CN117964497B - A method for synthesizing 3,3-difluorocyclopentanamine hydrochloride - Google Patents
A method for synthesizing 3,3-difluorocyclopentanamine hydrochlorideInfo
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- CN117964497B CN117964497B CN202410112757.3A CN202410112757A CN117964497B CN 117964497 B CN117964497 B CN 117964497B CN 202410112757 A CN202410112757 A CN 202410112757A CN 117964497 B CN117964497 B CN 117964497B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07—ORGANIC CHEMISTRY
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- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a synthesis method of 3, 3-difluoro cyclopentylamine hydrochloride, and particularly relates to the technical field of chemical synthesis. The synthesis method comprises the steps of taking 2-cyclopentenone and phthalimide as raw materials, and sequentially carrying out Michael addition reaction, deoxidization fluorination, phthaloyl protecting group removal, boc protection and deprotection salification reaction to obtain 3, 3-difluoro cyclopentylamine hydrochloride. The invention has reasonable synthetic route and process design, takes 2-cyclopentenone as the initial raw material, has mild reaction condition, simple post-treatment method, strong operability, low-cost and easily obtained raw materials and reagents, and total yield of 43.6 percent, and is a synthetic method with large-scale preparation value.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of 3, 3-difluoro cyclopentylamine hydrochloride.
Background
The 3, 3-difluoro cyclopentylamine hydrochloride has important application in the fields of medicine and new medicine research and development, and the compound with the structural fragment shows wide biological activity and has vigorous demand in the field of medicine research and development. Patent CN 102459267a reports the inhibitory activity of compound 8 on JAK for the treatment of diseases involving the immune system and inflammation including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e. malignant epithelial tumors), patent CN 114340634A reports that compound 9 has CDK kinase inhibitory activity and can be used in the treatment of tumors, patent CN 107001372a reports that compound 10 is useful in methods of treating or preventing cancer such as melanoma.
The synthesis method of 3, 3-difluorocyclopentylamine hydrochloride is reported in the literature as follows:
1. The patents CN 102459267 and CN107001372 report a synthesis method of 3, 3-difluorocyclopentylamine hydrochloride, with a total yield of 50.3%. The route is as follows:
The reported synthesis method has the following defects that firstly TMSN3 is adopted as an amino source, and the low-molecular-weight azide has great safety risk, so that the amplification feasibility of the method is limited, the noble metal palladium is adopted for the reduction of the second azide and is a pressurized reaction, the economy is poor, and thirdly, the product after the second step of reaction needs column chromatography, so that the possibility of the amplification production is further limited. Thus, the above-described disadvantages make the synthesis method impossible to prepare on a large scale.
2. Patent CN 105111201 reports a synthesis method of 3, 3-difluorocyclopentylamine hydrochloride, and does not report a specific synthesis yield, but the purification mode of each step of reaction product is column chromatography, and the feasibility of amplified production is not provided. The route is as follows:
3. Patent CN114340634 reports a synthesis method of 3, 3-difluoro cyclopentylamine hydrochloride, does not report a synthesis yield, the initial raw material 3-amino cyclopentanol is expensive, a toxic metal chromium PCC oxidant and noble metal palladium are used in the synthesis process, the economy is poor, and the mass production feasibility is not realized. The synthetic route is as follows:
4. literature Journal ofFluorine Chemistry 2017,199,60-66 reports a method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride, and the total yield is 30.1%. The 3-oxo-1-cyclopentane carboxylic acid serving as the initial raw material is high in price, TMSN3 is adopted as an amino source in the last step, the production safety risk is increased, and the feasibility of large-scale preparation is not realized. The synthetic route is as follows:
Disclosure of Invention
Therefore, the invention provides a synthesis method of 3, 3-difluoro cyclopentylamine hydrochloride to solve the problems.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides a method for synthesizing 3, 3-difluoro cyclopentylamine hydrochloride, which is characterized in that 2-cyclopentenone and phthalimide are used as raw materials, and Michael addition reaction, deoxidization fluorination, phthaloyl protecting group removal, tert-butoxycarbonyl (Boc) protection and deprotection salification reaction are sequentially carried out to prepare 3, 3-difluoro cyclopentylamine hydrochloride;
the reaction route is as follows:
Further, the Michael addition reaction is that 2-cyclopentenone (formula 1) and phthalimide (formula 2) are dissolved in a solvent, the temperature is controlled to be 0-5 ℃, then alkali is slowly added, the temperature is raised to 20-25 ℃ after the addition, the stirring reaction is completed, water is added, and the filtration is carried out, so that the compound shown in the formula 3 is obtained.
The invention discloses a synthesis method of 3, 3-difluoro cyclopentylamine hydrochloride, in particular to a method for screening and synthesizing a compound of formula 3 by an amino source reagent, which is found that under the reaction conditions, the generation of byproducts can be greatly reduced, the yield is improved, the post-treatment process is simplified, and the method is suitable for industrial production.
Further, the deoxidization and fluorination reaction is that the compound of the formula 3 is dissolved in a solvent, the temperature of the system is controlled to be 0-5 ℃, then a fluorinating reagent diethylaminosulfur trifluoride (DAST) is slowly added, saturated sodium bicarbonate is added after the reaction is finished, and the compound of the formula 4 is obtained after phase separation and spin drying.
Further, the removal of the phthaloyl protecting group and the tert-butoxycarbonyl (Boc) are that the compound shown in the formula 4 is dissolved in acetic acid, hydrochloric acid is added, the temperature of the system is controlled to be 100-110 ℃, stirring is carried out, the solvent is dried after the reaction is finished, alcohol is added for dissolution, boc anhydride is added, and the solvent is dried by rotation, so that the compound shown in the formula 6 is obtained.
Further, the deprotection salification of the tert-butyloxycarbonyl (Boc) is carried out by adding into solvent, controlling temperature at 0-5 deg.C, slowly adding into hydrogen chloride solution, stirring for reacting, filtering, washing, and drying to obtain pure product of the compound of formula 7.
Further, the molar ratio of the 2-cyclopentenone of the formula 1 to the phthalimide of the formula 2 to the alkali is 1.0:1.0-1.5:0.1-0.2, and/or,
The alkali is sodium bicarbonate or sodium carbonate or potassium carbonate or sodium phosphate or potassium phosphate or sodium tert-butoxide or potassium tert-butoxide, and/or,
The solvent is N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
The research shows that the solvent is DMF and sodium carbonate is used as alkali, which is more beneficial to improving the reaction efficiency and the yield of the product.
Further, the deoxidization and fluorination reaction is carried out in the presence of a fluorination reagent and a solvent, wherein the molar ratio of the compound of the formula 3 to the fluorination reagent is 1.0:2.0-4.0, and/or,
The fluorinating agent is diethylaminosulfur trifluoride (DAST) or thiomorpholine trifluoride, and/or,
The solvent is tetrahydrofuran or dichloromethane or 1, 2-dichloroethane, and/or,
The temperature of the deoxidization fluorination reaction is 0-5 ℃.
Further, the phthaloyl protecting group is removed and protected by tert-butoxycarbonyl (Boc), namely, dissolving a compound shown in a formula 4 in acetic acid, adding hydrochloric acid for reflux, wherein the mass volume ratio of the compound shown in the formula 4 to the acetic acid to the hydrochloric acid is 1.0:5-10:5-10, and/or adding alcohol for dissolution, and adding Boc anhydride, wherein the mole ratio of the compound shown in the formula 5 to the Boc anhydride is 1:1.1-1.5;
The hydrochloric acid concentration is 5N or 10N, and/or,
The alcohol is methanol or 95% ethanol.
The removal of the acid condition of the phthaloyl is more favorable for the conventional hydrazine hydrate condition to seriously influence the purification of the intermediate, and the separation and purification of the compound of the formula 6 after the protection of the tert-butoxycarbonyl (Boc) are more concise.
Further, the deprotection of the tert-butyloxycarbonyl group (Boc) to form a salt is performed in the presence of a compound of formula 6, a hydrogen chloride solution and a solvent, wherein the molar ratio of the compound of formula 6 to the hydrogen chloride is 1.0:1.5-2.0, and/or,
The hydrogen chloride solution is hydrogen chloride ethanol solution or hydrogen chloride ethyl acetate solution or hydrogen chloride dioxane solution or hydrogen chloride tetrahydrofuran solution, and/or,
The solvent is water, tetrahydrofuran, dioxane or ethyl acetate.
The research shows that the dioxane solution product added with hydrogen chloride has better properties, higher purity and yield by using tetrahydrofuran as a solvent.
The invention has the following advantages:
The invention has reasonable synthetic route and process design, takes 2-cyclopentenone as the initial raw material, has mild reaction condition, simple post-treatment method, strong operability, low-cost and easily obtained raw materials and reagents, and total yield of 43.6 percent, and is a synthetic method with large-scale preparation value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It will be apparent to those of ordinary skill in the art that the drawings in the following description are exemplary only and that other implementations can be obtained from the extensions of the drawings provided without inventive effort.
The structures, proportions, sizes, etc. shown in the present specification are shown only for the purposes of illustration and description, and are not intended to limit the scope of the invention, which is defined by the claims, so that any structural modifications, changes in proportions, or adjustments of sizes, which do not affect the efficacy or the achievement of the present invention, should fall within the ambit of the technical disclosure.
FIG. 1 is a HPLC purity profile of 6-tert-butoxycarbonyl-2-amino-6-azaspiro [3.4] octane provided in example 1 of the present invention;
FIG. 2 is a MS plot of 6-t-butoxycarbonyl-2-amino-6-azaspiro [3.4] octane provided in example 1 of the present invention.
Detailed Description
Other advantages and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, which, by way of illustration, is to be read in connection with certain specific embodiments, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides a synthesis method of 6-tert-butoxycarbonyl-2-amino-6-azaspiro [3.4] octane, which comprises the following steps:
(1) Michael addition reaction
Compound 1 (5.0 Kg,60.976mol,1.0 eq) was added to the reaction vessel, DMF (50L) was added, compound 2 (8.97 Kg,60.976mol,1.0 eq) was added, cooled to 0 ℃, sodium carbonate solid (646.4 g,6.098mol,0.1 eq) was added in portions, the reaction was stirred for 12H, uplc monitored for no starting compound 1, water (100L) was added, stirred for 2H, filtered, the filter cake was washed with water (10L), and dried to give compound 311.88Kg, yield 85%, HPLC 90.5%, LC-MS: [ m+h ] = 230.24, directly into the next reaction without purification.
(2) Deoxofluorination reaction
Compound 3 (11.880 Kg,51.823mol,1.0 eq) obtained in step (1) was dissolved in dichloromethane (60L), the temperature was controlled to 0 ℃, diethylaminosulfur trifluoride (DAST) (20.88 Kg, 129.5538 mol,2.5 eq) was added dropwise, the reaction was stirred for 3H, uplc showed that starting material 3 disappeared, the reaction system was added to saturated sodium bicarbonate (50L), stirred for 1H quenching reaction, water washed (5 l×2), saturated sodium chloride (5 l×2), and concentrated to give compound 4 (9.764 Kg, yield 75%, HPLC 92.3%), LC-MS: [ m+h ] = 252.23. The reaction was carried forward without purification.
(3) Removal of the phthaloyl protecting group and protection with t-butoxycarbonyl (Boc)
Compound 4 (5.0 Kg,19.902 mol) is dissolved in 30L glacial acetic acid, 10N hydrochloric acid (15L) is slowly heated and refluxed for 6H, concentrated, 5L of 95% ethanol is added for dissolution, and concentrated for 2 times to obtain a hydrochloride crude product of the compound of formula 5, 20L of 95% ethanol is added for dissolution, and (Boc) 2 O (5.513 Kg,23.882mol,1.2 eq) is added in portions, stirred and reacted for 12H at 25 ℃ and the solvent is dried by a rotary dryer to obtain the compound of formula 6, (3.545 Kg, HPLC 92%, LC-MS: [ M+H ] = 222.25 yield 80.5%), and the next reaction is carried out without purification.
(1) Boc protection and removal of salification
The obtained compound 6 (2.0 Kg, 9.040mol) was added into a reaction kettle, 10L of tetrahydrofuran was added for dissolution, the temperature was lowered to 0 ℃, a dioxane solution (4M, 4.52L,2.0 eq) of hydrogen chloride was added dropwise into the system for stirring and reaction for 8 hours, a large amount of white solid was precipitated, and the compound of formula 7 was obtained by filtration, washing with 2L of tetrahydrofuran and drying. (1.21 Kg, yield 85%, HPLC purity profile as shown in FIG. 1, purity 99.42%, MS profile as shown in FIG. 2, LC-MS: [ M+H ] =121.0).
Example 2
This example provides a method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride that differs from example 1 only in the deoxygenation fluorination reaction conditions.
The deoxofluorination reaction of this example is as follows:
Compound 3 (11.660 Kg,51.823mol,1.0 eq) was dissolved in dichloromethane (60L), the temperature was controlled to 0 ℃, diethylaminosulfur trifluoride (DAST) (18.378 Kg, 114.01mmol, 2.2 eq) was added dropwise for not less than 1H, the reaction was stirred for 3H, uptc showed the disappearance of starting material 3, the reaction system was added to saturated sodium bicarbonate (50L), stirred for 1H to quench the reaction, water was washed (5 l×2), saturated sodium chloride (5 l×2), and concentrated to give compound 4 (7.811 Kg, yield 60%, HPLC 85%), LC-MS: [ m+h ] = 252.23. The reaction was carried forward without purification.
Comparative example 1
This comparative example provides a synthesis of 3, 3-difluorocyclopentylamine hydrochloride which differs from example 1 only in the removal of the phthaloyl protecting group and the t-butoxycarbonyl (Boc) protecting reaction conditions.
Compound 4 (5.0 kg,19.902 mol) was dissolved in 30L of methanol, slowly 40% hydrazine hydrate (3L), stirred at room temperature for reaction for 12H, the solid was filtered, the filter cake was washed with 5L of methanol to obtain filtrate, concentrated to obtain crude compound of formula 5, 20L of 95% ethanol was added for dissolution, (Boc) 2 O (5.513 kg,23.882mol,1.2 eq) was added in portions, stirred at 25 ℃ for reaction for 12H, the solvent was dried by spin-drying, 10L of MTBE was added for slurrying purification to obtain compound of formula 6, (2.642 kg, hplc 80%, LC-MS: [ m+h ] = 222.25 yield 60.0%) without purification into the next reaction.
Comparative example 2
This comparative example provides a process for the synthesis of 3, 3-difluorocyclopentylamine hydrochloride which differs from example 1 only in the reaction conditions of the deoxofluorination.
Compound 3 (11.880 Kg,51.823mol,1.0 eq) was dissolved in dichloromethane (60L), the temperature was controlled to 0 ℃, thiomorpholine trifluoride (MOST) (22.698 Kg,129.58mol,2.5 eq) was added dropwise for not less than 1H, the reaction was stirred for 6H, UPLC showed the disappearance of starting material 3, the reaction system was added to saturated sodium bicarbonate (50L), stirred for 1H quench reaction, water washed (5L X2), saturated sodium chloride (5L X2), and concentrated to give compound 4 (5.207 Kg, yield 40%, HPLC 88%), LC-MS: [ M+H ] = 252.23. The reaction was carried forward without purification.
While the invention has been described in detail in the foregoing general description and specific examples, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (9)
1. A synthetic method of 3, 3-difluoro cyclopentylamine hydrochloride is characterized in that 2-cyclopentenone and phthalimide are used as raw materials, and Michael addition reaction, deoxidization fluorination, phthaloyl protecting group removal, tert-butoxycarbonyl (Boc) protection and deprotection salification reaction are sequentially carried out to prepare 3, 3-difluoro cyclopentylamine hydrochloride;
the reaction route is as follows:
2. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 1, wherein the Michael addition reaction comprises the steps of dissolving 2-cyclopentenone of formula 1 and phthalimide of formula 2 in a solvent, controlling the temperature to be 0-5 ℃, slowly adding alkali, after the addition, raising the temperature to 20-25 ℃, after the stirring reaction, adding water, and filtering to obtain the compound shown in formula 3.
3. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 2, wherein the deoxidization fluorination reaction comprises the steps of dissolving a compound of formula 3 in a solvent, controlling the temperature of the system to be 0-5 ℃, slowly adding a fluorinating reagent diethylaminosulfur trifluoride, adding saturated sodium bicarbonate after the reaction is finished, separating phases, and spin-drying to obtain the compound of formula 4.
4. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 3, wherein the removal of phthaloyl protecting groups and tert-butoxycarbonyl groups comprises the steps of dissolving a compound of formula 4 in acetic acid, adding hydrochloric acid, controlling the temperature of a system to be 100-110 ℃, stirring, spinning a solvent after the reaction is completed, adding alcohol for dissolution, adding Boc anhydride, and spinning the solvent to obtain the compound of formula 6.
5. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 4, wherein the deprotection salification of tert-butoxycarbonyl (Boc) comprises the steps of adding a compound of formula 6, controlling the temperature to be 0-5 ℃, slowly adding a hydrogen chloride solution, stirring for reaction, filtering, washing and drying to obtain a pure compound of formula 7.
6. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 5,
The molar ratio of the 2-cyclopentenone of the formula 1 to the phthalimide of the formula 2 to the alkali is 1.0:1.0-1.5:0.1-0.2, and/or,
The alkali is sodium bicarbonate or sodium carbonate or potassium carbonate or sodium phosphate or potassium phosphate or sodium tert-butoxide or potassium tert-butoxide, and/or,
The solvent is N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
7. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 6,
The deoxidization and fluorination reaction is carried out in the presence of a fluorination reagent and a solvent, wherein the molar ratio of the compound of the formula 3 to the fluorination reagent is 1.0:2.0-4.0, and/or,
The fluorinating agent is diethylaminosulfur trifluoride (DAST) or thiomorpholine trifluoride, and/or,
The solvent is tetrahydrofuran or dichloromethane or 1, 2-dichloroethane, and/or,
The temperature of the deoxidization fluorination reaction is 0-5 ℃.
8. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 7, wherein the phthaloyl protecting group is removed and protected by tert-butoxycarbonyl (Boc), wherein a compound of formula 4 is dissolved in acetic acid, hydrochloric acid is added for reflux, the mass volume ratio of the compound of formula 4 to acetic acid to hydrochloric acid is 1.0:5-10:5-10, and/or alcohol is added for dissolution, boc anhydride is added, and the molar ratio of the compound of formula 5 to Boc anhydride is 1:1.1-1.5;
The hydrochloric acid concentration is 5N or 10N, and/or,
The alcohol is methanol or 95% ethanol.
9. The method for synthesizing 3, 3-difluorocyclopentylamine hydrochloride according to claim 8, wherein the deprotection of tert-butoxycarbonyl (Boc) to form a salt is performed in the presence of a compound of formula 6, a hydrogen chloride solution and a solvent, wherein the molar ratio of the compound of formula 6 to hydrogen chloride is 1.0:1.5-2.0, and/or,
The hydrogen chloride solution is hydrogen chloride ethanol solution or hydrogen chloride ethyl acetate solution or hydrogen chloride dioxane solution or hydrogen chloride tetrahydrofuran solution, and/or,
The solvent is water, tetrahydrofuran, dioxane or ethyl acetate.
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