CN116332794A - Preparation method of aryl nitrile compound - Google Patents
Preparation method of aryl nitrile compound Download PDFInfo
- Publication number
- CN116332794A CN116332794A CN202111602499.XA CN202111602499A CN116332794A CN 116332794 A CN116332794 A CN 116332794A CN 202111602499 A CN202111602499 A CN 202111602499A CN 116332794 A CN116332794 A CN 116332794A
- Authority
- CN
- China
- Prior art keywords
- compound
- organic solvent
- phosphine ligand
- reaction
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 aryl nitrile compound Chemical class 0.000 title abstract description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000003446 ligand Substances 0.000 claims abstract description 33
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 33
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000002940 palladium Chemical class 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 24
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 6
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 3
- 239000013068 control sample Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000035484 reaction time Effects 0.000 claims 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 150000001502 aryl halides Chemical class 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 3
- 241001530392 Aphos Species 0.000 description 3
- 238000012369 In process control Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000005609 Rosenmund-von Braun cyanation reaction Methods 0.000 description 2
- 238000000297 Sandmeyer reaction Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical group C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UVVYFYLSZIMKMC-UHFFFAOYSA-N 4-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=CC2=C1CCC2=O UVVYFYLSZIMKMC-UHFFFAOYSA-N 0.000 description 1
- YPFCOVSGWXUQEY-UHFFFAOYSA-N 4-bromoinden-1-one Chemical compound BrC1=C2C=CC(C2=CC=C1)=O YPFCOVSGWXUQEY-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001409 amidines Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an aryl nitrile compound. The preparation method of the compound II provided by the invention comprises the following steps: in water and organic solvent, compound I, palladium salt, K 4 [Fe(CN) 6 ].3H 2 And (3) carrying out a cyanation reaction on the O and phosphine ligand to obtain the compound shown in the formula II. The preparation method can control the purity and the yield of the compound II in a higher intermediate process.
Description
Technical Field
The invention relates to a preparation method of an aryl nitrile compound.
Background
Aryl nitriles are an important class of organic compounds (Acc.Chem.Res.2001, 34,563;Chem.Rev.2003,103,2035) that are widely distributed in various natural products, pharmaceuticals, agricultural products, materials, and pigments. The cyanide-containing compound can be converted to a variety of functional groups such as carboxylic acids, amides, amines, aldehydes, ketones, tetrazoles, amidines, and the like by chemical reactions such as hydrolysis, hydration, reduction, nucleophilic addition, cycloaddition, and the like. In view of the importance of aryl nitriles in the fields of chemistry, pharmacy and biology, it is particularly necessary to develop new methods for the efficient synthesis of aryl nitriles.
Traditional methods for synthesizing aryl nitriles mainly include Sandmeyer reaction (a) ber.dtsch.chem.ges.1884,17,1633; b) Chem.ber.1884,17,2650; c) Chem.ber.1885,18,1492; d) Chem.ber.1885,18,1946), rosenmund-von Braun reaction (chem.ber.1919, 2,1749) and ammoxidation (ind.eng.chem.1949, 41,1846; ind. Eng. Chem.1950,42,796).
a) Sandmeyer reaction/Rosenmund-von Braun reaction
b) Ammonia oxidation process
The first two methods respectively take aryl azo and aryl halide as raw materials, and require equivalent CuCN, and have the advantages of harsh reaction conditions, large heavy metal pollution, narrow substrate range and low reaction efficiency. The ammoxidation method uses toluene as a raw material, and the reaction is carried out under the conditions of high temperature and high pressure, so that the equipment requirement is high, the operation difficulty is high, and the substrate is limited.
In recent years, transition metal catalyzed cyanation of aryl halides, aryl organometallic reagents and aryl C-H bonds has evolved (Chem.Soc.Rev.2011, 40,5049;Adv.Synth.Catal.2017,359,4068;ACS Catal.2016,6,5989;Org.Biomol.Chem.2018,16,7084;Inorganica Chimica Acta.2018,469,408;Chem.Asian.J.2018,13,482;J.Organometallic Chem.2020,920,121337;Tetrahedron.2020,76,131388;RSC Adv.2020,10,33683;Adv.Synth.Catal.2020,362,4543). Wherein, the transition metal catalyzed cyanidation reaction substrate of aryl halide is easy to obtain, the reaction applicability is wide, the operation condition is not harsh, and the method becomes the most important method for synthesizing aryl cyanide compounds.
c) Transition metal catalyzed cyanation of aryl halides, aryl organometallic reagents and aryl C-H bonds
Among the numerous catalysts (e.g., pd, cu, ni, rh, co, fe and Ru), palladium salts are the most commonly used catalysts due to their high catalytic efficiency and good substrate suitability. Conventional sources of cyano include KCN, naCN, cuCN, zn (CN) 2 And TMSCN, etc. Wherein NaCN and KCN are highly toxic substances, cuCN and Zn (CN) 2 Serious heavy metal pollution can be caused, and the TMSCN is easy to absorb moisture and release harmful HCN gas. In addition, the excess cyano ion present in the reaction system may coordinate with the metal, causing deactivation of the catalyst. In view of the above drawbacks, it is particularly necessary to develop a low-toxicity, slow-release cyano source.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel preparation method of the compound II. The invention provides a preparation method of a compound II. The preparation method can obtain the compound II with higher intermediate process control (IPC is in process control) purity and yield.
The invention provides a preparation method of a compound II, which comprises the following steps: in water and organic solvent, compound I, palladium salt, K 4 [Fe(CN) 6 ].3H 2 Carrying out a cyanation reaction on the O and phosphine ligand to obtain a compound shown in a formula II;
The organic solvent is DMAc, t-BuOH or 1, 4-dioxane;
when the organic solvent is DMAc, the phosphine ligand is Ph 2 DavePhosRuPhosAnd DPEPhos->One or more of the following;
In one embodiment, when the organic solvent is DMAc, the phosphine ligand is Ph 2 DavePhos; when the organic solvent is t-BuOH, the phosphine ligand is dppf; when the organic solvent is 1, 4-dioxane, the phosphine ligand is S-Phos and/or dppf.
In one embodiment, the organic solvent is DMAc and the phosphine ligand is Ph 2 DavePhos。
In one embodiment, the palladium salt is a divalent palladium salt, e.g., pdCl 2 。
In one embodiment, X is Br.
In one embodiment, in the cyanation reaction, the compounds I and K 4 [Fe(CN) 6 ].3H 2 The molar ratio of O is conventional in the art, for example 1: (0.2-0.5), for example 1:0.5.
in one embodiment, the molar ratio of compound I to palladium salt in the cyanation reaction is conventional in the art, for example 1: (0.01-0.05), for example 1:0.05.
in one embodiment, the molar ratio of compound I to phosphine ligand in the cyanation reaction is conventional in the art, e.g. 1: (0.02-0.1), for example 1:0.1.
in one embodiment, the ratio of the volume to mass of the organic solvent to the compound I in the cyanation reaction is conventional in the art, for example, from 10 to 30mL/g, and further for example, 20mL/g.
In one embodiment, the ratio of the volume mass of water to the volume mass of compound I in the cyanation reaction is conventional in the art, for example, 3-10mL/g; for example, the concentration is 5mL/g.
In one embodiment, the palladium salt is reacted with the phosphine ligand in the cyanation reaction for 5 to 10 minutes before reacting with the compounds I and K 4 [Fe(CN) 6 ].3H 2 O reaction.
In one embodiment, in the cyanation reaction, K 4 [Fe(CN) 6 ].3H 2 O is K 4 [Fe(CN) 6 ].3H 2 O aqueous solutions, e.g. of said K 4 [Fe(CN) 6 ].3H 2 The molar concentration of the O aqueous solution is 5 to 15mol/L, for example 9mol/L.
In one embodiment, the cyanation reaction temperature is conventional in the art, e.g., 80-120 ℃, e.g., 95-105 ℃ or 90-100 ℃.
In one embodiment, the cyanation reaction is carried out for a period of time conventional in the art, such as 18 to 24 hours, with the compound I substantially disappearing or no longer reacting.
In one embodiment, the cyanation reaction is carried out at 100℃for 18 hours.
In one embodiment, the cyanation reaction is carried out under sealed conditions.
In one embodiment, the cyanation reaction further comprises: cooling to room temperature after the reaction, adding an organic solvent for dissolution, preparing an HPLC (high performance liquid chromatography) central control sample, and determining the conversion rate of the reaction and the purity of the intermediate process control of the aryl nitrile compound through HPLC; preferably, the organic solvent is acetonitrile.
The DMAc used in the invention is N, N-dimethylacetamide, and t-BuOH is tertiary butanol.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
(1) The compound II is prepared by controlling the purity and the yield in a higher intermediate process;
(2) Mild reaction condition, low cost and non-toxic K 4 [Fe(CN) 6 ].3H 2 O is a cyano source, the reaction operation is simple, the material consumption is small, the waste is low, and a way is provided for the industrial production of the compound II.
Drawings
FIG. 1 is a high performance liquid chromatography spectrum of example 1.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The conversion and purity in the following examples were calculated according to the following formulas:
the conversion% = molar amount of compound of formula II/[ compound i+compound of formula II ] is 100%.
IPC purity of the aryl nitrile compound in the invention%o=formula II compound%.
The names and structures of phosphine ligands in the following examples correspond to the following:
example 1
Into a glass bottle, 30.1. Mu.L [0.177mg, 1. Mu. Mol,0.05eq.,3.5mg PdCl was added 2 Dissolved in 600. Mu.L (7.1 vol.) DMAc]PdCl 2 Solution, 55.3. Mu.L [4.221mg, 20. Mu. Mol,1 eq.) and 50.7mg of 4-bromo-1-indenone were dissolved in 648. Mu.L (12.9 vol.) of DMAc]4-bromo-1-indanone solution, 22.6. Mu.L [4.224mg (10. Mu. Mol,0.5 eq.) 232.3mg K 4 [Fe(CN) 6 ]·3H 2 O was dissolved in 1100. Mu.L (5 vol.) of pure water]K 4 [Fe(CN) 6 ]·3H 2 O aqueous solution, 0.76mg Ph was added 2 DavePHOS (0.763 mg, 2. Mu. Mol,0.1 eq.) was adjusted and the reaction solution temperature was controlled between 95-105℃and stirred continuously for 18 hours; and cooling to room temperature, performing central control sampling, detecting the obtained reaction liquid by using a high performance liquid chromatography, wherein the conversion rate is 100%, and the purity of the target product is 94.9%. Analysis conditions: agilent 1260 liquid chromatograph and ultraviolet detector, eclipse Plus C18 (50X 4.6mm,1.8 μm) column, mobile phase: a is 0.05% formic acid aqueous solution, B is 0.05% formic acid acetonitrile solution. The detection wavelength is 220nm at 40 ℃ and 1.5 mL/min. The results are shown in FIG. 1.
Examples 2-3: the difference from example 1 is only the kind and amount of phosphine ligand, specifically table 1 below:
table 1:
examples 4-7: the difference from example 1 is the phosphine ligand type and amount and the solvent type, as shown in Table 2 below:
table 2:
examples | Phosphine ligand species | Phosphine ligand dosage | Solvent(s) | Conversion/purity |
Example 4 | S-Phos | 0.821mg,2μmol,0.1eq. | 1, 4-Dioxahexacyclic ring | 97%/93.0% |
Example 5 | DPEPhos | 0.539mg,1μmol,0.05eq. | 1, 4-Dioxahexacyclic ring | 79%/77.8% |
Example 6 | dppf | 0.554mg,1μmol,0.05eq. | 1, 4-Dioxahexacyclic ring | 99%/93.1% |
Example 7 | dppf | 0.554mg,1μmol,0.05eq. | t-BuOH | 100%/90.5% |
。
Comparative examples 1 to 5: the difference from example 1 is that only the kind and amount of phosphine ligand are different, specifically the following table 3:
table 3:
examples | Phosphine ligand species | Phosphine ligand dosage | Conversion/purity |
Example 1 | X-Phos | 0.953mg,2μmol,0.1eq. | 1%/0.8% |
Example 2 | S-Phos | 0.821mg,2μmol,0.1eq. | 43%/40.5% |
Example 3 | XantPhos | 0.579mg,1μmol,0.05eq. | 40%/38.2% |
Example 4 | dppf | 0.554mg,1μmol,0.05eq. | 40%/38.5% |
Example 5 | APhos | 0.531mg,2μmol,0.1eq. | 4%/3.6% |
。
Comparative examples 6 to 7: the only difference from example 1 is the type of solvent, specifically table 4 below:
table 4:
comparative examples 8 to 17: the difference from example 1 is the phosphine ligand species and amount and the solvent species, as shown in Table 5 below:
table 5:
examples | Phosphine ligand species | Phosphine ligand dosage | Solvent(s) | Conversion/purity |
Example 8 | X-Phos | 0.953mg,2μmol,0.1eq. | 1, 4-Dioxahexacyclic ring | 15%/15.3% |
Example 9 | RuPhos | 0.933mg,2μmol,0.1eq. | 1, 4-Dioxahexacyclic ring | 2%/1.9% |
Example 10 | XantPhos | 0.579mg,1μmol,0.05eq. | 1, 4-Dioxahexacyclic ring | 20%/18.9% |
Example 11 | APhos | 0.531mg,2μmol,0.1eq. | 1, 4-Dioxahexacyclic ring | 2%/2.2% |
Example 12 | X-Phos | 0.953mg,2μmol,0.1eq. | t-BuOH | 1%/1.0% |
Example 13 | S-Phos | 0.821mg,2μmol,0.1eq. | t-BuOH | 1%/0.8% |
Example 14 | RuPhos | 0.933mg,2μmol,0.1eq. | t-BuOH | 1%/0.5% |
Example 15 | DPEPhos | 0.539mg,1μmol,0.05eq. | t-BuOH | 1%/0.8% |
Example 16 | XantPhos | 0.579mg,1μmol,0.05eq. | t-BuOH | 1%/0.5% |
Example 17 | APhos | 0.531mg,2μmol,0.1eq. | t-BuOH | 2%/1.5% |
。
Claims (10)
1. A process for the preparation of compound II, characterized in that it comprises the steps of: in water and organic solvent, compound I, palladium salt, K 4 [Fe(CN) 6 ].3H 2 Carrying out a cyanation reaction on the O and phosphine ligand to obtain a compound shown in a formula II;
The organic solvent is DMAc, t-BuOH or 1, 4-dioxane;
when the organic solvent is DMAc, the phosphine ligand is Ph 2 DavePhos, ruPhos and DPEPhos;
when the organic solvent is t-BuOH, the phosphine ligand is dppf;
when the organic solvent is 1, 4-dioxane, the phosphine ligand is S-Phos and/or dppf.
2. The process for preparing compound II according to claim 1, wherein when the organic solvent is DMAc, the phosphine ligand is Ph 2 DavePhos; when the organic solvent is t-BuOH, the phosphine ligand is dppf; when the organic solvent is 1, 4-dioxane, the phosphine ligand is S-Phos or dppf.
3. The process for preparing compound II according to claim 1, wherein the organic solvent is DMAc and the phosphine ligand is Ph 2 DavePhos。
4. The process for preparing compound II according to claim 1, wherein the palladium salt is a divalent palladium salt.
5. The process for preparing compound II according to claim 4, wherein the palladium salt is PdCl 2 。
6. The process for the preparation of compound II according to claim 1, wherein said process for the preparation of compound II satisfies one or more of the following conditions:
(1) In the cyanation reaction, the compounds I and K 4 [Fe(CN) 6 ].3H 2 The molar ratio of O is 1: (0.2-0.5);
(2) In the cyanation reaction, the molar ratio of the compound I to the palladium salt is 1: (0.01-0.05);
(3) In the cyanation reaction, the molar ratio of the compound I to phosphine ligand is 1: (0.02-0.1).
7. The process for the preparation of compound II according to claim 1, wherein said process for the preparation of compound II satisfies one or more of the following conditions:
(1) In the cyanation reaction, the compounds I and K 4 [Fe(CN) 6 ].3H 2 The molar ratio of O is 1:0.5;
(2) In the cyanation reaction, the molar ratio of the compound I to the palladium salt is 1:0.05;
(3) In the cyanation reaction, the molar ratio of the compound I to phosphine ligand is 1:0.1;
(4) The volume-mass ratio of the organic solvent to the compound I is 10-30mL/g;
(5) The volume-mass ratio of the water to the compound I is 3-10mL/g;
(6) In the cyanidation reaction, the palladium salt reacts with the phosphine ligand for 5-10min, and then reacts with the compounds I and K 4 [Fe(CN) 6 ].3H 2 O reaction;
(7) In the cyanidation reaction, K 4 [Fe(CN) 6 ].3H 2 O is K 4 [Fe(CN) 6 ].3H 2 An aqueous O solution;
(8) The temperature of the cyanation reaction is 80-120 ℃;
(9) The cyanation reaction time is 18-24h.
8. The process for the preparation of compound II according to claim 7, wherein the process for the preparation of compound II satisfies one or more of the following conditions:
(1) The volume-mass ratio of the organic solvent to the compound I is 20mL/g;
(2) The volume-mass ratio of the water to the compound I is 5mL/g;
(3) The K is 4 [Fe(CN) 6 ].3H 2 The molar concentration of the O aqueous solution is 5-15mol/L, for example 9mol/L;
(4) The temperature of the cyanation reaction is 95-105 ℃ or 90-100 ℃.
9. The method of preparing compound II according to claim 8, wherein the method of preparing compound II satisfies one or more of the following conditions:
(1) X is Br;
(2) The cyanation reaction is carried out at 100 ℃ for 18 hours;
(3) The K is 4 [Fe(CN) 6 ].3H 2 The molar concentration of the O aqueous solution is 9mol/L;
(4) The cyanation reaction is carried out under sealed conditions.
10. The process for the preparation of compound II according to any one of claims 1 to 9, wherein the cyanation reaction further comprises: cooling to room temperature after the reaction, adding an organic solvent for dissolution, and preparing an HPLC (high performance liquid chromatography) central control sample; preferably, the organic solvent is acetonitrile.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111602499.XA CN116332794A (en) | 2021-12-24 | 2021-12-24 | Preparation method of aryl nitrile compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111602499.XA CN116332794A (en) | 2021-12-24 | 2021-12-24 | Preparation method of aryl nitrile compound |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116332794A true CN116332794A (en) | 2023-06-27 |
Family
ID=86879415
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111602499.XA Pending CN116332794A (en) | 2021-12-24 | 2021-12-24 | Preparation method of aryl nitrile compound |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116332794A (en) |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101717350A (en) * | 2009-12-08 | 2010-06-02 | 南京工业大学 | Synthetic method of aryl cyanide in water solution |
CN102452867A (en) * | 2010-10-25 | 2012-05-16 | 中国科学技术大学 | Method for preparing aryl acetonitrile compound |
CN109761848A (en) * | 2019-01-22 | 2019-05-17 | 四川大学 | A method of preparing nitrile |
CN109956940A (en) * | 2019-05-14 | 2019-07-02 | 上海贤鼎生物科技有限公司 | A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide |
CN110003049A (en) * | 2019-05-13 | 2019-07-12 | 苏州山青竹生物医药有限公司 | A method of preparing 4- cyano -1- indone |
US20190224172A1 (en) * | 2016-09-29 | 2019-07-25 | Celgene International Ii Sarl | Compounds and methods for treating lupus |
CN110117237A (en) * | 2018-02-05 | 2019-08-13 | 中国科学院上海有机化学研究所 | A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds |
US20200392128A1 (en) * | 2017-03-23 | 2020-12-17 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
US20210163485A1 (en) * | 2017-05-17 | 2021-06-03 | Oppilan Pharma Ltd. | Heterocyclic Compounds for the Treatment of Disease |
CN113072551A (en) * | 2020-01-03 | 2021-07-06 | 上海翰森生物医药科技有限公司 | Nitrogen-containing biphenyl derivative inhibitor, preparation method and application thereof |
-
2021
- 2021-12-24 CN CN202111602499.XA patent/CN116332794A/en active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101717350A (en) * | 2009-12-08 | 2010-06-02 | 南京工业大学 | Synthetic method of aryl cyanide in water solution |
CN102452867A (en) * | 2010-10-25 | 2012-05-16 | 中国科学技术大学 | Method for preparing aryl acetonitrile compound |
US20190224172A1 (en) * | 2016-09-29 | 2019-07-25 | Celgene International Ii Sarl | Compounds and methods for treating lupus |
US20200392128A1 (en) * | 2017-03-23 | 2020-12-17 | Jacobio Pharmaceuticals Co., Ltd. | Novel heterocyclic derivatives useful as shp2 inhibitors |
US20210163485A1 (en) * | 2017-05-17 | 2021-06-03 | Oppilan Pharma Ltd. | Heterocyclic Compounds for the Treatment of Disease |
CN110117237A (en) * | 2018-02-05 | 2019-08-13 | 中国科学院上海有机化学研究所 | A kind of preparation method of aromatic nitriles or alkenyl nitrile compounds |
CN109761848A (en) * | 2019-01-22 | 2019-05-17 | 四川大学 | A method of preparing nitrile |
CN110003049A (en) * | 2019-05-13 | 2019-07-12 | 苏州山青竹生物医药有限公司 | A method of preparing 4- cyano -1- indone |
CN109956940A (en) * | 2019-05-14 | 2019-07-02 | 上海贤鼎生物科技有限公司 | A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide |
CN113072551A (en) * | 2020-01-03 | 2021-07-06 | 上海翰森生物医药科技有限公司 | Nitrogen-containing biphenyl derivative inhibitor, preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Barluenga et al. | Synthesis of spiroquinolines through a one‐pot multicatalytic and multicomponent cascade reaction | |
CN102898264B (en) | Catalytic preparation process for aromatic nitrile or heteroaromatic nitrile | |
CN110294689B (en) | Method for preparing nitrile compound by dehydrogenation of primary amine under catalysis of ruthenium metal complex | |
CN112321628B (en) | Preparation method of beta-dimethylphenyl silicon substituted organic nitrile compound | |
CN110003011A (en) | It is a kind of using nitrate as the preparation method of the nitroolefin derivative in nitro source | |
CN116332794A (en) | Preparation method of aryl nitrile compound | |
CN109761848B (en) | Method for preparing nitrile | |
CN107501338B (en) | Preparation method of 2, 6-diaminopyridine condensed 4-carboxybenzaldehyde bis-Schiff base cobalt complex | |
CN102746185B (en) | Preparation process of aromatic nitrile compound | |
Qu et al. | Asymmetric cyanohydrin formation from aldehydes catalyzed by manganese Schiff base complexes | |
US11680075B2 (en) | Application of 4-MePhNHLi in catalyzing hydroboration reaction of imine and borane | |
CN113173894B (en) | Method for continuously synthesizing tetrahydrofuran-3-ketone | |
Qian et al. | Enantioselective 1, 4-addition of diarylphosphine oxides to α, β-unsaturated ketones catalyzed by oxazaborolidines | |
CN106111132A (en) | A kind of Pd Zn bimetallic catalyst for preparing aryl cyanides | |
CN107513078B (en) | Preparation method of 2, 6-diaminopyridine condensed 3-carboxybenzaldehyde bis-Schiff base cobalt complex | |
CN111871458A (en) | Magnetic material supported chiral imidazolium salt catalyst and preparation method and application thereof | |
CN107513079B (en) | Preparation method of 2, 6-diaminopyridine o-carboxybenzaldehyde bis-Schiff base cobalt complex | |
CN117756719A (en) | Preparation method of 6-cyanoindazole compound | |
CN103130811B (en) | Synthesis method of 5,6-2H-pyrrolo[1,5-c] quinazoline compounds | |
US11891408B2 (en) | Application of lithium 4-methoxyaniline in catalysis of hydroboration reaction of imine and borane | |
CN113372255B (en) | Method for synthesizing 2-substituted indole derivative under catalysis of copper | |
US11845068B2 (en) | Use of n-butyllithium for catalyzing hydroboration of imine and borane | |
CN111732556B (en) | Deuterated loxapine medicine and preparation method thereof | |
CN115894361A (en) | Method for synthesizing 1-acetyl-6-cyano-tetrahydroquinoline by palladium catalysis | |
CN110922285A (en) | Method for preparing aryl primary amide by metal catalysis one-pot method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |