CN115636724A - 4-fluoro-4-methylcyclohexanol and preparation method thereof - Google Patents
4-fluoro-4-methylcyclohexanol and preparation method thereof Download PDFInfo
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Abstract
The invention discloses 4-fluoro-4-methylcyclohexanol and a preparation method thereof, wherein the preparation method comprises the steps of taking 1, 4-cyclohexanedione monoethylene glycol (compound II) as a raw material, adding a proper amount of Grignard reagent to obtain 8-methyl-1, 4-dioxaspiro [4,5] decane-8-ol (compound III); dissolving 8-methyl-1, 4-dioxyspiro [4,5] decane-8-ol (compound III) in an organic solvent, adding a proper fluorinating agent under the protection of inert gas and at low temperature to obtain 8-methyl-1, 4-dioxyspiro [4,5] decane-8-fluorine (compound IV); converting the compound IV into 4-fluoro-4-methylcyclohexanone (compound V) under the action of a hydrochloric acid solution with a proper concentration; and finally, under the protection of nitrogen and the action of a reducing agent sodium borohydride, obtaining the 4-fluoro-4-methylcyclohexanol (compound I). The preparation method disclosed by the invention is mild in reaction conditions, simple and convenient to operate, and capable of realizing rapid preparation in laboratories and industrial production.
Description
Technical Field
The invention belongs to the technical field of intermediate synthesis, and particularly relates to a preparation method of 4-fluoro-4-methylcyclohexanol.
Background
Tumor cells have the property of immunological escape, making them difficult to cure at all. In recent years, the pathway targeting programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1) plays an important role in participating in tumor immunity. Since 2020, small molecule drug development against PD-L1-related targets is actively underway. In particular, cyclohexanol containing fluorine and derivatives thereof are being widely used as potential PD-1 pathway, PD-L1 pathway antibodies or inhibitors in the treatment of major tumor diseases such as ovarian cancer. The functionalized 4-fluoro-4-methylcyclohexanol is used as an antibody of PD-L1 and an IDO1 inhibitor, and a brand new lead compound is provided for the field of developing medicaments for treating related tumor diseases. At present, in the medical field of combined medicine, namely combined medicine, for treating malignant tumors, 4-fluoro-4-methylcyclohexanol is also one of the most studied fluorine-containing medicine small molecules.
In the prior art, the synthetic route of the 4-fluoro-4-methylcyclohexanol is not reported or scientific research documents. Other fluorine-containing cyclohexanol derivatives have the disadvantages of extremely low yield, use of highly toxic organic solvents, and unsuitability for industrial production, such as a method for synthesizing 4-fluorocyclohexanol (WO 2013/189841,2013, a 1), which specifically includes:
reagents and conditions: pyridine and chloroform as solvent at 25 deg.c for 12 hr; the yield was 58%.
(b) Diethyl amino sulfur trifluoride and dichloromethane are used as solvents, and are protected by inert gas at the temperature of-78-25 ℃ for 3 hours. The yield was 9%.
(c) Lithium hydroxide monohydrate, methanol/dichloromethane (1 v/v) as solvent, 25 ℃,5h.
The method uses compound VI (1, 4-cyclohexanediol) as a starting material, and the first step involves using chloroform from the list of class 2B carcinogens and toxic and harmful water pollutants as a solvent. The second step reaction (b) requires a low temperature of-78 deg.C and a very low yield of only 9%, and is not suitable for mass production.
Disclosure of Invention
In order to solve the problems, the invention provides 4-fluoro-4-methylcyclohexanol and a preparation method thereof, wherein the 4-fluoro-4-methylcyclohexanol is a small molecular compound with potential antitumor drug activity. The preparation method solves the technical problems that similar fluorine-containing cyclohexanol derivatives are not friendly to the environment, have high biological toxicity and low synthesis yield, are not suitable for large-scale production and the like in the synthesis process in the prior art. The preparation method has the advantages of cheap raw materials, environmental friendliness, simple and convenient operation, easy control of the total reaction, high yield and the like.
The invention is realized by the following technical scheme:
1. the invention aims to provide 4-fluoro-4-methylcyclohexanol which has a chemical structural formula as follows:
the invention also aims to provide a preparation method of 4-fluoro-4-methylcyclohexanol, which takes 1, 4-cyclohexanedione monoethylene glycol condensate (compound II) as a raw material, and adds a proper amount of a Grignard reagent to obtain 8-methyl-1, 4-dioxyspiro [4,5] decan-8-ol (compound III); dissolving 8-methyl-1, 4-dioxyspiro [4,5] decane-8-ol (compound III) in an organic solvent, adding a proper fluorinating agent under the protection of inert gas and at low temperature to obtain 8-methyl-1, 4-dioxyspiro [4,5] decane-8-fluorine (compound IV); converting the compound IV into 4-fluoro-4-methylcyclohexanone (compound V) under the action of a hydrochloric acid solution with a proper concentration; and finally, under the protection of nitrogen and the action of a reducing agent sodium borohydride, obtaining the 4-fluoro-4-methylcyclohexanol (compound I).
Further, the synthetic route of the preparation method comprises the following steps:
preferably, in the step of preparing the compound III by condensing 1, 4-cyclohexanedione monoethylene glycol (compound II), the Grignard reagent is methyl magnesium bromide;
preferably, in the step of preparing the compound III by using the compound II, the molar ratio of the compound II to the format reagent is in a range of 1.
Preferably, in the step of preparing the compound IV from the compound III, the type of the organic solvent used is THF.
Preferably, in the step of preparing compound IV from compound III, the fluorine reagent used is DAST BF 4 。
Preferably, in the step of preparing the compound IV from the compound III, an inert gas is used for protection, and the inert gas is nitrogen.
Preferably, in the step of preparing the compound V from the compound IV, the concentration of the hydrochloric acid solution used is 2Mol/L.
Preferably, in the step of preparing the compound V from the compound IV, the solvent of the hydrochloric acid solution is methanol.
Preferably, in the step of preparing compound I from compound V, a molar ratio of compound V to potassium borohydride is in the range of 1.
The 4-fluoro-4-methylcyclohexanol and the preparation method thereof of the invention have at least the following beneficial technical effects:
the invention provides a simple, convenient and effective synthetic route, obtains the unreported 4-fluoro-4-methylcyclohexanol by synthesis, solves the defects of the prior synthetic technology, has mild reaction conditions and simple and convenient operation, and can realize the rapid preparation in laboratories and industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
On the contrary, the invention is intended to cover alternatives, modifications, equivalents and alternatives which may be included within the spirit and scope of the invention as defined by the appended claims. Furthermore, in the following detailed description of the present invention, certain specific details are set forth in order to provide a better understanding of the present invention. It will be apparent to one skilled in the art that the present invention may be practiced without these specific details.
The following examples serve to illustrate the invention. In the examples, parts are by weight, percentages are by weight and temperatures are in degrees centigrade, unless otherwise indicated. The relationship between parts by weight and parts by volume is the same as the relationship between grams and cubic centimeters.
Abbreviations for the reagents involved in the examples are as follows:
NaBH4: sodium borohydride;
DAST·BF 4 : n, N-diethyl-S, S-difluoro-thioimine tetrafluoroborate;
and (3) DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene;
PE: petroleum ether;
THF: tetrahydrofuran;
MTBE: methyl tert-butyl acid;
DCM: dichloromethane;
EA: and (3) ethyl acetate.
MeOH: methanol.
Example 1
This example proposes a method for preparing 4-fluoro-4-methylcyclohexanol, the synthetic route of which includes:
the specific contents of the compound II for preparing the compound III comprise:
MeMgBr (3M, 102.447mL, 2.4eq) was dissolved in THF (200 mL), cooled to 0-5 ℃ and then a solution of 1, 4-cyclohexanedione monoethylene glycol (20.00g, 128.059mmol, 1eq) in THF was added dropwise, followed by natural warming to 20 ℃. After the reaction overnight, TLC plates (P: E =3, 1, rf =0.3, I2) showed no starting material remaining. The system was poured into 300g of crushed ice, left to stand, most of the THF removed by rotary evaporation, extracted with EA (100ml × 2), and the organic phase was dried over anhydrous magnesium sulfate. After removal of EA by rotary evaporation, a white solid was obtained as compound III (19.00g, 110.323mmol,86.151%,1 eq) in 86% yield. Wherein the H NMR of compound III (400Mz, CDCl3) is: 3.98-3.93 (m, 4H), 1.91-1.86 (m, 2H), 1.72-1.70 (m, 4H), 1.62-1.58 (m, 2H), 1.27 (s, 3H), 1.27-1.25 (d, 1H).
The concrete contents of compound III for preparing compound IV comprise:
8-methyl-1, 4-dioxyspiro [4,5] decan-8-ol (compound III) (19.00g, 110.323mmol, 1eq) was dissolved in DCM (200 mL) and DAST BF4 (27.790g, 121.356mmol, 1.1eq) was added in portions under nitrogen protection. After the addition, DBU (25.193g, 165.485mmol, 1.5eq) is added dropwise, and the reaction is continued at the temperature of-55 ℃ to-45 ℃. After 3 hours, TLC showed (P: E =5, 1, rf =0.66, I2) no starting material remained. Adding 100ml of saturated NaHCO3 solution to quench the reaction, standing for layering, drying an organic phase by anhydrous sodium sulfate, and performing rotary evaporation to obtain a colorless liquid, namely the compound IV. Wherein the nuclear magnetic H NMR of compound IV (400Mz, CDCl3) is: 4.00-3.94 (m, 4H), 1.94-1.88 (m, 4H), 1.78-1.67 (m, 2H), 1.61-1.59 (m, 2H), 1.40-1.37 (d, 3H).
Compound IV specific details for the preparation of compound V include:
8-methyl-1, 4-Dioxospiro [4,5] decan-8-fluoro (Compound IV) (4.800g, 27.553mmol, 1eq) was dissolved in THF (20 mL) and 10mL of 2M HCl in tetrahydrofuran was added dropwise with stirring at room temperature 20 ℃. After 6 hours of reaction, TLC plates (P: E =5, 1, rf =0.5, I2) showed no starting material remaining. To the system was added 50ml EA and 40ml saturated NaHCO3 solution was added dropwise, adjusting PH =8 or so. And then the system is layered, the organic phase is dried by anhydrous sodium sulfate, and colorless liquid is obtained after rotary evaporation, namely the compound V and is directly put into the next reaction.
Compound V specific details for the preparation of compound I include:
4-fluoro-4-methylcyclohexanone (Compound V) (3.500g, 26.890mmol, 1eq) was dissolved in MeOH (40 mL), and under nitrogen protection, solid NaBH4 (712.113mg, 18.823mmol, 0.7eq) was added in portions, and after addition, the reaction was continued for 2 hours. TLC plates (P: E =5, 1, rf =0.37, I2) showed disappearance of starting material. 50ml EA and 50ml water were added to the system, the layers were separated by standing, and the organic phase was dried over Na2SO 4. And (3) performing rotary evaporation and sand making, and passing through a column (mobile phase P: E =20: 1-8. Wherein the nuclear magnetic H NMR of compound I (400Mz, CDCl3) is: 3.64-3.59 (m, 1H), 1.97-1.92 (m, 2H), 1.83-1.79 (m, 2H), 1.70-1.54 (m, 3H), 1.53-1.41 (m, 2H), 1.40-1.37 (d, 3H).
Example 2
This example proposes a method for preparing 4-fluoro-4-methylcyclohexanol, the synthetic route of which includes:
the specific contents of preparing the compound III by using the compound II comprise:
MeMgCl (3M, 102.447mL, 2.4eq) is dissolved in THF (200 mL), after cooling to 0-5 ℃ a solution of 1, 4-cyclohexanedione monoethylene glycol (20.00g, 128.059mmol, 1eq) in THF is added dropwise and the temperature is then raised to 20 ℃ naturally. After the reaction overnight, TLC plates (P: E = 3. The system was poured into 300g of crushed ice, left to stand, most of the THF removed by rotary evaporation, extracted with EA (100ml × 2), and the organic phase dried over anhydrous magnesium sulfate. After removal of EA by rotary evaporation, a white solid was obtained as compound III (19.00g, 110.323mmol,86.151%,1 eq) in 86% yield. Wherein the H NMR of compound III (400Mz, CDCl3) is: 3.98-3.93 (m, 4H), 1.91-1.86 (m, 2H), 1.72-1.70 (m, 4H), 1.62-1.58 (m, 2H), 1.27 (s, 3H), 1.27-1.25 (d, 1H).
The concrete contents of compound III for preparing compound IV comprise:
8-methyl-1, 4-dioxyspiro [4,5] decan-8-ol (compound III) (19.00g, 110.323mmol, 1eq) was dissolved in THF (200 mL) and DAST BF4 (27.790g, 121.356mmol, 1.1eq) was added in portions under nitrogen protection. After the addition, DBU (25.193g, 165.485mmol, 1.5eq) was added dropwise, and the reaction was continued while maintaining the temperature between-55 ℃ and-45 ℃. After 3 hours, TLC showed (P: E =5, 1, rf =0.66, I2) no starting material remained. Adding 100ml of saturated NaHCO3 solution to quench the reaction, standing for layering, drying an organic phase by anhydrous sodium sulfate, and performing rotary evaporation to obtain a colorless liquid, namely the compound IV. Wherein the nuclear magnetic H NMR of compound IV (400Mz, CDCl3) is: 4.00-3.94 (m, 4H), 1.94-1.88 (m, 4H), 1.78-1.67 (m, 2H), 1.61-1.59 (m, 2H), 1.40-1.37 (d, 3H).
Compound IV specific details for the preparation of compound V include:
8-methyl-1, 4-Dioxospiro [4,5] decan-8-fluoro (Compound IV) (4.800g, 27.553mmol, 1eq) was dissolved in THF (20 mL) and 10mL of 4M HCl in methanol was added dropwise with stirring at room temperature 20 ℃. After 6 hours of reaction, TLC plates (P: E =5, 1, rf =0.5, I2) showed no starting material remaining. To the system was added 50ml EA and 40ml saturated NaHCO3 solution was added dropwise, adjusting PH =8 or so. And then the system is layered, the organic phase is dried by anhydrous sodium sulfate, and colorless liquid is obtained after rotary evaporation, namely the compound V is directly put into the next reaction.
The concrete contents for preparing the compound I by the compound V comprise:
4-fluoro-4-methylcyclohexanone (Compound V) (3.500g, 26.890mmol, 1eq) was dissolved in MeOH (40 mL), and under nitrogen protection, solid NaBH4 (712.113mg, 18.823mmol, 0.7eq) was added in portions, and after addition, the reaction was continued for 2 hours. TLC plates (P: E =5, 1, rf =0.37, I2) showed disappearance of starting material. Adding 50ml EA and 50ml water, standing for layering, and collecting organic phase with MgSO 4 And (5) drying. And (3) performing rotary evaporation and sand making, and passing through a column (mobile phase P: E =20: 1-8. Wherein the nuclear magnetic H NMR (400Mz, CDCl3) of compound I is: 3.64-3.59 (m, 1H), 1.97-1.92 (m, 2H), 1.83-1.79 (m, 2H), 1.70-1.54 (m, 3H), 1.53-1.41 (m, 2H), 1.40-1.37 (d, 3H).
Claims (10)
1. 4-fluoro-4-methylcyclohexanol characterized by the chemical structural formula:
2. a preparation method of 4-fluoro-4-methylcyclohexanol is characterized in that 1, 4-cyclohexanedione monoethylene glycol condensate (compound II) is used as a raw material, and a proper amount of Grignard reagent is added to obtain 8-methyl-1, 4-dioxyspiro [4,5] decan-8-ol (compound III); dissolving 8-methyl-1, 4-dioxyspiro [4,5] decane-8-ol (compound III) in an organic solvent, adding a proper fluorinating agent under the protection of inert gas and at low temperature to obtain 8-methyl-1, 4-dioxyspiro [4,5] decane-8-fluorine (compound IV); converting the compound IV into 4-fluoro-4-methylcyclohexanone (compound V) under the action of a hydrochloric acid solution with a proper concentration; finally, under the protection of nitrogen and the action of sodium borohydride, 4-fluoro-4-methylcyclohexanol (compound I) is obtained.
3. The method of claim 2, wherein the step of condensing 1, 4-cyclohexanedione monoethylene glycol (compound II) to produce compound III comprises using one of methyl magnesium bromide, methyl magnesium chloride and methyl lithium as a Grignard reagent.
4. A method according to claim 2 or 3, wherein in the step of preparing the compound III from the compound II, the molar ratio of the compound II to the format reagent is in the range of 1-0.95-1.
5. The process according to claim 2, wherein the organic solvent used in the step of preparing compound IV from 8-methyl-1, 4-dioxaspiro [4,5] decan-8-ol (compound III) is one of DCM, meOH, ethanol, EA, THF or 1, 6-dioxane.
6. The method according to claim 2, wherein in the step of preparing compound IV from compound III, the fluorinating agent is diethylaminosulfur trifluoride DAST BF 4 HF solution, potassium fluoride or sodium fluoride.
7. The method according to claim 2, wherein the compound III is protected with an inert gas such as nitrogen or argon in the step of preparing the compound IV.
8. The method according to claim 2, wherein the concentration of the hydrochloric acid solution in the step of converting 8-methyl-1, 4-dioxyspiro [4,5] decane-8-fluoro (compound IV) into 4-fluoro-4-methylcyclohexanone (compound V) is not more than 6 Mol/L.
9. The method according to claim 2, wherein in the step of converting 8-methyl-1, 4-dioxospiro [4,5] decane-8-fluoro (Compound IV) to Compound V, the solvent of the hydrochloric acid solution is one of water, dioxane, EA or methanol.
10. The method of claim 2, wherein in the step of converting 4-fluoro-4-methylcyclohexanone (compound V) to 4-fluoro-4-methylcyclohexanol (compound I), the molar ratio of compound V to potassium borohydride is in the range of 1.66-1.5.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150175594A1 (en) * | 2012-06-19 | 2015-06-25 | Hoffmann-La Roche Inc. | New bicyclic thiophenylamide compounds |
| CN111434661A (en) * | 2019-01-11 | 2020-07-21 | 爱科诺生物医药股份有限公司 | Aromatic heterocyclic compound with cell necrosis inhibitory activity and application thereof |
| US20220281886A1 (en) * | 2019-05-22 | 2022-09-08 | Merck Sharp Dohme Corp. | Natriuretic peptide receptor a agonists useful for the treatment of cardiometabolic diseases, kidney disease and diabetes |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150175594A1 (en) * | 2012-06-19 | 2015-06-25 | Hoffmann-La Roche Inc. | New bicyclic thiophenylamide compounds |
| CN111434661A (en) * | 2019-01-11 | 2020-07-21 | 爱科诺生物医药股份有限公司 | Aromatic heterocyclic compound with cell necrosis inhibitory activity and application thereof |
| US20220281886A1 (en) * | 2019-05-22 | 2022-09-08 | Merck Sharp Dohme Corp. | Natriuretic peptide receptor a agonists useful for the treatment of cardiometabolic diseases, kidney disease and diabetes |
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