CN107673978B - Intermediate of 2, 2-difluorocycloalkyl methylamine and preparation method thereof - Google Patents
Intermediate of 2, 2-difluorocycloalkyl methylamine and preparation method thereof Download PDFInfo
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- CN107673978B CN107673978B CN201710907970.3A CN201710907970A CN107673978B CN 107673978 B CN107673978 B CN 107673978B CN 201710907970 A CN201710907970 A CN 201710907970A CN 107673978 B CN107673978 B CN 107673978B
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- 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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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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Abstract
The invention discloses an intermediate of 2, 2-difluoro cycloalkyl methylamine and a preparation method thereof, the method takes cycloalkanone (compound II) as a raw material, a compound III is prepared by Mannich reaction, the compound III reacts with a fluorinating reagent to prepare a compound IV, the compound IV and hydrogen are subjected to reduction reaction in the presence of a catalyst to remove benzyl, and the 2, 2-difluoro cycloalkyl methylamine (compound I) is prepared.
Description
Technical Field
The invention relates to the field of heterocyclic organic chemical synthesis, in particular to an intermediate of 2, 2-difluorocycloalkyl methylamine and a preparation method thereof.
Background
2, 2-difluorocycloalkylmethylamine is an important pharmaceutical intermediate, and US2013345204a1 reports that a part of lactam analogs containing 2, 2-difluorocycloalkylmethylamine structural fragments, as allosteric modulators of the glutamate receptor subtype 5(mGluR5) receptor, may be used for the treatment or prevention of disorders associated with glutamate dysfunction and diseases in which the mGluR5 subtype of receptor is involved, but no related reports are known about the synthesis process of 2, 2-difluorocycloalkylmethylamine.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide an intermediate of 2, 2-difluorocycloalkylmethylamine and a preparation method thereof, and the method is simple and convenient to operate, high in yield and suitable for large-scale preparation.
The technical scheme is as follows:
the present invention provides a compound of structural formula IV:
wherein: n is 1,2 or 3; bn is benzyl.
Specifically, compound IV is selected from the following compounds:
the invention also provides a preparation method of the compound IV, which comprises the following steps:
wherein: n is 1,2 or 3; the formaldehyde reagent is selected from 40% formaldehyde aqueous solution, paraformaldehyde, trioxymethylene or methylal.
In the process of preparing the compound III from the compound II, the reaction system is preferably a buffer system with pH of 3-6. The above buffer system comprises: glycine/hydrochloric acid system, potassium hydrogen phthalate/hydrochloric acid system, disodium hydrogen phosphate/citric acid system, citric acid/sodium hydroxide/hydrochloric acid system, citric acid/sodium citrate system, acetic acid/sodium acetate system, disodium hydrogen phosphate/sodium dihydrogen phosphate system, disodium hydrogen phosphate/potassium dihydrogen phosphate system, potassium dihydrogen phosphate/sodium hydroxide system, etc.
In the process of preparing the compound III from the compound II, the molar ratio of the compound II to the formaldehyde reagent to the dibenzylamine is 1: 1-3; the reaction solvent is selected from water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or toluene; the reaction temperature is 0-110 ℃.
In the process of preparing a compound IV from the compound III, a fluorinating reagent is diethylaminosulfur trifluoride or bis (2-methoxyethyl) aminosulfur trifluoride; the molar ratio of the compound III to the fluorinating reagent is 1: 1-1: 5; the reaction solvent is selected from dichloromethane, trichloromethane or 1, 2-dichloroethane; the reaction temperature is-80-40 ℃.
Further, the present invention provides a process for preparing a compound of formula I or a hydrochloride salt thereof, comprising:
wherein: n is 1,2 or 3; the hydrochloric acid is hydrochloric acid solution or hydrochloric acid gas.
In the process of preparing the compound I from the compound IV, the catalyst is selected from palladium carbon or palladium hydroxide carbon; the mass ratio of the compound IV to the catalyst is 1: 0.05-1: 0.5; the solvent is selected from methanol, ethanol or tetrahydrofuran.
Further, compound I can be prepared by the following method:
wherein: n is 1,2 or 3; the formaldehyde reagent is selected from 40% formaldehyde aqueous solution, paraformaldehyde, trioxymethylene or methylal.
In the process of preparing the compound III from the compound II, the reaction system is preferably a buffer system with pH of 3-6. The above buffer system comprises: glycine/hydrochloric acid system, potassium hydrogen phthalate/hydrochloric acid system, disodium hydrogen phosphate/citric acid system, citric acid/sodium hydroxide/hydrochloric acid system, citric acid/sodium citrate system, acetic acid/sodium acetate system, disodium hydrogen phosphate/sodium dihydrogen phosphate system, disodium hydrogen phosphate/potassium dihydrogen phosphate system, potassium dihydrogen phosphate/sodium hydroxide system, etc.
In the process of preparing the compound III from the compound II, the molar ratio of the compound II to the formaldehyde reagent to the dibenzylamine is 1: 1-3; the reaction solvent is selected from water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or toluene; the reaction temperature is 0-110 ℃.
In the process of preparing a compound IV from the compound III, a fluorinating reagent is diethylaminosulfur trifluoride or bis (2-methoxyethyl) aminosulfur trifluoride; the molar ratio of the compound III to the fluorinating reagent is 1: 1-1: 5; the reaction solvent is selected from dichloromethane, trichloromethane or 1, 2-dichloroethane; the reaction temperature is-80-40 ℃.
In the process of preparing the compound I from the compound IV, the catalyst is selected from palladium carbon or palladium hydroxide carbon; the mass ratio of the compound IV to the catalyst is 1: 0.05-1: 0.5; the solvent is selected from methanol, ethanol or tetrahydrofuran.
Has the advantages that: the preparation method has the advantages of short route steps, mild conditions, simple and convenient operation and stable process, the total preparation route of the compound I is 3-step reaction, and the total yield can reach 83.5%. The yield of the two steps of preparing the compound III and preparing the compound IV from the compound II can reach 83.5 percent, the purification is convenient, the scale-up production is easy, and more remarkably, the raw material compound II, namely the cycloalkanone, has low price and sufficient market, and the whole synthesis process is safe and environment-friendly, and is a new process method for synthesizing the target compound.
Detailed description of the preferred embodiments
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of Compound III-1:
compound II-1(10.00g, 0.143mol, 1.0e.q.), 40% aqueous formaldehyde solution (10.50g, 0.143mol, 1.0e.q.), and dibenzylamine (27.60g, 0.143mol, 1.0e.q.) -were added to toluene (200mL), followed by addition of sodium acetate (2.30g, 0.028mol, 0.2e.q.) and acetic acid (1.70g, 0.028mol, 0.2e.q.), heating to 110 ℃ after completion of the reaction, stirring and reacting for 15 hours, LC-MS monitoring completion of the reaction, pouring the reaction solution into saturated aqueous sodium bicarbonate solution (200mL), separating the layers, extracting the aqueous phase with ethyl acetate (100mL × 3), combining the organic phases, washing with saturated brine (200mL × 1), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 38.39g of compound III-1 as a pale yellow oil with a yield of 96.3%.1H-NMR(400MHz,CDCl3):(ppm)7.39-7.25(m,10H),3.69-3.64(m,4H),3.03-2.96(m,1H),2.91-2.79(m,2H),2.72-2.67(m,1H),2.21-2.12(m,1H),1.75-1.66(m,1H),1.33-1.26(m,1H)。
Preparation of Compound IV-1:
dissolving a compound III-1(16.00g, 0.057mol, 1.0e.q.) in dichloromethane (200mL), cooling in an ice-water bath to less than 5 ℃, dropwise adding diethylaminosulfur trifluoride (31.40g, 0.195mol, 3.4e.q.) into the reaction system, naturally heating to 15 ℃ after adding, stirring for 48 hours, monitoring the reaction by TLC, pouring the reaction solution into a saturated sodium bicarbonate aqueous solution (500mL), separating the liquid by layers, extracting the aqueous phase with dichloromethane (100mL × 2), combining organic phases, washing with saturated saline (200mL × 1), drying with anhydrous sodium sulfate, filtering, and performing sand-making column chromatography (SiO 2)2200-300 mesh, 1: 0-30: 1) to obtain 14.96g of compound IV-1 as a pale yellow oily substance, with the yield: 86.7 percent.1H-NMR(400MHz,CDCl3):(ppm)7.39-7.24(m,10H),3.68-3.64(m,2H),3.53-3.50(d,2H),3.07-2.96(m,1H),2.80-2.75(m,1H),2.60-2.55(m,1H),2.46-2.29(m,2H),1.92-1.82(m,1H),1.43-1.34(m,1H)。
Preparation of Compound I-1:
compound IV-1(10.00g, 0.033mol, 1.0e.q.) was dissolved in methanol (200mL), then 1.7M HCl in methanol (19.4mL) was added, palladium on carbon hydroxide (3.00g) was added after stirring for 5 minutes, the reaction was stirred at 30 ℃ for 48 hours with introduction of hydrogen, LC-MS monitored for completion of the reaction, filtered, and the mother liquor was concentrated to give compound I-1 hydrochloride as a white solid 5.3g, yield: 100 percent.1H-NMR(400MHz,D2O):(ppm)3.28-3.20(m,1H),3.16-3.04(m,2H),2.58-2.44(m,2H),2.04-1.96(m,1H),1.57-1.49(m,1H)。
Example 2
Preparation of Compound III-2:
adding compound II-2(20.00g, 0.238mol, 1.0e.q.), paraformaldehyde (14.30g, 0.476mol, 2.0e.q.) and dibenzylamine (91.78g, 0.476mol, 2.0e.q.) to ethanol (300mL), adding potassium hydrogen phthalate (19.42g, 0.095mol, 0.4e.q.) and concentrated hydrochloric acid (4mL, 0.047mol, 0.2e.q.), stirring at room temperature for 1 hour, heating to 75 deg.C, stirring for 20 hours, LC-MS monitoring the reaction, concentrating the reaction solution, pouring into saturated sodium bicarbonate water solution (200mL), separating the layers, extracting the aqueous phase with ethyl acetate (200mL × 3), combining the organic phases, washing with saturated water, drying with anhydrous sodium sulfate, filtering, concentrating to obtain compound III-2 as a light yellow oil, 65.08g, yield: 93.3 percent.
Preparation of Compound IV-2:
dissolving a compound III-2(20.00g, 0.068mol, 1.0e.q.) in trichloromethane (200mL), cooling to-80 ℃, dropwise adding bis (2-methoxyethyl) aminosulfur trifluoride (75.40g, 0.341mol, 5.0e.q.) into the reaction system, naturally heating to 20 ℃ after adding, stirring for 24 hours, monitoring the reaction by TLC, pouring the reaction solution into a saturated sodium bicarbonate aqueous solution (500mL), carrying out layered liquid separation, extracting an aqueous phase with dichloromethane (100mL × 2), combining organic phases, washing with saturated saline (200mL × 1), drying with anhydrous sodium sulfate, filtering, concentrating to obtain a compound IV-2 which is 17.72g of a light yellow oily substance, wherein the yield is 82.4%. Es+＝316.52(M+1)。
Preparation of Compound I-2:
dissolving a compound IV-2(17.72g, 0.056mol, 1.0e.q.) in ethanol (300mL), stirring for 5 minutes, adding palladium carbon (1.00g), stirring at 45 ℃, introducing 3MPa hydrogen, stirring for reaction for 30 hours, monitoring the reaction by LC-MS for completion, filtering, concentrating a mother solution to obtain a light yellow oily liquid, dissolving in acetone (80mL), introducing hydrochloric acid gas, and performing suction filtration to obtain a hydrochloride of the compound I-2 as a white solid, wherein the yield is 9.47 g: 98.2 percent.
Example 3
Preparation of Compound III-3:
compound II-3(19.63g, 0.200mol, 1.0e.q.), methylal (45.66g, 0.600mol, 3.0e.q.) and dibenzylamine (115.8g, 0.600mol, 3.0e.q.) were added to water (400mL), then sodium citrate (5.88g, 0.020mol, 0.1e.q.) and citric acid (7.68g, 0.040mol, 0.2e.q.) were added, and after the addition, the reaction was stirred at 0 ℃ for 3 hours, then the temperature was raised to room temperature and stirred for 18 hours, LC-MS monitored completion of the reaction, ethyl acetate (300mL) was added, and the mixture was stirredSodium bicarbonate was added to the reaction mixture in portions to give a pH of about 7, the mixture was separated into layers, the aqueous phase was extracted with ethyl acetate (200mL × 3), the organic phases were combined, washed with saturated brine (400mL × 1), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (SiO 2)2200-300 mesh, 1: 0-10: 1) to give 55.83g of compound III-3 as a pale yellow oil, yield: 90.8 percent.
Preparation of Compound IV-3:
dissolving the compound III-3(30.74g, 0.100mol, 1.0e.q.) in 1, 2-dichloroethane (500mL), cooling in an ice-water bath to less than 10 ℃, dropwise adding diethylaminosulfur trifluoride (16.12g, 0.100mol, 1.0e.q.) into the reaction system, heating to 40 ℃ after addition, stirring for 48 hours, monitoring the reaction by TLC, pouring the reaction solution into a saturated sodium bicarbonate aqueous solution (500mL), carrying out layering and liquid separation, extracting the aqueous phase with dichloromethane (200mL × 2), combining the organic phases, washing with saturated saline (400mL × 1), drying with anhydrous sodium sulfate, filtering, and carrying out column chromatography (SiO 2)2200-300 mesh, 1: 0-30: 1) to obtain 28.50g of compound IV-3 as a pale yellow oily substance, yield: 86.5 percent. Es+＝330.51(M+1)。
Preparation of Compound I-3:
compound IV-3(18.57g, 0.100mol, 1.0e.q.) was dissolved in tetrahydrofuran (300mL), palladium on carbon hydroxide (9.00g) was added, the reaction was stirred with hydrogen gas at 25 ℃ for 48 hours, LC-MS monitored for completion of the reaction, filtered, and the mother liquor was concentrated to give compound I-3 as a colorless liquid 14.41g, yield: 96.6 percent.
Claims (4)
1. A process for preparing a compound of structural formula (IV) comprising:
wherein: n is 1,2 or 3;
the formaldehyde reagent is selected from 40% formaldehyde aqueous solution, paraformaldehyde or methylal;
in the process of preparing a compound III from a compound II, a reaction system is a buffer system with the pH value of 3-6, and the buffer system is selected from a glycine/hydrochloric acid system, a potassium hydrogen phthalate/hydrochloric acid system, a disodium hydrogen phosphate/citric acid system, a citric acid/sodium hydroxide/hydrochloric acid system, a citric acid/sodium citrate system, an acetic acid/sodium acetate system, a disodium hydrogen phosphate/sodium dihydrogen phosphate system, a disodium hydrogen phosphate/potassium dihydrogen phosphate system or a potassium dihydrogen phosphate/sodium hydroxide system;
in the process of preparing the compound III from the compound II, the molar ratio of the compound II to a formaldehyde reagent to dibenzylamine is 1: 1-3, and a reaction solvent is selected from water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or toluene; the reaction temperature is 0-110 ℃;
in the process of preparing a compound IV from a compound III, a fluorinating reagent is diethylaminosulfur trifluoride or bis (2-methoxyethyl) aminosulfur trifluoride, the molar ratio of the compound III to the fluorinating reagent is 1: 1-1: 5, and a reaction solvent is selected from dichloromethane, trichloromethane or 1, 2-dichloroethane; the reaction temperature is-80-40 ℃.
2. A process for the preparation of a compound of formula (I) or a hydrochloride salt thereof, comprising:
or:
or:
wherein: n is 1,2 or 3;
the hydrochloric acid is hydrochloric acid solution or hydrochloric acid gas;
also included is a process for the preparation of compound IV as claimed in claim 1.
3. The method according to claim 2, wherein the catalyst is palladium on carbon or palladium on carbon hydroxide in the preparation of compound I from compound IV.
4. The preparation method according to claim 2 or 3, wherein in the process of preparing the compound I from the compound IV, the mass ratio of the compound IV to the catalyst is 1: 0.05-1: 0.5; the solvent is selected from methanol, ethanol or tetrahydrofuran.
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| CN112279759B (en) * | 2019-07-25 | 2023-10-03 | 南京富润凯德生物医药有限公司 | Method for synthesizing 2-fluorocyclobutyl methylamine and intermediate thereof |
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Non-Patent Citations (4)
| Title |
|---|
| Ammonium-Directed Oxidation of Cyclic Allylic and Homoallylic Amines;Christopher W. Bond等;《J. Org. Chem. 》;20090731;第74卷;第6735–6748页 * |
| Ammonium-Directed Oxidation of Cyclic Allylic and Homoallylic Amines;Christopher W. Bond等;《J. Org. Chem.》;20090731;第74卷;第6735–6748页 * |
| Stereoselective syntheses and transformations of chiral 1,3-aminoalcohols and 1,3-diols derived from nopinone;Z. Szakonyi等;《Tetrahedron: Asymmetry 》;20141231;第25卷;第1138–1145页 * |
| Synthesis of gem-difluorocyclopentane/hexane building blocks;Kostiantyn P. Melnykov等;《Journal of Fluorine Chemistry》;20170502;第199卷;第60–66页 * |
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