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CN108191647B - Synthesis method of 2, 2-difluoro dicarboxylic acid dialkyl ester - Google Patents

Synthesis method of 2, 2-difluoro dicarboxylic acid dialkyl ester Download PDF

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CN108191647B
CN108191647B CN201810154079.1A CN201810154079A CN108191647B CN 108191647 B CN108191647 B CN 108191647B CN 201810154079 A CN201810154079 A CN 201810154079A CN 108191647 B CN108191647 B CN 108191647B
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difluorodicarboxylate
fluorination
esterification
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CN108191647A (en
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胡国宜
胡锦平
俞梦龙
李喜龙
奚小金
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Jiangsu Sunlight Pharmaceutical Chemical Material Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
    • C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction

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Abstract

The invention discloses a method for synthesizing 2, 2-difluoro dicarboxylic acid dialkyl ester, which comprises the following steps: (A) 2-cycloalken-1-one of formula I is directly fluorinated or chlorinated and then fluorinated to obtain 3, 3-difluorocycloalkene of formula II; (B) the 2, 2-difluorodicarboxylic acid dialkyl ester of the formula III is obtained from the 3, 3-difluorocycloalkene of the formula II by simultaneous oxidation and esterification or by oxidation followed by esterification. Wherein, the chlorination reagent adopted for chlorination and then fluorination is oxalyl chloride, and the fluorination reagent adopted is triethylamine trihydrofluoride; the reaction system adopted by the simultaneous oxidation and esterification is ozone gas/sodium ethoxide, and the reaction temperature is-75 to-15 ℃. The method has the advantages of novel synthetic route, less environmental pollution, lower production cost, simple and easily-operated reaction conditions, higher reaction safety and fewer side reactions, and particularly can obtain higher reaction yield by selecting proper reaction conditions, the total yield can reach more than 82 percent at most, and the method is suitable for industrial production.

Description

Synthesis method of 2, 2-difluoro dicarboxylic acid dialkyl ester
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a synthesis method of 2, 2-difluoro dicarboxylic acid dialkyl ester.
Background
DPP-4 inhibitor, i.e. dipeptidyl peptidase 4 inhibitor, is a kind of medicine for treating type II diabetes, and the medicine can inhibit the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), improve the level of endogenous GLP-1 and GIP, promote the release of insulin by islet beta cells, and inhibit the secretion of glucagon by islet alpha cells, thereby improving insulin level, reducing blood sugar, and being difficult to induce hypoglycemia and increase body weight.
Gemigliptin (Gemigliptin) is a novel DPP-4 inhibitor developed by LG Life Science Ltd. Clinical studies show that the geigeritin has good effects whether being used for single treatment or being used for combined treatment with other antihyperglycemic drugs. Diethyl 2, 2-difluoroglutarate is an important intermediate for synthesizing the geagliptin (see international patent document WO2006104356A1 and Chinese document CN 101151265A).
For diethyl 2, 2-difluoroglutarate, the prior art discloses two synthetic routes:
(A) prepared by directly carrying out Michael addition reaction on ethyl acrylate and bromodifluoroacetic acid ethyl ester (see international patent document WO2013115595A1 and Chinese document CN 104159884A).
The disadvantages of this route are: (1) the Michael addition reaction is in competition with the 1, 2-addition reaction, resulting in a low yield; (2) the possibility of obtaining yields of more than 95% is most likely related to the use of the relatively expensive Tetramethylethylenediamine (TMEDA), which leads to increased production costs; (3) more copper powder is needed, the method is not environment-friendly, and the method is not suitable for industrial production.
(B) Prepared by directly carrying out fluorination reaction on diethyl 2-ketoglutarate (see U.S. patent document US 4324730A).
The disadvantages of this route are: (1) the fluorination reaction inevitably competes with 4-position fluorination, resulting in lower yields, less than 60%; (2) requires the addition of a strong fluorinating agent SF at a low temperature of-78 DEG C4Not only the reaction conditions are harsh, but also the safety is low, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the problems and provide a synthetic method of 2, 2-difluoro dicarboxylic acid dialkyl ester, which has the advantages of less environmental pollution, lower production cost, simple and easily operated reaction conditions, higher reaction safety and higher yield and is suitable for industrial production.
The technical scheme for realizing the purpose of the invention is as follows: a method for synthesizing dialkyl 2, 2-difluorodicarboxylate, comprising:
(A) reacting 2-cycloalken-1-one of formula I to obtain 3, 3-difluorocycloalkene of formula II;
(B) the dialkyl 2, 2-difluorodicarboxylate of the formula III is obtained by reacting a 3, 3-difluorocycloolefin of the formula II.
The specific synthetic route is as follows:
Figure 100002_DEST_PATH_IMAGE002
。
wherein n in the formulas I to III is an integer of 0 to 6, preferably an integer of 1 to 4, and more preferably 1; r in the formula III is C1～10Alkyl, preferably C1～4Alkyl, more preferably ethyl.
The reaction in the step A is direct fluorination or chlorination followed by fluorination; to obtain higher yields, chlorination followed by fluorination is preferred.
The fluorinating agent used for the direct fluorination is diethylaminosulfur trifluoride (hereinafter abbreviated as DAST), bis (2-methoxyethyl) aminosulfur trifluoride (hereinafter abbreviated as BAST), or morpholine sulfur trifluoride (hereinafter abbreviated as Morph-DAST); preferably DAST.
The molar ratio of the fluorinating agent used for the direct fluorination to the 2-cycloalken-1-one of the formula I is 1: 1 to 4: 1, preferably 2: 1.
The chlorinating agent used for chlorination and then fluorination is one of oxalyl chloride, thionyl chloride, silicon tetrachloride and phosphorus pentachloride, and is preferably oxalyl chloride.
The fluorination reagent adopted for chlorination and fluorination is triethylamine trihydrofluoride.
The mole ratio of the chlorination reagent, triethylamine trihydrofluoride and the 2-cycloolefine-1-ketone with the formula I adopted for chlorination and fluorination is (0.8-2.0): (0.3-1.5): 1, and the preferred ratio is 1: 0.7: 1.
The reaction of the step A is carried out in an organic solvent; the organic solvent is one or two of chlorobenzene, toluene, 1, 2-dichloroethane and 1, 4-dioxane.
The reaction temperature in the step A is 0-60 ℃; the reaction time is 3-24 h.
The reaction in the step B is simultaneous oxidation and esterification or oxidation and esterification; to obtain higher yields, simultaneous oxidation and esterification are preferred.
The reaction system adopted by the simultaneous oxidation and esterification is ozone gas/sodium alkoxide; preferably ozone gas/sodium ethoxide.
The dosage of the sodium alkoxide is 2-3 times of the molar dosage of the 3, 3-difluorocycloolefin in the formula II.
The temperature of the simultaneous oxidation and esterification reaction is-75 to-15 ℃, and is preferably-20 ℃.
The oxidizing agent adopted by the oxidation and esterification is sodium iodate or potassium permanganate.
The dosage of the oxidant is 1-2 times of the molar dosage of the 3, 3-difluorocycloolefin in the formula II.
When the adopted oxidant is sodium iodate, the reaction in the step B is 0-75 ℃, and the preferable temperature is 45 ℃.
When the adopted oxidant is sodium iodate, rhodium trichloride, ruthenium trichloride or osmium tetroxide serving as a catalyst is also required to be added; the dosage of the catalyst is 1-10% of the molar dosage of the 3, 3-difluorocycloolefin in the formula II.
When the oxidant used is potassium permanganate, the reaction in step B is-35 to-5 ℃, preferably-20 ℃.
The reaction of the step B is carried out in an organic solvent; the organic solvent is one or two of dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether and dimethyl sulfoxide (DMSO).
The invention has the following positive effects: (1) the invention has the advantages of novel synthetic route, less environmental pollution, lower production cost, simple and easy operation of reaction conditions, higher reaction safety and less side reaction. (2) The method can obtain higher reaction yield by selecting proper reaction conditions, the total yield can reach more than 82 percent at most, and the method is suitable for industrial production.
Detailed Description
(example 1)
This example is a preparation of 3, 3-difluorocyclopentene by chlorination followed by fluorination, as follows:
6.15g of 2-cyclopenten-1-one (75 mmol) was dissolved in 80mL of anhydrous chlorobenzene, and 9.52g of oxalyl chloride (75 mmol) was added dropwise thereto, and the reaction system was kept at an internal temperature of less than 20 ℃ for 20min without bubble evolution.
The reaction mixture was cooled to 0 ℃ and 16.16g of triethylamine (160 mmol) and 8.37g of triethylamine trihydrofluoride (52 mmol) were added in this order, and the mixture was stirred at 40 ℃ for 3 hours.
After the reaction is finished, cooling the reaction system to 0 ℃, adding 50mL of water, stirring, standing, separating, washing the organic layer with deionized water, separating the water phase, drying the organic layer with anhydrous sodium sulfate, filtering, distilling at normal pressure, and collecting the fraction with the boiling point lower than 70 ℃ to obtain 6.86g of colorless transparent liquid 3, 3-difluorocyclopentene, wherein the yield is 87.9%.
(examples 2 to 5)
All the examples are chlorinated and then fluorinated to prepare the 3, 3-difluorocyclopentene, and the specific method is basically the same as that of example 1 except for the differences shown in Table 1.
TABLE 1
Example 1 Example 2 Example 3 Example 4 Example 5
2-cyclopenten-1-ones 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol
Chlorination reagent 9.52g oxalyl chloride/75 mmol 8.93g thionyl chloride/75 mmol 15.64g phosphorus pentachloride/75 mmol 19.05g oxalyl chloride/150 mmol 7.62g oxalyl chloride/60 mmol
Triethylamine trihydrofluoride salt 8.37g/52mmol 8.37g/52mmol 8.37g/52mmol 18.11g/112.5mmol 7.25g/45mmol
3, 3-difluorocyclopentene 6.86g 6.65g 6.62g 6.94g 6.40g
Yield of 87.9% 85.3% 84.9% 89.0% 82.1%
(example 6)
This example is a direct fluorination to prepare 3, 3-difluorocyclopentene as follows:
6.15g of 2-cyclopenten-1-one (75 mmol) were dissolved in 150mL of 1, 2-dichloroethane, 24.15g of DAST (150 mmol) were slowly added dropwise thereto, and the reaction was stirred at room temperature for 6 hours while maintaining the internal temperature at less than 20 ℃.
After the reaction is finished, washing, standing, separating liquid, washing the organic layer with deionized water, separating water phase, drying the organic layer with anhydrous sodium sulfate, filtering, distilling at normal pressure, collecting fractions with boiling points lower than 70 ℃ to obtain 5.93g of colorless transparent liquid 3, 3-difluorocyclopentene, wherein the yield is 76.0%.
(examples 7 to 10)
All the examples are directly fluorinated to prepare 3, 3-difluorocyclopentene, and the specific method is basically the same as that of example 6 except that the differences are shown in Table 2.
TABLE 2
Example 6 Example 7 Example 8 Example 9 Example 10
2-cyclopenten-1-ones 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol 6.15g/75mmol
DAST 24.15g/150mmol / / 12.08g/75mmol 36.23g/225mmol
BAST / 33.15g/150mmol / / /
Morph-DAST / / 26.25g/150mmol / /
3, 3-difluorocyclopentene 5.93g 5.90g 5.92g 5.86g 5.95g
Yield of 76.0% 75.6% 75.9% 75.1% 76.3%
(example 11)
This example is a process for preparing diethyl 2, 2-difluoroglutarate by simultaneous oxidation and esterification, as follows:
the 3, 3-difluorocyclopentene (66 mmol) obtained in example 1 was dissolved in 132mL of dichloromethane, 55mL of a 2.5mol/L aqueous solution of sodium ethoxide was added, and then cooled to-20 ℃ and ozone gas was slowly introduced, and the reaction system turned pale blue after 50 min.
After the reaction, stopping introducing ozone gas, adding methyl tert-butyl ether and water into the reaction system for dilution, stirring, standing for liquid separation, extracting a water layer by using methyl tert-butyl ether, combining organic phases, drying an organic layer by using anhydrous sodium sulfate, filtering, concentrating a filtrate to obtain a bright yellow oily substance, carrying out reduced pressure distillation, and collecting a main fraction to obtain 13.6g of light yellow transparent liquid 2, 2-diethyl difluoroglutarate, wherein the yield is 92.0%.
The overall yield of the two steps was 81.0%.
(examples 12 to 15)
All the examples are to prepare 2, 2-difluoro-diethyl glutarate by simultaneous oxidation and esterification, and the specific method is basically the same as that of example 11 except that the difference is shown in Table 3.
TABLE 3
Example 11 Example 12 Example 13 Example 14 Example 15
3, 3-difluorocyclopentene 66mmol 66mmol 66mmol 66mmol 66mmol
2.5mol/L sodium ethoxide aqueous solution 55mL 60mL 55mL 55mL 60mL
Reaction temperature -20℃ -20℃ -30℃ -20℃ -30℃
Organic solvent 132mL of methylene chloride 132mL of methylene chloride 132mL of methylene chloride 132mL of diethyl ether 132mL of tetrahydrofuran
2, 2-Difluoropentanedioic acid diethyl ester 13.6g 13.7g 13.5g 13.4g 13.1g
Yield of 92.0% 92.7% 91.3% 90.6% 88.6%
(examples 16 to 18)
Diethyl 2, 2-difluoroadipate, dimethyl 2, 2-difluoropimelate and diethyl 2, 2-difluorosuberate were synthesized by the methods of example 1 and example 11, and are specifically shown in table 4.
TABLE 4
Examples 1 and 11 Example 16 Example 17 Example 18
2-cycloalken-1-ones 6.15g of 2-cyclopenten-1-one- 75mmol 7.2g of 2-cyclohexen-1-one/75 mmol 8.25g of 2-cyclohepten-1-one/75 mmol 9.3g of 2-cycloocten-1-one/75 mmol
3, 3-difluorocycloalkene 6.86g of 3, 3-difluorocyclopentene 7.72g of 3, 3-difluorocyclohexene 8.64g of 3, 3-difluorocycloheptene 9.45g of 3, 3-difluorocyclooctene
Dialkyl 2, 2-difluorodicarboxylate Esters 13.6g of diethyl 2, 2-difluoroglutarate Esters 13.9g of diethyl 2, 2-difluoroadipate 12.7g of dimethyl 2, 2-difluoropimelate 14.4g of diethyl 2, 2-difluorooctanedioate
Two-step overall yield 81.0% 77.9% 75.6% 72.2%

Claims (9)

1. A method for synthesizing dialkyl 2, 2-difluorodicarboxylate is characterized by comprising the following steps:
(A) reacting 2-cycloalken-1-one of formula I to obtain 3, 3-difluorocycloalkene of formula II;
(B) reacting 3, 3-difluorocycloalkene of formula II to obtain 2, 2-difluorodicarboxylic acid dialkyl ester of formula III;
the specific synthetic route is as follows:
Figure DEST_PATH_IMAGE002
；
wherein n in the formulas I to III is an integer of 0 to 6; r in the formula III is C1～10An alkyl group;
the reaction in the step A is direct fluorination or chlorination followed by fluorination; the reaction in the step B is simultaneous oxidation and esterification.
2. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 1, wherein: n in formulas I to III is an integer of 1 to 4; r in the formula III is C1～4An alkyl group.
3. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 2, wherein: n in formulas I to III is 1; r in the formula III is ethyl.
4. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 1, wherein: the reaction in the step A is chlorination and then fluorination; the adopted chlorinating agent is one of oxalyl chloride, thionyl chloride, silicon tetrachloride and phosphorus pentachloride; the fluorination reagent used was triethylamine trihydrofluoride salt.
5. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 4, wherein: the mol ratio of the chlorination reagent to the triethylamine trihydrofluoride salt to the 2-cycloen-1-one of the formula I is (0.8-2.0): (0.3-1.5): 1.
6. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 5, wherein: the molar ratio of the chlorinating agent, triethylamine trihydrofluoride and 2-cycloalken-1-one of the formula I is 1: 0.7: 1.
7. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 4, wherein: the chlorinating agent used was oxalyl chloride.
8. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 1, wherein: the reaction in the step B is simultaneous oxidation and esterification; the adopted reaction system is ozone gas/sodium alcoholate; the using amount of the sodium alkoxide is 2-3 times of the molar using amount of the 3, 3-difluorocycloolefin shown in the formula II; the reaction temperature is-75 to-15 ℃.
9. The method of synthesizing dialkyl 2, 2-difluorodicarboxylate of claim 8, wherein: the adopted reaction system is ozone gas/sodium ethoxide; the reaction temperature was-20 ℃.
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