CN110066233A - A kind of preparation method of monosubstituted amine compounds - Google Patents
A kind of preparation method of monosubstituted amine compounds Download PDFInfo
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- CN110066233A CN110066233A CN201810059292.4A CN201810059292A CN110066233A CN 110066233 A CN110066233 A CN 110066233A CN 201810059292 A CN201810059292 A CN 201810059292A CN 110066233 A CN110066233 A CN 110066233A
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- -1 amine compounds Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 24
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 109
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 11
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 150000008065 acid anhydrides Chemical class 0.000 abstract 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- RZUOHKMLGRUSMK-UHFFFAOYSA-N (1-ethoxy-1-methoxy-2-methylpropan-2-yl) hypofluorite Chemical compound COC(C(C)(C)OF)OCC RZUOHKMLGRUSMK-UHFFFAOYSA-N 0.000 description 1
- PONXTPCRRASWKW-ZIAGYGMSSA-N (1r,2r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-ZIAGYGMSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/10—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring nitrogen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of monosubstituted amine compounds, belong to field of pharmaceutical chemistry technology.Method of the invention is reacted by the way that bisamination is closed object with n,N-Dimethylformamide dimethylacetal, first cyclization; then open loop is replaced by acid anhydrides, then sloughs protecting group, can obtain mono-substituted amine compounds in high yield; disubstituted impurity content is low, has preferable application value.
Description
Technical Field
The invention relates to a preparation method of a mono-substituted amine compound, belonging to the technical field of pharmaceutical chemistry.
Background
The (1R,2R) -1, 2-diphenyl ethylene diamine or its (1S,2S) or (1R,2S) or (1S,2R) configurational isomer, the compound of which structure has two amino groups, one of which is substituted by a leaving group, is commonly used for preparing various catalyst compounds for chiral synthesis and widely used in medicine preparation. Because of the "symmetry" of the structure, two amino groups are present in the structure, and when a hydrogen on an amino group is substituted, a double-substituted compound in which one hydrogen of the two amino groups is substituted respectively is easily produced, and it is difficult to obtain a mono-substituted amine compound in which only one hydrogen of one amino group is substituted, so it is necessary to study a method for producing the mono-substituted amine compound.
Disclosure of Invention
The invention aims to provide a simple and high-yield method for preparing mono-substituted amine compound shown as a formula (I) in an industrial production manner, wherein R1As a leaving group, such as methylsulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl, phenylsulfonyl, and the like; r2And R3Each independently is hydrogen, orSubstituted or unsubstituted groups, such as optionally substituted or unsubstituted: linear or branched alkyl, alkoxy, halogen, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, including but not limited to any substituted or unsubstituted: methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, fluorine, chlorine, bromine, iodine, nitro, cyano, phenyl, 4-methylphenyl, naphthyl, pyridyl or imidazolyl, etc., wherein the compound shown in the formula (I) has two chiral centers and can be in (1R,2R), (1S,2S), (1R,2S) or (1S,2R) configuration, or be racemic or be a mixture of various configurations;
the inventor finds that a diamino compound is directly subjected to substitution reaction, a disubstituted compound shown in the following formula is easily generated, the yield of a monosubstituted compound is particularly low, the diamino compound is protected and then reacted, the monosubstituted compound can be obtained at a high yield, and the configuration in the reaction process is not influenced. Therefore, the invention provides a preparation method, which comprises the steps of carrying out cyclization on a protecting group on a raw material diamino compound, then carrying out ring opening substitution, and then carrying out deprotection to obtain a mono-substituted target amine compound, wherein the di-substituted target amine compound has low content of disubstituted impurities and higher application value.
The invention provides a preparation method of a monosubstituted compound shown as a formula (I). A process for preparing a compound of formula (I) comprising: carrying out deprotection reaction on the compound shown in the formula (03) under acid or alkali conditions to obtain the compound shown in the formula (I),
wherein R is1As a leaving group, such as methylsulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl, phenylsulfonyl, and the like; r2And R3Each independently is hydrogen, or an optionally substituted or unsubstituted substituent, such as optionally substituted or unsubstituted: linear or branched alkyl, alkoxy, halogen, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, including but not limited to any substituted or unsubstituted: methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, fluoro, chloro, bromo, iodo, nitro, cyano, phenyl, 4-methylphenyl, naphthyl, pyridyl or imidazolyl and the like. The compound shown in the formula (I) can be in (1R,2R), (1S,2S), (1R,2S) or (1S,2R) configuration, or be racemic or be in a mixture of various configurations.
The deprotection reaction is carried out under the condition of acid or alkali, and the acid is hydrochloric acid, sulfuric acid or the combination of the hydrochloric acid and the sulfuric acid; the base is LiOH, NaOH, KOH, or a combination thereof. In some embodiments, the deprotection reaction is carried out under acidic conditions, and the acid is hydrochloric acid with a concentration of not less than 4 mol/L. In some embodiments, the deprotection reaction is carried out under alkaline conditions, and the concentration of the aqueous solution of the alkali is not less than 10% (mass fraction).
The reaction solvent of the deprotection reaction is methanol, ethanol, isopropanol or a mixed solvent thereof.
The reaction temperature of the deprotection reaction is 40-100 ℃.
After the deprotection reaction is finished, the reaction mixed solution is subjected to post-treatment to obtain a compound (I), wherein the post-treatment comprises the following steps: cooling the reaction mixed solution to 0-40 ℃, adjusting the pH of the reaction mixed solution to 8-9, extracting with an extraction solvent such as ethyl acetate and the like, washing the obtained organic phase with water, and concentrating the obtained organic phase to obtain a crude compound (I); recrystallizing the obtained crude compound (I) to obtain a compound (I) product, wherein the extraction solvent can be dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methyl acetate, toluene, or a combination thereof.
The recrystallization includes: mixing the crude product of the compound (I) with a solvent such as methyl tert-butyl ether, heating to 40-80 ℃, stirring for 0.1-10 hours, then cooling to 0-40 ℃, separating and drying the obtained solid to obtain the product of the compound (I).
In some embodiments, the compound represented by formula (03) is subjected to deprotection reaction in ethanol at 60-85 ℃ for 6-12 hours under the condition of adding hydrochloric acid, after the reaction is finished, the reaction mixed solution is cooled to 0-40 ℃, the pH of the reaction mixed solution is adjusted to 8-9, then ethyl acetate is used for extraction, the obtained organic phase is washed once by water, and the obtained organic phase is concentrated to obtain a crude product; mixing the obtained crude product with methyl tert-butyl ether, heating to 45-65 ℃, stirring for 0.1-2 hours, then cooling to 10-30 ℃, separating the solid, optionally washing the solid with a crystallization solvent, and drying the obtained solid to obtain the compound (I) product.
The compound represented by the above formula (03) can be produced from the compound represented by the formula (02). A process for preparing a compound of formula (03), comprising: a compound represented by the formula (02) and a compound R1-O-R1Obtaining a compound shown in a formula (03) through reaction,
wherein R is1，R2，R3As previously mentioned, the configuration of the compound may be any configuration.
In some embodiments, a method of preparing a compound of formula (03), comprising: under the inert gas atmosphere, a compound shown as a formula (02) is mixed with a compound R in an organic solvent under the condition of adding alkali1-O-R1Reacting at-30-0 ℃, after the reaction is finished, adding water into the reaction mixed solution, and concentrating the obtained organic phase to be dry to obtain a compound shown as a formula (03); wherein R is1As previously described.
Said compoundsR1-O-R1The feeding molar ratio of the compound shown as the formula (02) to the compound shown as the formula (02) is 1:1-1.5:1, preferably 1.2:1-1.4: 1; compound R1-O-R1The use amount is too much, so that the amount of the disubstituted impurities is increased easily, and the generation of the target product is not facilitated if the amount is too little. In some embodiments, the compound of formula (02) is reacted with compound R1-O-R1The reaction is carried out at the temperature of minus 30 ℃ to minus 5 ℃, which is beneficial to obtaining reaction products and reducing impurities, and more impurities are easily generated when the temperature is too high.
The organic solvent may be dichloromethane or toluene, preferably dichloromethane. The amount of the organic solvent to be used is 3mL to 12mL, preferably 3mL to 8mL, per one gram of the compound represented by the formula (02).
The base can be triethylamine, diethylamine, N-methylmorpholine, N, N-diisopropylethylamine; n, N-diisopropylethylamine is preferred. The charging molar ratio of the compound represented by the formula (02) to the base is 1:1 to 1:2, preferably 1:1.3 to 1: 1.5. The excessive consumption of alkali is easy to increase impurities, and the excessive consumption of alkali is not beneficial to the generation and the obtaining of products.
The obtained compound shown in the formula (03) can be used for preparing the compound (I) after purification, and can also be directly used in the reaction for preparing the compound (I).
In some embodiments, a compound of formula (02) is reacted with a compound R in dichloromethane with the addition of N, N-diisopropylethylamine under an inert gas atmosphere1-O-R1Reacting at-20 deg.C to-5 deg.C for 0.5 hr to 2 hr, mixing with water, and concentrating the organic phase to obtain the compound represented by formula (03).
The compound represented by the above formula (02) can be produced from the compound represented by the formula (01). A process for preparing a compound of formula (02) comprising: reacting the compound shown in the formula (01) with N, N-dimethylformamide dimethyl acetal (hereinafter, DMF-DMA) to obtain a compound shown in a formula (02),
wherein R is1，R2，R3As previously mentioned, the configuration of the compound may be any configuration.
In some embodiments, a method of preparing a compound of formula (02) comprises: reacting the compound shown in the formula (01) with DMF-DMA at 40-100 ℃ for 5-14 hours, then cooling the reaction mixed solution to 20-40 ℃, and concentrating to dryness to obtain a crude compound shown in the formula (02).
The obtained compound represented by the formula (02) or a crude product thereof may be recrystallized with a solvent to improve the purity thereof. The solvent is n-hexane, cyclohexane, toluene, methyl tert-butyl ether, dichloromethane, or a combination thereof. The amount of the solvent used is 3mL to 10mL, preferably 3mL to 5mL, per gram of the crude compound represented by the formula (02).
In some embodiments, the recrystallization with a solvent comprises: dissolving the obtained compound shown as the formula (02) or a crude product thereof by using a solvent, stirring for 0.1-2 hours, cooling to 0-25 ℃, crystallizing, separating generated solid, optionally washing the solid by using the solvent, and drying to obtain the compound (02).
In some embodiments, the crude compound of formula (02) is dissolved in cyclohexane. In some embodiments, the crude compound of formula (02) is dissolved in n-hexane. In some embodiments, the crude compound represented by formula (02) is dissolved in a mixed solvent of cyclohexane and at least one selected from the group consisting of dichloromethane, toluene and methyl t-butyl ether. The inventor finds that the compound shown in the formula (02) with high purity can be obtained by recrystallization of normal hexane or cyclohexane, but the compound is easy to agglomerate and is difficult to separate, and seed crystals are required to be added and/or gradient cooling is required; and recrystallization from a mixed solvent of cyclohexane and at least one member selected from the group consisting of methylene chloride, toluene and methyl t-butyl ether, the resulting solid dispersion is easily separated to discharge.
In some embodiments, the crude compound of formula (02) is dissolved in a solvent mixture of cyclohexane and toluene. In some embodiments, the crude compound of formula (02) is dissolved in a mixed solvent of cyclohexane and toluene at a volume ratio of cyclohexane to toluene of 10:1 to 20:1, preferably 10:1 to 15: 1. In some embodiments, the crude compound of formula (02) is dissolved in a solvent mixture of cyclohexane and toluene at a cyclohexane to toluene volume ratio of 10:1 to 15:1, and the total amount of solvent used is 3mL to 5mL per gram of crude compound.
The feeding molar ratio of the compound shown in the formula (01) to DMF-DMA is 1:1-1:1.5, and the preferable feeding molar ratio is 1:1-1:1.2, so that the method is favorable for reducing the generation of impurities, and is favorable for concentration in the post-reaction treatment process and recrystallization to separate out solids.
In some embodiments, the compound of formula (01) is reacted with DMF-DMA at a temperature of 65 ℃ to 85 ℃ to facilitate the formation of the product.
In some embodiments, the compound of formula (01) is reacted with DMF-DMA for a reaction time of 7 hours to 9 hours, which facilitates the formation of the product and reduces impurities.
In some embodiments, R1Is methylsulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or phenylsulfonyl.
In some embodiments, R2，R3Are each hydrogen.
In some embodiments, R2，R3Each optionally substituted or unsubstituted: methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, fluoro, chloro, bromo, iodo, nitro, cyano, phenyl, 4-methylphenyl, naphthyl, pyridyl or imidazolyl.
In some embodiments, R2，R3Each optionally substituted or unsubstituted: methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, nitro, cyano or phenyl.
The method provided by the invention can obtain the monosubstituted compound (I) with higher yield.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the invention, g: g; mL: ml; mol: molar ratio; DEG C: c, centigrade degree; h: hours; min: the method comprises the following steps of (1) taking minutes; DEG C: and C.
In the invention, the room temperature refers to the ambient temperature and is 0-30 ℃, or 0-25 ℃ or 15-25 ℃.
In the following examples, R2And R3Are all hydrogen, R1Is trifluoromethanesulfonyl; r1，R2And R3For other groups, substitution of the relevant starting materials or reactants can be carried out by the following method.
Example 1
Adding 50g of the compound (01) and 30.9g (1.1eq) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) into a 500mL single-neck bottle, heating to 70 ℃, condensing and refluxing, reacting for 8h, cooling to room temperature, and concentrating at 40 ℃ to dryness to obtain a yellow crude product; adding 160mL of cyclohexane into the crude product, stirring, heating to 80 ℃, and refluxing until the cyclohexane is completely dissolved; then cooling to room temperature, filtering, washing a filter cake for 1 time by 50mL of cyclohexane, and performing vacuum drying for 6h at 50-60 ℃ to obtain 49.7g of a milky white product which is a compound shown as a formula (02), wherein the yield is 95% and the purity is 99.4%.
The obtained product is: 1H NMR (400MHz, deuterated DMSO) δ 7.51-7.31(m,6H),7.28(t, J ═ 7.3Hz,2H),7.24-7.20(m,4H),4.54(s, 2H); 13C NMR (101MHz, deuterated DMSO). delta. 154.72,144.64,128.93,127.53,126.82.
Example 2
Adding 10g of the compound shown as the formula (02) into a reaction bottle, dissolving 40mL of dichloromethane, adding 8.5g (1.46eq) of N, N-diisopropylethylamine, dissolving 16.0g (1.26eq) of trifluoromethanesulfonic anhydride in 25mL of dichloromethane in a constant-pressure dropping funnel, placing the mixture in a low-temperature tank at minus 10 ℃ after nitrogen replacement for 3 times, stirring for 30min, slowly dropwise adding the trifluoromethanesulfonic anhydride solution, continuing to react for 1h after the dropwise addition is finished, adding 40mL of water into the reaction solution after the reaction is finished, washing 1 time, and carrying out reduced pressure rotary evaporation on the organic phase to obtain 22g of an oily product with the purity of 85.3%; can be directly used for the next reaction without purification.
The obtained product is:1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.40(s,1H),7.30-7.19(m,6H),7.17-7.06(m,4H),5.55–5.44(d,1H),4.78(d,J＝10.7Hz,1H),1.84(s,1H)；
[M+H]+＝373.2。
example 3
22g (purity 85.3%) of the crude compound (03) in the last step is added into a reaction bottle, 20mL of ethanol and 15mL of concentrated hydrochloric acid are added, the temperature is raised to 80 ℃ and reflux is carried out for 8h, after the reaction is finished, the temperature is reduced to room temperature, 30% sodium hydroxide aqueous solution is used for adjusting the pH value to 8-9, 100mL of ethyl acetate is added for extraction for 1 time, the organic phase is washed for 1 time by water, and an oily crude product is obtained by decompression rotary evaporation and concentration; 70mL of methyl tert-butyl ether is added into the crude product, the temperature is raised to 55 ℃, the mixture is stirred for 1h and then cooled to room temperature, the mixture is filtered, a filter cake is washed for 2 times by 100mL of methyl tert-butyl ether, the dosage of each time is 50mL, and the wet product is dried in vacuum at 55 ℃ for 8h to obtain 12.2g of the compound (I), the chemical purity is 97.8 percent, and the disubstituted impurity is 0.37 percent.
The obtained product is:1H NMR(400MHz,CDCl3)δ7.49-7.30(m,10H),4.74(d,J＝2.6Hz,1H),4.43(d,J＝2.9Hz,1H)；
[M+H]+＝345.1。
example 4
89.6g of the compound shown in the formula (02) is added into a reaction bottle, 76.1g (1.46eq) of N, N-diisopropylethylamine is dissolved in 370mL of dichloromethane, 143.3g (1.26eq) of trifluoromethanesulfonic anhydride is dissolved in 150mL of dichloromethane in a constant pressure dropping funnel, nitrogen is replaced for 3 times and then the mixture is placed in a low-temperature tank at minus 10 ℃, after stirring for 30min, the trifluoromethanesulfonic anhydride solution is slowly dropped, the reaction is continued for 1h after the dropping is finished, after the reaction is finished, 200mL of water is added into the reaction liquid for 1 time, and the organic phase is subjected to reduced pressure rotary evaporation to obtain 205g of oily product with the purity of 86.2 percent and can be directly used for the next reaction without purification.
Example 5
Adding 205g (purity is 86.2%) of the crude compound (03) in the last step into a reaction bottle, adding 200mL of ethanol and 150mL of concentrated hydrochloric acid, heating to 80 ℃, refluxing for 8h, cooling to room temperature after the reaction is finished, adjusting the pH to 8-9 by using 30% sodium hydroxide aqueous solution, adding 300mL of ethyl acetate, extracting for 1 time, washing an organic phase by using water for 1 time, concentrating under reduced pressure to obtain an oily crude product, adding 650mL of methyl tert-butyl ether into the obtained crude product, heating to 55 ℃, stirring for 1h, cooling to room temperature, filtering, washing a filter cake by using 200mL of methyl tert-butyl ether for 2 times, wherein the dosage is 100mL each time, and drying a wet product at 55 ℃ for 8h in vacuum to obtain 118g of the compound (I), the chemical purity is 94.2%, and the.
Example 6
Adding 10g of the compound shown as the formula (02) into a reaction bottle, dissolving 40mL of dichloromethane, adding 8.5g (1.46eq) of N, N-diisopropylethylamine, dissolving 16.0g (1.26eq) of trifluoromethanesulfonic anhydride in 25mL of dichloromethane in a constant-pressure dropping funnel, placing the mixture in a low-temperature tank at minus 10 ℃ after nitrogen replacement for 3 times, stirring for 30min, slowly dropwise adding the trifluoromethanesulfonic anhydride solution, continuing to react for 1h after the dropwise addition is finished, adding 40mL of water into the reaction solution after the reaction is finished, washing 1 time with water, and carrying out reduced pressure rotary evaporation on the organic phase to obtain 20.8g of oily matter with the purity of 88%, wherein the oily matter is a crude compound (03) and can be directly used for the next reaction without purification.
Example 7
Adding 20.8g (purity is 88%) of the crude compound (03) in the previous step into a reaction bottle, adding 30mL of ethanol and 50mL of a 15% aqueous solution of sodium hydroxide by mass fraction, heating to 80 ℃, refluxing for 8h, cooling to room temperature after the reaction is finished, adding 100mL of ethyl acetate, extracting for 1 time, washing the organic phase with water for 1 time, concentrating under reduced pressure to obtain an oily crude product, adding 70mL of methyl tert-butyl ether into the obtained crude product, heating to 55 ℃, stirring for 1h, cooling to room temperature, filtering, washing a filter cake with 100mL of methyl tert-butyl ether for 2 times with 50mL of dosage each time, and drying the wet product in vacuum at 55 ℃ for 8h to obtain 10.8g of the compound (I), wherein the chemical purity is 96.9% and the disubstituted impurity is 0..
Example 8 comparative example
2g of the compound (01) is added into a reaction bottle, 1.43g (1.46eq) of N, N-diethylisopropylamine is added into 15mL of dichloromethane for dissolution, 2.96g (1.26eq) of trifluoromethanesulfonic anhydride is added into a constant pressure dropping funnel with 10mL of dichloromethane for replacement by nitrogen, the mixture is placed in a low-temperature tank at minus 10 ℃ for replacement, after stirring for 30min, the trifluoromethanesulfonic anhydride solution is slowly added dropwise, reaction is continued for 1h after dropping is finished, and the reaction solution is detected to show that only 27.8% of the compound (I) is contained and the disubstituted impurity reaches 33.6%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (11)
1. A process for preparing a compound of formula (I) comprising: carrying out deprotection reaction on the compound shown in the formula (03) under the acid or alkali condition to obtain the compound shown in the formula (I),
wherein,
R1methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or benzenesulfonyl;
R2and R3Each independently hydrogen, or optionally substituted or unsubstituted: methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, fluoro, chloro, bromo, iodo, nitro, cyano, phenyl, 4-methylphenyl, naphthyl, pyridyl or imidazolyl.
2. The method of claim 1, further comprising: reacting a compound shown as a formula (02) with a compound R in an organic solvent under the condition of adding alkali1-O-R1Reacting at minus 30 ℃ to minus 5 ℃ to obtain a compound shown as a formula (03),
wherein R is1，R2，R3As claimed in claim 1.
3. The method of claim 1, further comprising: reacting the compound shown in the formula (01) with N, N-dimethylformamide dimethyl acetal to obtain a compound shown in a formula (02),
wherein R is1，R2，R3As claimed in claim 1.
4. The method of claim 1, wherein the acid is hydrochloric acid, sulfuric acid, or a combination thereof; the base is LiOH, NaOH, KOH, or a combination thereof.
5. The process of claim 1, wherein the compound (I) is obtained by mixing with methyl tert-butyl ether, heating to 40-80 ℃, stirring for 0.1-10 hours, cooling to 0-40 ℃, separating, and drying the obtained solid to obtain the compound (I) product.
6. The method of claim 2, compound R1-O-R1The feeding molar ratio of the compound shown in the formula (02) to the compound shown in the formula (02) is 1:1-1.5:1, and the feeding molar ratio of the compound shown in the formula (02) to the alkali is 1:1-1: 2.
7. The method according to claim 3, wherein the molar ratio of the compound represented by the formula (01) to N, N-dimethylformamide dimethyl acetal fed is 1:1 to 1: 1.5.
8. The process according to claim 3, wherein the compound represented by the formula (02) is dissolved in a solvent which is a mixture of cyclohexane and at least one member selected from the group consisting of methylene chloride, toluene and methyl t-butyl ether, stirred for 0.1 to 2 hours, then cooled to 0 to 25 ℃, separated to form a solid, optionally washed with the solvent, and dried to obtain the compound (02).
9. The method of claim 1, wherein the compound represented by formula (03) is subjected to deprotection reaction in ethanol at 60-85 ℃ for 6-12 hours under the condition of adding hydrochloric acid, after the reaction is finished, the reaction mixed solution is cooled to 0-40 ℃, the pH of the reaction mixed solution is adjusted to 8-9, then ethyl acetate is used for extraction, the obtained organic phase is washed once by water, and the obtained organic phase is concentrated to obtain a crude product; mixing the obtained crude product with methyl tert-butyl ether, heating to 45-65 ℃, stirring for 0.1-2 hours, then cooling to 10-30 ℃, separating the solid, optionally washing the solid with a crystallization solvent, and drying the obtained solid to obtain the compound (I) product.
10. The process according to claim 2, wherein the compound of formula (02) is reacted with the compound R in dichloromethane under an inert gas atmosphere with the addition of N, N-diisopropylethylamine1-O-R1Reacting at-20 deg.C to-5 deg.C for 0.5 hr to 2 hr, mixing with water, and concentrating the organic phase to obtain the compound represented by formula (03).
11. The method of any one of claims 1-10, wherein R1Is methylsulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl or phenylsulfonyl; r2，R3Are each hydrogen.
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