CN103910634B - The preparation method of sitagliptin intermediate - Google Patents
The preparation method of sitagliptin intermediate Download PDFInfo
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- CN103910634B CN103910634B CN201310732949.6A CN201310732949A CN103910634B CN 103910634 B CN103910634 B CN 103910634B CN 201310732949 A CN201310732949 A CN 201310732949A CN 103910634 B CN103910634 B CN 103910634B
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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
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The present invention relates to the preparation method of sitagliptin intermediate, the method uses low-toxic organic solvent to prepare the target product of high-purity high-yield as reaction dissolvent, and is conducive to production safety, suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of medicine and its intermediate, belong to pharmaceutical technology field.
Background technology
Xi Gelieting, is a kind of oral antihyperglycemic medicine, can be promoted in diabetes B patient by increasing active intestines
The level of pancreas hormone and improve glycemic control.
Preparing in the method for Xi Gelieting, it is necessary to first prepare a kind of important intermediate, its structure such as (I1) is shown,
Safely and efficiently large-scale industrial production intermediate (I1), is of great significance industrial production Xi Gelieting；
The method of Xi Gelieting is prepared in more documents, this intermediate is prepared and uses acetonitrile, tetrahydrofuran etc. to be used as reaction dissolvent.
In preparation process, used solvent is different according to its toxicity, also different to the toxic of worker's health,
Influence to drug quality is also different.Pharmacopoeia of each country has all carried out solvent stringent classification, will be common according to the toxicity of solvent
Solvent is divided into three classes：Wherein first kind solvent refers to the known solvent can be carcinogenic and be harmful to by strong doubt to human and environment,
In the conceived case, should avoid using this kind of solvent, such as benzene (2ppm), carbon tetrachloride (4ppm)；Second class solvent refers to
No genotoxicity but the solvent for having animal carcinogenicity, such as acetonitrile (410ppm), hexahydrotoluene (1180ppm)；Three classes are molten
Agent refers to the solvent to human body low toxicity, and in the case of without demonstration, the amount of residual solvent is acceptable not higher than 0.5%.According to point
Class, acetonitrile, tetrahydrofuran equal solvent belong to the second class solvent, its toxicity is larger, volatile, there is intense irritation smell or easy
Peroxide is produced, it is unfavorable to environment, operator's health and production safety, it is unsuitable for industrialized production.
The content of the invention
Summary of the invention
Here a kind of method for preparing sitagliptin intermediate is provided, by using hypotoxicity reaction dissolvent, is solved
The problem of harmful effect of the existing method to environment and operating personnel, mass produce suitable for industrialization；And can be in high yield
This intermediate is prepared to high-purity.
Detailed description of the invention
Here the method for providing the compound that one kind is prepared as shown in formula (I1), the method can solve existing method pair
The problem of harmful effect of environment and operating personnel, mass produce suitable for industrialization；And can high-purity it make in high yield
It is standby to obtain this intermediate, and then industrialized production prepares Xi Gelieting.
Intermediate (I1)：
In general formula (I1), R1, R2, R3, R4, R5Each hydrogen, halogen, the alkyl of C1-C6, C1-C6 are selected from identical or differently
Alkoxy；R7Selected from hydroxyl, the alkoxy of C1-C6, halogen, CH2Ph or OCH2Ph；Wherein " C1-C6 " refers to 1 to 6 carbon,
" Ph " refers to phenyl.
The method of prepare compound (I1) is included by compound (01) and compound (02) in low-toxic organic solvent, warp
Serial reaction is crossed to be prepared；Compound (01) and compound (02) structure are respectively as following formula (01) and formula (02) are shown：
Wherein, R6Selected from hydroxyl, halogen；M is alkali metal ion；R1, R2, R3, R4, R5, R7It is fixed in definition and general formula (I1)
Justice is identical.
In some embodiments, R1, R4For hydrogen；R2, R3, R5For fluorine.
In some embodiments, R7Selected from methoxyl group, ethyoxyl, tert-butoxy.
In some embodiments, M is sodium ion, potassium ion.
Wherein, the low-toxic organic solvent refers to that oral median lethal dose (oral LD50, mouse (rat)) is higher than
2900mg/Kg, 3000mg/Kg, 3500mg/Kg, 4000mg/Kg, 4500mg/Kg, 5000mg/Kg or 5500mg/Kg (milligram/
Kilogram) organic solvent.
In some embodiments, the low-toxic organic solvent does not include being also easy to produce the molten of peroxide in atmosphere
Agent.
In some embodiments, low-toxic organic solvent is esters solvent.
In some embodiments, compound (01) and compound (02) are in low-toxic organic solvent, by serial anti-
The method of compound shown in formula (I1) is answered to include the following steps：
Step (a) and step (b) in no particular order, by step (a) and step after in step (a) and step (b), the reaction was complete
(b) product carries out step (c), and compound (I1) is prepared；Step (a), step (b) and step (c) are identical or different
Low-toxic solvent in carry out, preferably identical low-toxic solvent；
MgCl in step (b)2For anhydrous magnesium chloride, step (b) carries out in the presence of a base, and the alkali is triethylamine or N, N-
Diisopropyl ethyl amine or its combination, in some embodiments, alkali is triethylamine；
Step (c) includes reaction in alkaline conditions and then is reacted again by acid decarboxylation, obtains compound (I1), the alkali
For triethylamine or N, N- diisopropyl ethyl amine or its combination, the acid is inorganic acid, organic acid or its combination；In some realities
Apply in scheme, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, citric acid or its combination；The alkali is three second in some embodiments
Amine, the acid is hydrochloric acid.
In some embodiments, low-toxic organic solvent is ethyl acetate, isopropyl acetate or its combination.
In some embodiments, the method for compound includes shown in formula (I1)：Compound and formula shown in formula (01)
(02) compound shown in passes through serial reaction in low-toxic organic solvent, and compound shown in formula (I1) is prepared；Wherein,
R1, R4For hydrogen, R2, R3, R5For fluorine, R6For hydroxyl or halogen, R7As defined in general formula (I1).
In some embodiments, the method for compound includes shown in formula (I1)：Compound and formula shown in formula (01)
(02) compound shown in passes through serial reaction in esters solvent, and compound shown in formula (I1) is prepared；Wherein, R1, R4For
Hydrogen, R2, R3, R5For fluorine, R6For hydroxyl, R7For ethyoxyl, M is potassium ion.
In some embodiments, the method for compound shown in formula (I1) includes following reaction：
Wherein, step (a), step (b) and step (c) carry out in identical or different low-toxic solvent, preferably identical low
Toxic solvents, MgCl in step (b)2For anhydrous magnesium chloride, K is potassium ion, and step (b) carries out in the presence of a base, and step (c) is first
In alkaline conditions then reaction is reacted by acid decarboxylation again, and compound (I1) is prepared；In some embodiments, step
(a), step (b) and step (c) carry out in esters solvent；In some embodiments, step (a), step (b) and step
(c) carried out in ethyl acetate or isopropyl acetate, alkali used in step (b) is triethylamine, in step (c), first in triethylamine
In the presence of reaction then acted on through persalt, compound (I1) is prepared：3- carbonyls -4- (2,4,5- trifluorophenyls) butyric acid second
Ester.
Embodiment
In order to make those skilled in the art more fully understand technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can from the market be bought or can be by method system described in the invention
It is standby and obtain.
Embodiment 1
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120
Milliliter stirring anhydrous ethyl acetate in, be stirred at room temperature 2 it is small when；By 9.5 grams of 2,4,5- trifluoro benzene acetic acids and N, N ' two miaow of-carbonyl
9.73 grams of azoles stirred in 50 milliliters of ethyl acetate 0.5 it is small when, this mixed liquor is added in previous reaction liquid；It is mixed anti-
Answer liquid when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust pH to
PH is less than 3, and layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and is obtained
13.2 grams of grease.
Embodiment 2
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120
Milliliter stirring isopropyl acetate in, be stirred at room temperature 2 it is small when, by 9.5 grams of 2,4,5- trifluoro benzene acetic acid and N, N '-carbonyl dimidazoles
9.73 grams when stirring 0.5 is small in 50 milliliters of isopropyl acetates, this mixed liquor is added in previous reaction liquid, mixed anti-
Answer liquid when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust pH to
PH is less than 3, and layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and is obtained
13.1 grams of grease.
Embodiment 3
20.82 grams, N of mono-tert-butyl malonate sylvite, 27.5 milliliters of N- diisopropyl ethyl amines and anhydrous magnesium chloride 11.97
Gram be added separately in the ethyl acetate of 120 milliliters of stirrings, be stirred at room temperature 2 it is small when, by 9.5 grams of 2,4,5- trifluoro benzene acetic acid and N,
9.73 grams of N '-carbonyl dimidazoles stirred in 50 milliliters of ethyl acetate 0.5 it is small when, this mixed liquor is added to previous reaction liquid
In, mixed reaction solution is cooled to 15 DEG C -25 DEG C, it is water-soluble to add 10% hydrochloric acid when 50 DEG C of -60 DEG C of stirring reaction 6-8 are small
Liquid, adjusts pH to pH and is less than 3, layering, organic layer saturated common salt water washing 3 times, organic layer is dense after being dried with anhydrous sodium sulfate
Contracting is evaporated, and obtains 15.1 grams of grease.
Embodiment 4
24.39 grams of malonic acid list benzene methyl sylvite, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to
120 milliliters stirring isopropyl acetates in, be stirred at room temperature 2 it is small when, by 9.5 grams of 2,4,5- trifluoro benzene acetic acid and N, N '-carbonyl two
9.73 grams of imidazoles stirred in 50 milliliters of isopropyl acetates 0.5 it is small when, this mixed liquor is added in previous reaction liquid, after mixing
Reaction solution when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust
PH to pH is less than 3, and layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated,
Obtain 16.28 grams of grease.
Embodiment 5
20.82 grams of mono-tert-butyl malonate sylvite, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to
120 milliliters stirring isopropyl acetates in, be stirred at room temperature 3 it is small when, by 10.43 grams of 2,4,5- trifluoro phenyllacetyl chloride and N, N '-carbonyl
9.73 grams of base diimidazole stirred in 50 milliliters of isopropyl acetates 0.5 it is small when, this mixed liquor is added in previous reaction liquid, mix
Reaction solution after conjunction when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution,
Adjust pH to pH<3, layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated,
Obtain 15.0 grams of grease.
The present invention method be described by preferred embodiment, related personnel substantially can present invention,
Method described herein and application are modified or suitably changed with combining in spirit and scope, to realize and using the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, institute
Have similar replacement and change it is apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (4)
1. the method that one kind prepares the compound as shown in formula (I1),
Wherein, R1, R4For hydrogen, R2, R3, R5For fluorine, R7For ethyoxyl；Including：
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120 milliliters
In the anhydrous ethyl acetate of stirring, be stirred at room temperature 2 it is small when；By 9.5 grams of 2,4,5- trifluoro benzene acetic acids and N, N '-carbonyl dimidazoles
9.73 grams in 50 milliliters of ethyl acetate stirring 0.5 it is small when, this mixed liquor is added in previous reaction liquid；Mixed reaction
Liquid when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust pH to
PH is less than 3, and layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and is obtained
Compound shown in formula (I1).
2. the method that one kind prepares the compound as shown in formula (I1),
Wherein, R1, R4For hydrogen, R2, R3, R5For fluorine, R7For ethyoxyl；Including：
17.85 grams of potassium ethyl malonate salt, 11.97 grams of 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120 milliliters
In the isopropyl acetate of stirring, be stirred at room temperature 2 it is small when, by 9.5 grams of 2,4,5- trifluoro benzene acetic acid and N, N '-carbonyl dimidazoles 9.73
When stirring 0.5 is small gram in 50 milliliters of isopropyl acetates, this mixed liquor is added in previous reaction liquid, mixed reaction solution
When 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust pH to pH
Less than 3, layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and obtains formula
(I1) compound shown in.
3. the method that one kind prepares the compound as shown in formula (I1),
Wherein, R1, R4For hydrogen, R2, R3, R5For fluorine, R7For ethyoxyl；Including：
11.97 grams of 24.39 grams of malonic acid list benzene methyl sylvite, 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120 millis
Rise stirring isopropyl acetate in, be stirred at room temperature 2 it is small when, by 9.5 grams of 2,4,5- trifluoro benzene acetic acid and N, N '-carbonyl dimidazoles
9.73 stirring 0.5 is small gram in 50 milliliters of isopropyl acetates, this mixed liquor is added in previous reaction liquid, it is mixed anti-
Answer liquid when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust pH
It is less than 3 to pH, layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and is obtained
To compound shown in formula (I1).
4. the method that one kind prepares the compound as shown in formula (I1),
Wherein, R1, R4For hydrogen, R2, R3, R5For fluorine, R7For ethyoxyl；Including：
11.97 grams of 20.82 grams of mono-tert-butyl malonate sylvite, 22 milliliters of triethylamine and anhydrous magnesium chloride are added separately to 120 millis
In the isopropyl acetate for rising stirring, be stirred at room temperature 3 it is small when, by 10.43 grams of 2,4,5- trifluoro phenyllacetyl chloride and N, N ' two miaow of-carbonyl
9.73 grams of azoles stirred in 50 milliliters of isopropyl acetates 0.5 it is small when, this mixed liquor is added in previous reaction liquid, it is mixed
Reaction solution when 50 DEG C of -60 DEG C of stirring reactions 6 are small -8 it is small when, be cooled to 15 DEG C -25 DEG C, add 10% aqueous hydrochloric acid solution, adjust
PH to pH<3, layering, organic layer saturated common salt water washing 3 times, organic layer is concentrated after being dried with anhydrous sodium sulfate and is evaporated, and is obtained
Compound shown in formula (I1).
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| CN201310117110 | 2013-04-04 | ||
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| CN201310732949.6A CN103910634B (en) | 2012-12-29 | 2013-12-25 | The preparation method of sitagliptin intermediate |
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| CN106831783B (en) * | 2017-01-10 | 2019-02-22 | 苏利制药科技江阴有限公司 | A kind of synthetic method of phosphoric acid sitagliptin intermediate |
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| CN1449388A (en) * | 2000-08-31 | 2003-10-15 | 艾博特公司 | Process and intermediates for preparing retroviral protease inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1449388A (en) * | 2000-08-31 | 2003-10-15 | 艾博特公司 | Process and intermediates for preparing retroviral protease inhibitors |
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| Title |
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| 2, 3, 4, 5 -四氟苯甲酰乙酸乙酯的合成;王斌等;《化学试剂》;20011231;第23卷(第6期);372-373 * |
| 异丁酰乙酸乙酯的合成;刘伟等;《化学试剂》;20061231;第28卷(第9期);561-562 * |
| 磷酸西他列汀的合成;王建塔等;《中国医药工业杂志》;20111231;第42卷(第8期);561-564 * |
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