above-mentioned steps 1) described in acid be selected from HCl or H2SO4One of
Or it is several.
In the preferred embodiments of the present invention, above-mentioned steps 2) described in catalyst be 2,2,6,6- tetramethyl piperazines
Pyridine oxide (TEMPO)/NaBr.
In the preferred embodiments of the present invention, above-mentioned steps 2) described in oxidant be sodium hypochlorite.
In the preferred embodiments of the present invention, above-mentioned steps 1) in, esterification occurs under an acid catalysis, it is used
Acid is inorganic acid, such as the mixture that sulfuric acid, hydrochloric acid are two or more, preferably sulfuric acid；Reaction can carry out under the conditions of solvent refluxing,
Reaction temperature is solvent reflux temperature at this time, can also be carried out under other normal conditions, and reaction temperature at this time is 50 DEG C~100
℃。
In the preferred embodiments of the present invention, above-mentioned steps 2) in, used catalyst and oxidant can be any
Applicable catalyst oxidant, reaction temperature are -20~40 DEG C, and the reaction time is 1~3h after oxidant is added.
Compared with the existing method for preparing 7- halogen -2- oxoheptanoate, the present invention has following technological merit:
1) sticky intermediate formula III obtained by step associated with the prior art, compound is compared, the intermediate that the present invention obtains
III compound of formula be solid, have good chemical stability and thermal stability, be easy to carry out subsequent purification with react.
2) last handling process of the method for the present invention is simple, simplifies operational sequence, reduces production cost.
3) present invention is prepared for intermediate 7- halogen -2- hydroxyl heptamide, with goodization by new synthetic method
Stability and thermal stability are learned, the equipment used is simpler, and intermediate is easily purified, and impurity is few, good product quality, and improves
Production environment, entire technique are more conducive to large-scale production.
Specific embodiment
In order to keep the purpose of the present invention, technical solution and beneficial effect clearer, present invention following specific embodiments
It is illustrated, but the present invention is limited to absolutely not these examples.
Detecting instrument of the present invention is as follows:
400MHz FT-NMR nuclear magnetic resonance pop instrument, model Mercury Plus 400, Varian company；
Q-TOF mass spectrograph, agilent company；
FT-IR Fourier Transform Infrared Spectrometer, model NEXUS-470, Nicolet company.
Part reaction equation is as follows:
Embodiment 1
The preparation of compound ii
In reaction flask, water (600ml), sodium hydrogensulfite (80g, 0.77mol) are put into, stirring is cooled to 35 DEG C, is added
6- chlorine hexanal (82g, 0.6mol) after heat preservation 1 hour, 30% NaCN solution (130g, 0.8mol) is added dropwise at 35-40 DEG C, greatly
It is added dropwise within about 0.5 hour.After heat preservation 0.5 hour, static layering, oil reservoir is compound ii, weight in wet base 104g.The product without
Purifying is directly used in the next step.
Embodiment 2
The preparation of compound III
In 500 milliliters of reaction flask, potassium carbonate (6.2g, 0.045mol), water (80ml), dimethyl sulfoxide are successively put into
(40g), compound ii (104g, the 0.65mol) stirring that embodiment 1 obtains, control temperature starts to be added dropwise between 35-40 DEG C double
Oxygen water, it is about 2 hours time-consuming.After being added dropwise, 3 hours are kept the temperature between 35-40 DEG C.After heat preservation terminates, add water
(100g) is cooled between 10-15 DEG C and is stirred 1 hour.Filtering, washing, a small amount of toluene washing, the white flakes shape crystallization of drying
Compound III 80g, yield 80%.
Mp:116.5-117.5 DEG C.1H-NMR[CDCl3]: δ 1.45-1.80 (m, 8H, CH2)3.32(s,1H,CH)3.55-
3.60(t,2H,Cl-CH2)3.65(t,2H,NH2)4.05(S,1H,OH).MS-TOF (m/z): 202.0602 [M+Na].IR
(KBr):3385.93312.82942.12913.82851.81650.11085.0654.0cm-1。
Embodiment 3
The preparation of compounds Ⅳ
It in reaction flask, puts into compound III (70g, 0.39mol), absolute alcohol 280ml, the concentrated sulfuric acid is added dropwise in stirring
(64g, 0.63mol).It is added dropwise, temperature rising reflux keeps the temperature 9 hours.Then 20-25 DEG C, small pH value=6-7 is cooled to, decompression is steamed
Evaporate recycling ethyl alcohol, at 50 DEG C, hereinafter, after distillation finishes, methylene chloride 250g, water 200g is added, stirring half is small in temperature control
When.Static layering, water layer add methylene chloride 70g extraction.Organic layer merges, and washing, methylene chloride is evaporated to obtain compound
IV 77 grams of light yellow oil, yield 95%.
1H-NMR[CDCl3]: δ 1.23-1.25 (t, 3H, CH3)1.37-1.73(m,8H,CH2)3.02(s,1H,CH)
3.46-3.49(t,2H,Cl-CH2)4.15(S,1H,OH)4.16-4.20(m,2H,O-CH2).MS-ESI (m/z): 230.9 [M+
Na]+。
The preparation of 4 compound 7- chlorine of embodiment -2- oxoheptanoate
In reaction flask, water (300ml), sodium bicarbonate (31.5g, 0.375mol), methylene chloride are successively put into
(385g), compounds Ⅳ (77g, 0.37mol), TEMPO (0.77g), potassium bromide (5.0g), cool to -1~-2 DEG C, in flask
There is ice generation, starts that aqueous sodium hypochlorite solution (360g, available chlorine content 10%) is added dropwise, be added dropwise within about 1 hour or so, control
Temperature processed is added dropwise less than 8 DEG C, keeps the temperature 2 hours, static layering is washed, 1% thiosulfuric acid with the hydrochloric acid (120g) of 2-3%
Sodium (120g) is washed, washing, and recycling methylene chloride obtains finished product 7- chlorine -73.9 grams of 2- oxoheptanoate to the greatest extent, yield 97%,
GC purity is greater than 98%.
Although invention has been described by referring to the preferred embodiment of the present invention, this field it is common
It will be appreciated by the skilled person that various changes can be made to it in the form and details, without departing from appended right
The spirit and scope of the present invention defined by claim.
Claims (8)
1. the method for preparing 7- halogen -2- oxoheptanoate, which is characterized in that intermediate as shown in following formula III using structural formula
Body,
The following steps are included:
1) with ethyl alcohol IV compound of esterification preparation formula occurs for III compound of formula under acid catalysis:
2) IV compound of formula in the presence of a catalyst, obtains type I compound with oxidant reaction:
Acid described in step 1) is selected from HCl or H2SO4One or more of,
Catalyst described in step 2) is 2,2,6,6- tetramethyl piperidine oxides (TEMPO)/NaBr,
Oxidant described in step 2) is sodium hypochlorite.
2. oxygen is added the method according to claim 1, wherein reaction temperature is -20~40 DEG C in step 2)
The reaction time is 1~3h after agent.
3. the method according to claim 1, wherein the synthetic method of the intermediate the following steps are included:
II compound of formula is dissolved in solvent, inorganic base is added, is hydrolyzed under the catalysis of hydrogen peroxide, obtains III chemical combination of formula
Object:
4. synthetic method according to claim 3, which is characterized in that the reaction temperature is controlled at 0-40 DEG C.
5. synthetic method according to claim 4, which is characterized in that the reaction temperature control is 35 DEG C.
6. synthetic method according to claim 3, which is characterized in that the molar equivalent ratio of II compound of formula and inorganic base is
1:0.01-0.10。
7. synthetic method according to claim 6, which is characterized in that the molar equivalent ratio of II compound of formula and inorganic base is
1:0.05。
8. synthetic method according to claim 3, which is characterized in that the solvent is that water, aqueous alcohol or aqueous diformazan are sub-
Sulfone, wherein the alcohol is selected from C1-C4Alcohol, the inorganic base are potassium carbonate or sodium carbonate.
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| CN101475481A (en) * | 2009-02-09 | 2009-07-08 | 浙江海翔药业股份有限公司 | Intermediate of cilastatin and preparation method thereof |
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| US5268501A (en) * | 1990-02-08 | 1993-12-07 | Sumitomo Chemical Company, Limited | Process for preparing haloketo acid derivatives |
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| CN101475481A (en) * | 2009-02-09 | 2009-07-08 | 浙江海翔药业股份有限公司 | Intermediate of cilastatin and preparation method thereof |
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