CN114685283B - Preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride - Google Patents
Preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride Download PDFInfo
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- CN114685283B CN114685283B CN202210359376.6A CN202210359376A CN114685283B CN 114685283 B CN114685283 B CN 114685283B CN 202210359376 A CN202210359376 A CN 202210359376A CN 114685283 B CN114685283 B CN 114685283B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- PMRVWCCUZFVRFL-UHFFFAOYSA-N 1-(fluoromethyl)cyclopropan-1-amine hydrochloride Chemical compound Cl.NC1(CF)CC1 PMRVWCCUZFVRFL-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 (1-hydroxymethyl cyclopropyl) -tert-butoxycarbonylamino Chemical group 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012025 fluorinating agent Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 claims description 2
- QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical group FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003682 fluorination reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 1
- XIWZLSFPKZDWMZ-UHFFFAOYSA-N F[S](F)F.CCNCC Chemical compound F[S](F)F.CCNCC XIWZLSFPKZDWMZ-UHFFFAOYSA-N 0.000 description 1
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 description 1
- 101000589450 Homo sapiens Poly(ADP-ribose) glycohydrolase Proteins 0.000 description 1
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100032347 Poly(ADP-ribose) glycohydrolase Human genes 0.000 description 1
- 102000057028 SOS1 Human genes 0.000 description 1
- 108700022176 SOS1 Proteins 0.000 description 1
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 1
- 101150100839 Sos1 gene Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C269/06—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 by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention provides a preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride, which comprises the following steps: the (1-hydroxymethyl cyclopropyl) -tert-butoxycarbonylamino is taken as a starting material, a compound shown in a formula III is obtained through fluorination, the compound shown in the formula III is acidified by concentrated hydrochloric acid to obtain 1- (fluoromethyl) cyclopropylamine hydrochloride, the operation is simple and convenient, the condition is mild, the equipment requirement is low, the raw materials are easy to obtain, the yield is high, the total yield of the two steps is more than 60%, and the blank of the prior art is filled.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride.
Background
1- (fluoromethyl) cyclopropylamine hydrochloride is a widely used pharmaceutical intermediate, and plays an important role in the research of new drugs, and introduction of fluorine atoms into lead compounds to improve physicochemical properties such as lipophilicity has become a common structural modification means. As described in international patent publication No. WO 2020092621A1, 1- (fluoromethyl) cyclopropylamine hydrochloride can be used as an intermediate for the preparation of compounds having HPK1 inhibitory activity for the treatment of diseases such as HBV, HIV, cancer and/or hyperproliferative; as further described in international patent publication No. WO 2019122129 A1, 1- (fluoromethyl) cyclopropylamine hydrochloride can be used as an intermediate for the preparation of a compound having SOS1 inhibitory activity for the treatment and/or prevention of oncologic diseases; in addition, there are compounds having PARG inhibitor activity as intermediates described in international patent publication No. WO 2016097749A1, and the like.
Literature j. Phys. Org. Chem.2015, 28-395 reports the preparation of the following approximate structural compounds:
no related report is found on the route and the preparation method of the 1- (fluoromethyl) cyclopropylamine hydrochloride.
Disclosure of Invention
The invention aims to provide a preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride, which is simple and convenient to operate, and the total yield of the two steps is more than 60%.
The technical scheme adopted by the invention is as follows: a process for the preparation of a compound of formula I comprising:
preferably, in the step of preparing the compound of formula III from the compound of formula II, the fluorinating agent is selected from sulfur tetrafluoride, triethylamine hydrofluoride, 2-difluoro-1, 3-dimethylimidazolidine, diethylaminosulfur trifluoride, N-diethyl-1, 2, 3-hexafluoropropylamine, (diethylamino) sulfur difluoride tetrafluoroborate, difluoro (morpholino) sulfonium tetrafluoroborate or bis (2-methoxyethyl) amino sulfur trifluoride.
Preferably, in the step of preparing the compound of formula III from the compound of formula II, the molar ratio of the compound of formula II to the fluorinating agent is 1:1 to 3.
Preferably, in the step of preparing the compound of formula III from the compound of formula II, the reaction solvent is selected from tetrahydrofuran, dichloromethane or diethyl ether.
Preferably, in the step of preparing the compound of formula III from the compound of formula II, the reaction temperature is-78 to 25 ℃.
Preferably, in the step of the compounds of formula III to the compounds of formula I, the molar ratio of the compounds of formula III to concentrated hydrochloric acid is 1:1 to 3.
Preferably, in the step of reacting the compound of formula III to the compound of formula I, the reaction solvent is selected from methanol, ethanol, methyl tert-butyl ether, acetone or ethyl acetate.
Preferably, in the step of reacting the compound of formula III to the compound of formula I, the reaction temperature is from-10 to 30 ℃.
The beneficial effects of the invention are as follows: the preparation route and the method of the 1- (fluoromethyl) cyclopropylamine hydrochloride have the advantages of ingenious design, simple and convenient operation, mild conditions, low equipment requirements, readily available raw materials and high yield, the total yield of the two steps reaches more than 60%, and the blank of the prior art is filled.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below in connection with specific embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. 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
Preparation of a compound of formula III:
the compound of formula II (10.00 g,0.053mol,1.0 eq) was dissolved in 100 ml of dichloromethane, cooled to-78℃with nitrogen, and (diethylamine) sulfur trifluoride (12.92 g,0.0795mol,1.5 eq) in dichloromethane (50 ml) was added dropwise, and the reaction mixture was naturally warmed to room temperature of 20℃and then stirred for 18 hours; to the mixture was added saturated sodium bicarbonate solution (50 ml), the two layers were separated, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 8.6 g of a brown oil, i.e., a compound of formula iii, in 85% yield.
1 HNMR(400MHz，CDCl 3 )δ(ppm):3.45-3.54(m，2H)，1.56(s，9H)，1.27-1.29(m， 2H)，1.19-1.25(m，2H)
Preparation of the compound of formula I:
the compound of formula III (4.00 g,0.021mol,1.0 eq) was dissolved in 40 ml of methanol, the temperature was controlled below 10℃and concentrated hydrochloric acid (1.5 g) was added dropwise, and the reaction mixture was naturally warmed to room temperature of 20℃and then stirred for 2 hours. The methanol was concentrated under reduced pressure to give 2g of a pale yellow solid, i.e., the compound of formula I in 76% yield.
1HNMR(400MHz，DMSO-d6)δ(ppm):8.87(s，3H)，4.58(s，1H)，4.46(s，1H)，1.08-1.13 (m，2H)，0.89-0.92(m，2H)
Example 2
Preparation of a compound of formula III:
the compound of formula II (20.00 g,0.106mol,1.0 eq) was dissolved in 250 ml of dichloromethane and N, N-diethyl-1, 2, 3-hexafluoropropylamine (30.75 g,0.137mol,1.3 eq) was added dropwise in dichloromethane (100 ml) and the reaction mixture was stirred at room temperature for 12 hours. To the mixture was added saturated sodium bicarbonate solution (100 ml) and the two layers separated. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 17.6 g of a pale yellow oil, i.e., the compound of formula III in 87% yield.
1 HNMR(400MHz，CDCl 3 )δ(ppm):3.45-3.55(m，2H)，1.55(s，9H)，1.27-1.29(m，2H)，1.18-1.25(m，2H)
Preparation of the compound of formula I:
the compound of formula III (15 g,0.079mol,1.0 eq) was dissolved in 100 ml of acetone, the temperature was controlled below 10℃and concentrated hydrochloric acid (6 g) was added dropwise, the reaction mixture was warmed naturally to room temperature of 20℃and then stirred for 2 hours. The acetone was concentrated under reduced pressure to give 8 g of a white solid, i.e. a compound of formula I in 80.8% yield.
1 HNMR(400MHz，DMSO-d6)δ(ppm):8.87(s，3H)，4.58(s，1H)，4.46(s，1H)，1.09-1.13 (m，2H)，0.88-0.91(m，2H)。
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A process for the preparation of a compound of formula I comprising:
，
in the step of preparing the compound of the formula III from the compound of the formula II, the reaction temperature is-78-25 ℃; in the step of the compounds of the formula III to the compounds of the formula I, the reaction temperature is-10-30 ℃.
2. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of formula III from the compound of formula II, the fluorinating agent is selected from sulfur tetrafluoride, triethylamine hydrofluoride, 2-difluoro-1, 3-dimethylimidazolidine, diethylaminosulfur trifluoride, N-diethyl-1, 2, 3-hexafluoropropylamine, (diethylamino) sulfur difluoride tetrafluoroborate, difluoro (morpholino) sulfonium tetrafluoroborate or bis (2-methoxyethyl) amino sulfur trifluoride.
3. The preparation method according to claim 1 or 2, characterized in that: in the step of preparing the compound of the formula II, the molar ratio of the compound of the formula II to the fluorinating agent is 1:1-3.
4. The preparation method according to claim 1 or 2, characterized in that: in the step of preparing the compound of formula III from the compound of formula II, the reaction solvent is selected from tetrahydrofuran, dichloromethane or diethyl ether.
5. The method of manufacturing according to claim 1, characterized in that: in the steps from the compound of the formula III to the compound of the formula I, the molar ratio of the compound of the formula III to the concentrated hydrochloric acid is 1:1-3.
6. The method of manufacturing according to claim 1, characterized in that: in the step of the compounds of formula III to the compounds of formula I, the reaction solvent is selected from methanol, ethanol, methyl tert-butyl ether, acetone or ethyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210359376.6A CN114685283B (en) | 2022-04-06 | 2022-04-06 | Preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210359376.6A CN114685283B (en) | 2022-04-06 | 2022-04-06 | Preparation method of 1- (fluoromethyl) cyclopropylamine hydrochloride |
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| CN114685283A CN114685283A (en) | 2022-07-01 |
| CN114685283B true CN114685283B (en) | 2024-02-27 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3484464A1 (en) * | 2016-03-22 | 2019-05-22 | Merck Sharp & Dohme Corp. | N1-phenylpropane-1,2-diamine compounds with selective activity in voltage-gated sodium channels |
| CN111217709A (en) * | 2018-11-27 | 2020-06-02 | 南京药石科技股份有限公司 | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride |
| CN112996789A (en) * | 2018-09-12 | 2021-06-18 | 诺华股份有限公司 | Antiviral pyridopyrazinedione compounds |
| WO2022017519A1 (en) * | 2020-07-24 | 2022-01-27 | 南京明德新药研发有限公司 | Quinazoline compound |
| WO2022184849A1 (en) * | 2021-03-04 | 2022-09-09 | Les Laboratoires Servier | Glp-1r agonists, uses and pharmaceutical compositions thereof |
| CN116917279A (en) * | 2020-08-07 | 2023-10-20 | 渤健马萨诸塞州股份有限公司 | BTK inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MA41179A (en) * | 2014-12-19 | 2017-10-24 | Cancer Research Tech Ltd | PARG INHIBITOR COMPOUNDS |
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2022
- 2022-04-06 CN CN202210359376.6A patent/CN114685283B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3484464A1 (en) * | 2016-03-22 | 2019-05-22 | Merck Sharp & Dohme Corp. | N1-phenylpropane-1,2-diamine compounds with selective activity in voltage-gated sodium channels |
| CN112996789A (en) * | 2018-09-12 | 2021-06-18 | 诺华股份有限公司 | Antiviral pyridopyrazinedione compounds |
| CN111217709A (en) * | 2018-11-27 | 2020-06-02 | 南京药石科技股份有限公司 | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride |
| WO2022017519A1 (en) * | 2020-07-24 | 2022-01-27 | 南京明德新药研发有限公司 | Quinazoline compound |
| CN116917279A (en) * | 2020-08-07 | 2023-10-20 | 渤健马萨诸塞州股份有限公司 | BTK inhibitors |
| WO2022184849A1 (en) * | 2021-03-04 | 2022-09-09 | Les Laboratoires Servier | Glp-1r agonists, uses and pharmaceutical compositions thereof |
Non-Patent Citations (2)
| Title |
|---|
| [New methods of constructing fluorinated organic compounds and their application];M Kirihara;《Yakugaku Zasshi.》;第120卷(第04期);第339-351页 * |
| Microwave Spectrum, Conformational Composition, and Dipole Moment of (Fluoromethyl)cyclopropane (C3H5CH2F);Samdal, Svein，等;《Journal of Physical Chemistry A》;第118卷(第12期);第2344-2352页 * |
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