CN108864185B - β -phosphonoenamine derivatives and process for their preparation - Google Patents

β -phosphonoenamine derivatives and process for their preparation Download PDF

Info

Publication number
CN108864185B
CN108864185B CN201810747025.6A CN201810747025A CN108864185B CN 108864185 B CN108864185 B CN 108864185B CN 201810747025 A CN201810747025 A CN 201810747025A CN 108864185 B CN108864185 B CN 108864185B
Authority
CN
China
Prior art keywords
benzamide
mmol
reaction
styryl
phosphonoenamine
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.)
Active
Application number
CN201810747025.6A
Other languages
Chinese (zh)
Other versions
CN108864185A (en
Inventor
邹建平
张栋梁
李成坤
张国玉
陶泽坤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Weng Houke
Original Assignee
Suzhou University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Suzhou University filed Critical Suzhou University
Priority to CN201810747025.6A priority Critical patent/CN108864185B/en
Publication of CN108864185A publication Critical patent/CN108864185A/en
Application granted granted Critical
Publication of CN108864185B publication Critical patent/CN108864185B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3826—Acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of β -phosphonoenamine derivative, which is characterized by comprising the following steps of dissolving enamine derivative, organic phosphine compound, manganese acetate and potassium carbonate in a solvent, and reacting at room temperature to obtain β -phosphonoenamine derivative.

Description

β -phosphonoenamine derivatives and process for their preparation
Technical Field
The invention belongs to the technical field of preparation of organic compounds, and particularly relates to a preparation method of β -phosphonoenamine derivatives.
Background
β -phosphonoenamine is an important class of compounds which can be readily converted to β -aminophosphonic acid which has a wide range of physiological activities such as antibacterial, nerve stimulating, cell growth and metabolism affecting, pain relieving, blood pressure regulating, plant growth regulating, and the like, and thus can be used as an anticancer drug, antibiotic, herbicide, bactericide, antagonist, anthocyanin synthesis inhibitor, fructose bisphosphatase inhibitor, and the like (see 1. Maier, l. Phosphorus Sulfur 1983, 14, 295; 2. AnnH. Hunt, Thomas K. Elzey,J. Antibiot.1988,41, 802; 3. Stephen, H.;Youssef, L. B.; Yolande, H.Synlett1993,135-36.) the synthesis of β -phosphonoenamine derivatives is mainly described as follows:
1. the condensation reaction of α -phosphonoacetonitrile and an imine ether is used for preparing the β -phosphonoenamine derivative, the method needs to carry out the reaction at high temperature, and raw materials are difficult to obtain;
2.β -phosphonoenamine derivatives are prepared from phosphonoacrylates by reaction with amines, the starting materials used in the process being difficult to obtain;
3.β -phosphonoenamine derivatives are prepared from alkylphosphonates by reaction with fluoroalkylnitriles, which require equivalent amounts of metallic lithium reagents, are harsh in reaction conditions, and are difficult to obtain as raw materials.
4.β -phosphonoenamine derivatives are prepared from the reaction of a vinyl phosphonate with an amine, which requires the use of a noble metal rhodium as a catalyst, and carbon monoxide and hydrogen.
In conclusion, it is very important to develop a preparation method of β -phosphonoenamine derivatives which is prepared from easily available raw materials, has mild reaction conditions, wide application range, high yield and low cost and meets the requirement of green chemistry.
Disclosure of Invention
The invention aims to provide an β -phosphonyl enamine derivative and a preparation method thereof.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a preparation method of β -phosphonyl enamine derivative comprises dissolving enamine derivative, organic phosphine compound, manganese acetate and potassium carbonate in solvent, and reacting at room temperature to obtain β -phosphonyl enamine derivative;
the enamine derivative is shown as the following structural general formula:
Figure 100002_DEST_PATH_IMAGE001
wherein R is1And R2Adopts one of the following schemes:
(1) R1is one of hydrogen, methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl, R2Is hydrogen;
(2) R2is one of methyl, methoxy, fluorine, chlorine and bromine, R1Are all hydrogen;
the organic phosphine compound is shown as the following structural general formula:
Figure 754239DEST_PATH_IMAGE002
r is one of methoxyl, ethoxyl, isopropoxy, tert-butoxy and phenyl;
the solvent is selected from: one of methanol, ethanol, acetonitrile, acetone and acetic acid.
The β -phosphonyl enamine derivative has a chemical structural general formula:
Figure DEST_PATH_IMAGE003
in the above technical scheme, the enamine derivative is selected from the group consisting of N- (styryl) benzamide, 2-chloro-N- (styryl) benzamide, 2-fluoro-N- (styryl) benzamide, 3-bromo-N- (styryl) benzamide, 4-methyl-N- (styryl) benzamide, 4-methoxy-N- (styryl) benzamide, 4-trifluoromethyl-N- (styryl) benzamide, 3,4, 5-trimethoxy-N- (styryl) benzamide, N- (styryl) thiophenecarboxamide, N- (2-methylbenzyl) benzamide, N- (styryl) benzamide, N- (2-methylbenzyl) benzamide, N- (N-bromo-N- (styryl) benzamide, N, One of N- (2-methoxystyryl) benzamide, N- (2-fluorostyryl) benzamide, N- (2-chlorostyryl) benzamide, N- (3-methylstyryl) benzamide, N- (3-chlorostyryl) benzamide, N- (4-methylstyryl) benzamide, N- (4-methoxystyryl) benzamide, N- (4-fluorostyryl) benzamide, N- (4-chlorostyryl) benzamide, and N- (4-bromostyryl) benzamide; the organic phosphine compound is selected from one of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite and diphenyl phosphine oxide.
In the technical scheme, the mol ratio of the enamine derivative, the organic phosphine compound, the manganese acetate and the potassium carbonate is 1: 2: 2.5: 2.
The invention also discloses application of enamine derivatives and organic phosphine compounds as substrates in preparing β -phosphonyl enamine derivatives, wherein the enamine derivatives are shown as the following structural general formula:
Figure 891959DEST_PATH_IMAGE001
wherein R is1And R2Adopts one of the following schemes:
(1) R1is one of hydrogen, methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl, R2Is hydrogen;
(2) R2is one of methyl, methoxy, fluorine, chlorine and bromine, R1Is hydrogen;
the organic phosphine compound is shown as the following structural general formula:
Figure 823006DEST_PATH_IMAGE002
r is one of methoxyl, ethoxyl, isopropoxy, tert-butoxy and phenyl.
Preferably, the preparation is carried out in the presence of manganese acetate and potassium carbonate at room temperature in a solvent.
The reaction process of the above technical scheme can be expressed as follows:
Figure 718281DEST_PATH_IMAGE004
the invention also discloses a preparation method of the compound A, which comprises the following steps:
(1) dissolving a compound A1, dimethyl phosphite, manganese acetate and potassium carbonate in a solvent, and reacting at room temperature to obtain a compound A2;
(2) reducing the compound A2 with hydrogen in the presence of Pd/C catalyst to obtain a compound A3;
(3) reacting the compound A3, paraformaldehyde and diethylamine under inert atmosphere to obtain a compound A4;
(4) compound a4 was reacted with concentrated hydrochloric acid to give compound a.
In the technical scheme, the molar ratio of the compound A1, the dimethyl phosphite, the manganese acetate and the potassium carbonate is 1: 2: 2.5: 2; the dosage of the Pd/C catalyst is 10 percent of the molar weight of the compound A2; the mol ratio of the compound A3 to the paraformaldehyde to the diethylamine is 1: 5: 1; concentrated hydrochloric acid is a conventional reagent and is used both as an acid and as a solvent.
In the technical scheme, the inert atmosphere is argon atmosphere.
Specifically, the preparation method of the compound A comprises the following steps:
enamine (A1) and dimethyl phosphite are used as raw materials, and the reaction steps are as follows:
(1) to a reaction flask were added enamine A1 (213 mg, 1 mmol), dimethyl phosphite (220 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL methanol. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) after the reaction is finished, carrying out chromatographic separation on the crude product by using a silica gel column to obtain a target product A2;
(4) a2 (321 mg, 1 mmol) was added to the reaction flask, dissolved by addition of tetrahydrofuran (12 mL), followed by addition of Pd/C catalyst (32.1 mg, 10 mol%). The mixture was reacted at room temperature for 6 hours under a hydrogen (1 atm) atmosphere. After the reaction is finished, carrying out chromatographic separation on the crude product by using a silica gel column to obtain a target product A3;
(5) adding A3 (323 mg, 1 mmol), paraformaldehyde (150 mg, 5 mmol), diethylamine (80 mg, 1 mmol) and anhydrous methanol (1 mL) into a reaction bottle, refluxing the mixture for 24h under the protection of argon, removing the solvent in vacuum after the reaction is finished, then adding toluene for distillation to remove the methanol, adding p-toluenesulfonic acid (1.5 mg, 0.01 mmol), anhydrous toluene (5 mL) and a4 Å molecular sieve, refluxing the mixture for 24h under the protection of argon, and separating a crude product by silica gel column chromatography after the reaction is finished to obtain a target product A4;
(6) a4 (335 mg, 1 mmol) and concentrated hydrochloric acid (20 mL) are added into a reaction flask, the mixture is heated and refluxed until the reaction is finished, 50 mL of water is added, dichloromethane is used for extraction, concentration and drying are carried out, and the crude product is recrystallized by ethanol/water to obtain the target product A.
The chemical structural formula and the reaction of the substances are as follows:
Figure DEST_PATH_IMAGE005
the prepared compound A is an existing antibiotic.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention uses enamine derivative as initiator, which has easily obtained raw material and various kinds; the products obtained by the method of the invention are of various types and can be directly used or used for other further reactions.
2. The invention has the advantages of mild reaction condition, high reaction speed, simple reaction operation and post-treatment process and higher yield, and is suitable for mass production.
Detailed Description
The invention is further described below with reference to the following examples:
the first embodiment is as follows: synthesis of N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The N- (styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (styryl) benzamide (223 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to a reaction flask, and the mixture was stirred at room temperature for reaction;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 90%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.09 (d,J= 11.2Hz, 1H), 7.77 (dd,J= 11.0, 7.9 Hz, 4H), 7.70 – 7.62 (m, 1H), 7.56 (d,J=7.6 Hz, 2H), 7.48 (dd,J= 20.9, 6.0 Hz, 7H), 7.41 – 7.28 (m, 7H)。
if the manganese acetate is replaced with copper bromide or silver nitrate, or the manganese acetate/potassium carbonate is replaced with copper bromide/silver nitrate, the product cannot be prepared.
Example two: synthesis of 2-chloro-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 2-chloro-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 2-chloro-N- (styryl) benzamide (257 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 88%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.43 (d,J= 11.4Hz, 1H), 7.80 - 7.76 (m, 5H), 7.69 (dd,J= 14.1, 11.5 Hz, 1H), 7.55 – 7.50(m, 2H), 7.47 - 7.42 (m, 4H), 7.38 – 7.27 (m, 8H)。
example three: synthesis of 2-fluoro-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 2-fluoro-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 2-fluoro-N- (styryl) benzamide (241 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of ethanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 87%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.78 – 8.70 (m,1H), 8.05 (t,J= 7.4 Hz, 1H), 7.77 (dd,J= 11.5, 7.6 Hz, 4H), 7.72 – 7.66(m, 1H), 7.55 – 7.42 (m, 7H), 7.38 – 7.33 (m, 2H), 7.32 – 7.26 (m, 3H), 7.21(dd,J= 17.7, 7.3 Hz, 1H), 7.01 (dd,J= 12.1, 8.5 Hz, 1H)。
example four: synthesis of 3-bromo-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 3-bromo-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 3-bromo-N- (styryl) benzamide (301 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of ethanol were added to a reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.05 (d,J= 11.3Hz, 1H), 7.85 – 7.73 (m, 5H), 7.65 (t,J= 11.5 Hz, 2H), 7.57 – 7.51 (m, 2H),7.50 – 7.44 (m, 4H), 7.39 (dd,J= 13.8, 7.5 Hz, 3H), 7.29 (dt,J= 18.0,12.6 Hz, 4H)。
example five: synthesis of 4-bromo-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 4-bromo-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 4-bromo-N- (styryl) benzamide (301 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL acetonitrile were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 89%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.07 (d,J= 11.4Hz, 1H), 7.80 (dd,J= 11.9, 7.2 Hz, 4H), 7.68 (dd,J= 13.6, 11.9 Hz, 1H),7.57 (dd,J= 6.9, 4.9 Hz, 4H), 7.54 – 7.44 (m, 6H), 7.44 – 7.39 (m, 2H),7.35 (t,J= 7.3 Hz, 3H)。
example six: synthesis of 4-methoxy-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 4-methoxy-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 4-methoxy-N- (styryl) benzamide (253 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL acetonitrile were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 89%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.03 (d,J= 10.6Hz, 1H), 7.85 – 7.73 (m, 4H), 7.63 (dd,J= 14.3, 11.7 Hz, 1H), 7.51 (dd,J=9.1, 5.0 Hz, 4H), 7.48 - 7.42 (m, 4H), 7.40 – 7.27 (m, 5H), 6.87 (d,J= 8.8Hz, 2H), 3.81 (s, 3H)。
example seven: synthesis of 4-methyl-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 4-methyl-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 4-methyl-N- (styryl) benzamide (237 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of acetic acid were added to a reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1),the expected product is obtained (yield 86%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.09 (d,J= 11.5Hz, 1H), 7.82 – 7.75 (m, 4H), 7.66 (dd,J= 14.3, 11.6 Hz, 1H), 7.55 – 7.51(m, 2H), 7.50 – 7.43 (m, 6H), 7.41 – 7.30 (m, 5H), 7.20 (d,J= 8.0 Hz, 2H),2.38 (s, 3H)。
example eight: synthesis of 4-trifluoromethyl-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
The method takes 4-trifluoromethyl-N- (styryl) benzamide as a raw material, and comprises the following reaction steps:
(1) 4-trifluoromethyl-N- (styryl) benzamide (291 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 87%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.12 (d,J= 11.0Hz, 1H), 7.80 – 7.73 (m, 4H), 7.72 - 7.62 (m, 5H), 7.53 (d,J= 7.1 Hz, 2H),7.50 - 7.43 ( m, 4H ), 7.41 – 7.36 (m, 2H), 7.31 (d,J= 7.5 Hz, 3H)。
example nine: synthesis of 3,4, 5-trimethoxy-N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) benzamide
3,4, 5-trimethoxy-N- (styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) into a reaction flask were added 3,4, 5-trimethoxy-N- (styryl) benzamide (313 mg, 1 mmol), diphenyl phosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 83%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.04 (d,J= 11.5Hz, 1H), 7.77 (dd,J= 11.9, 7.1 Hz, 4H), 7.62 (dd,J= 13.9, 11.7 Hz, 1H),7.52 (dd,J= 10.4, 4.2 Hz, 2H), 7.49 – 7.43 (m, 4H), 7.39 – 7.29 (m, 5H),6.76 (s, 2H), 3.85 (s, 3H), 3.77 (s, 6H)。
example ten: synthesis of N- (2- (diphenylphosphinyloxy) -2-phenylvinyl) thiophene-2-carboxamide
The N- (styryl) thiophene-2-formamide is used as a raw material, and the reaction steps are as follows:
(1) n- (styryl) thiophene-2-carboxamide (229 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of acetone were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 86%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ7.92 (d,J= 11.4Hz, 1H), 7.80 – 7.71 (m, 4H), 7.63 – 7.49 (m, 5H), 7.45 (t,J= 7.0 Hz, 4H),7.39 – 7.30 (m, 4H), 7.25 – 7.21 (m, 1H), 7.07 - 6.98 (m, 1H)。
example eleven: synthesis of (2-benzamido-1-styryl) dimethyl phosphonate
The N- (styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (styryl) benzamide (223 mg, 1 mmol), dimethyl phosphite (220 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 85%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.19 – 8.06 (m,2H), 7.64 – 7.60 (m, 2H), 7.52 (dd, J = 15.0, 7.5 Hz, 3H), 7.45 – 7.37 (m,5H), 3.78 (s, 3H), 3.75 (s, 3H)。
example twelve: synthesis of (2-benzamido-1-styryl) diethyl phosphonate
The N- (styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (styryl) benzamide (223 mg, 1 mmol), diethyl phosphite (276 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of acetic acid were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 88%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.21–8.07 (m, 2H),7.67–7.61 (m, 2H), 7.54 (dd,J= 15.0, 7.5 Hz, 3H), 7.48–7.38 (m, 5H), 4.60–4.40 (m, 4H), 1.35–1.15 (m, 6H)。
example thirteen: synthesis of (2-benzamido-1-styryl) diisopropyl phosphonate
The N- (styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (styryl) benzamide (223 mg, 1 mmol), diisopropyl phosphite (332 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 85%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.19–8.06 (m, 2H),7.64–7.60 (m, 2H), 7.52 (dd,J= 15.0, 7.5 Hz, 3H), 7.45–7.37 (m, 5H), 4.72–4.63 (m, 2H), 1.29 (d,J= 6.2 Hz, 6H), 1.23 (d,J= 6.2 Hz, 6H)；
example fourteen: synthesis of N- (2- (diphenylphosphinyloxy) -2- (2-methoxyphenyl) vinyl) benzamide
The N- (2-methoxy styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (2-Methoxystyrenyl) benzamide (253 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to a reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 83%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.09 (d,J= 11.2Hz, 1H), 8.05 (d,J= 7.7 Hz, 2H), 7.96 (dd,J= 31.2, 10.6 Hz, 1H), 7.60(dd,J= 11.6, 8.0 Hz, 4H), 7.48 (dd,J= 15.8, 8.5 Hz, 5H), 7.39 (d,J= 7.0Hz, 4H), 7.18 (t,J= 7.4 Hz, 1H), 6.89 (d,J= 6.8 Hz, 1H), 6.75 (t,J= 7.3Hz, 1H), 6.58 (d,J= 8.1 Hz, 1H), 3.18 (s, 2H)。
example fifteen: synthesis of N- (2- (diphenylphosphinyloxy) -2- (2-methylphenyl) vinyl) benzamide
The N- (2-methyl styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (2-Methylstyryl) benzamide (237 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.12 (d,J= 11.0Hz, 1H), 8.09 (dd,J= 5.3, 3.3 Hz, 2H), 7.90 (dd,J= 31.7, 10.5 Hz, 1H),7.57 – 7.46 (m, 9H), 7.44 – 7.35 (m, 4H), 7.13 (t,J= 7.5 Hz, 1H), 7.01 (d,J= 7.5 Hz, 1H), 6.95 (t,J= 7.5 Hz, 1H), 6.80 (d,J= 7.7 Hz, 1H), 1.67 (s,3H)。
example sixteen: synthesis of N- (2- (diphenylphosphinyloxy) -2- (2-fluorophenyl) vinyl) benzamide
The N- (2-fluorostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (2-Fluorostyryl) benzamide (241 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.20 (d,J= 11.0Hz, 1H), 8.17 – 8.03 (m, 3H), 7.69 (dd,J= 12.1, 7.5 Hz, 4H), 7.60 (dd,J=8.8, 4.5 Hz, 3H), 7.54 (t,J= 7.4 Hz, 2H), 7.51 – 7.44 (m, 4H), 7.23 (dd,J= 13.2, 7.0 Hz, 1H), 6.93 (dd,J= 15.3, 7.8 Hz, 2H), 6.78 (t,J= 7.6 Hz,1H)。
example seventeen: synthesis of N- (2- (diphenylphosphinyloxy) -2- (2-chlorophenyl) ethenyl) benzamide
The N- (2-chlorostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (2-chlorostyryl) benzamide (257 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.20 (d,J= 11.0Hz, 1H), 8.13 – 8.06 (m, 2H), 7.99 (dd,J= 30.7, 10.6 Hz, 1H), 7.62 – 7.46(m, 9H), 7.40 (td,J= 7.7, 3.0 Hz, 4H), 7.22 (d,J= 7.8 Hz, 1H), 7.14 (t,J= 7.7 Hz, 1H), 7.01 (t,J= 7.5 Hz, 1H), 6.88 (d,J= 7.7 Hz, 1H)。
example eighteen: synthesis of N- (2- (diphenylphosphinyloxy) -2- (3-methylphenyl) vinyl) benzamide
The N- (3-methyl styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (3-Methylstyryl) benzamide (237 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 90%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.12 (d,J= 8.3Hz, 1H), 7.78 (s, 4H), 7.58 – 7.48 (m, 6H), 7.45 (s, 4H), 7.41 – 7.36 (m,2H), 7.24 (s, 1H), 7.12 (d,J= 17.2 Hz, 2H), 2.28 (s, 3H)。
example nineteenth: synthesis of N- (2- (diphenylphosphinyloxy) -2- (3-chlorophenyl) ethenyl) benzamide
The N- (3-chlorostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (3-chlorostyryl) benzamide (257 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 88%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.03 (d,J= 11.6Hz, 1H), 7.77 (dd,J= 11.6, 7.5 Hz, 4H), 7.65 - 7.45 (m, 6H), 7.48 (dd,J=9.7, 4.4 Hz, 4H), 7.42 (t,J= 7.6 Hz, 2H), 7.37 – 7.29 (m, 3H), 7.24 (d,J=6.4 Hz, 1H)。
example twenty: synthesis of N- (2- (diphenylphosphinyloxy) -2- (4-methylphenyl) vinyl) benzamide
The N- (4-methyl styryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (4-Methylstyryl) benzamide (237 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.14 (d,J= 11.3Hz, 1H), 7.76 (dd,J= 11.5, 7.7 Hz, 4H), 7.68 – 7.62 (m, 1H), 7.57 (d,J=7.6 Hz, 2H), 7.53 – 7.48 (m, 3H), 7.47 – 7.42 (m, 4H), 7.39 (t,J= 7.6 Hz,2H), 7.18 (dd,J= 20.4, 7.8 Hz, 4H), 2.31 (s, 3H)。
example twenty one: synthesis of N- (2- (diphenylphosphinyloxy) -2- (4-methoxyphenyl) vinyl) benzamide
The N- (4-methoxystyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (4-Methoxystyrenyl) benzamide (253 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to a reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 83%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.10 (d,J= 11.3Hz, 1H), 7.76 (dd,J= 11.6, 7.4 Hz, 4H), 7.66 – 7.60 (m, 1H), 7.58 (d,J=7.5 Hz, 2H), 7.51 (d,J= 6.0 Hz, 3H), 7.46 (dd,J= 9.8, 4.5 Hz, 4H), 7.40(t,J= 7.6 Hz, 2H), 7.25 (d,J= 8.3 Hz, 1H), 6.89 (d,J= 8.5 Hz, 2H), 3.78(s, 3H)。
example twenty two: synthesis of N- (2- (diphenylphosphinyloxy) -2- (4-fluorophenyl) vinyl) benzamide
The N- (4-fluorostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (4-Fluorostyryl) benzamide (241 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) reaction junctionAfter completion of the reaction, the crude product was isolated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.01 (d,J= 11.3Hz, 1H), 7.76 (dd,J= 11.9, 7.2 Hz, 4H), 7.67 – 7.60 (m, 1H), 7.55 (dd,J=12.1, 4.4 Hz, 4H), 7.53 (d,J= 2.3 Hz, 1H), 7.47 (td,J= 7.4, 2.7 Hz, 4H),7.41 (t,J= 7.7 Hz, 2H), 7.32 (dd,J= 7.3, 5.5 Hz, 2H), 7.07 (t,J= 8.6Hz, 2H)。
example twenty three: synthesis of N- (2- (diphenylphosphinyloxy) -2- (4-chlorophenyl) ethenyl) benzamide
The N- (4-chlorostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (4-chlorostyryl) benzamide (257 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.02 (d,J= 11.5Hz, 1H), 7.82 – 7.70 (m, 4H), 7.66 – 7.51 (m, 6H), 7.51 - 7.45 (m, 4H), 7.42(t,J= 7.7 Hz, 2H), 7.35 (d,J= 8.5 Hz, 2H), 7.32 – 7.29 (m, 2H)。
example twenty-four: synthesis of N- (2- (diphenylphosphinyloxy) -2- (4-bromophenyl) vinyl) benzamide
The N- (4-bromostyryl) benzamide is used as a raw material, and the reaction steps are as follows:
(1) n- (4-bromophenylvinyl) benzamide (301 mg, 1 mmol), diphenylphosphine oxide (404 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL of methanol were added to the reaction flask. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) the crude product obtained after the reaction was completed was separated by column chromatography (dichloromethane: methanol = 100:1) to obtain the objective product (yield 85%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.05 (d,J= 11.0Hz, 1H), 7.76 (dd,J= 11.5, 7.7 Hz, 4H), 7.60 (t,J= 11.6 Hz, 3H), 7.54 –7.44 (m, 9H), 7.41 (t,J= 7.6 Hz, 2H), 7.24 (d,J= 7.8 Hz, 2H)。
example twenty-five: synthesis of antibiotic A53868A (A)
Figure 924134DEST_PATH_IMAGE006
Enamine (A1) and dimethyl phosphite are used as raw materials, and the reaction steps are as follows:
(1) to a reaction flask were added enamine A1 (213 mg, 1 mmol), dimethyl phosphite (220 mg,2 mmol), manganese acetate (580 mg, 2.5 mmol), anhydrous potassium carbonate (276 mg,2 mmol) and 10mL methanol. The mixture is stirred and reacted at room temperature;
(2) TLC followed the reaction until complete (about 0.5 hours);
(3) after the reaction, the crude product was separated by silica gel column chromatography to obtain the desired product A2 (yield 76%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3)：δ9.66 (s, 1H), 7.40 (s, 1H), 7.33 (dd,J=16.9, 10.1 Hz, 1H), 5.38 (dd,J= 16.8, 2.1 Hz, 1H), 5.07 (s, 2H), 4.60 (t,J= 7.3 Hz, 1H), 4.41 (dd,J= 10.0, 2.1 Hz, 1H), 3.54 (s, 2H), 1.86 (t,J=7.3 Hz, 1H), 1.68 – 1.55 (m, 2H), 0.98 (d,J= 6.2 Hz, 6H)。
(4) a2 (321 mg, 1 mmol) was added to the reaction flask, dissolved by addition of tetrahydrofuran (12 mL), followed by addition of Pd/C catalyst (32.1 mg, 10 mol%). The mixture was reacted at room temperature for 6 hours under a hydrogen (1 atm) atmosphere. Coarse after the reaction is finishedThe product was isolated by silica gel column chromatography to give the desired product A3 (91% yield). Analytical data for the product are as follows:1HNMR (400 MHz, CDCl3)：δ8.00 (s, 1H), 7.39 (s, 1H), 5.07 (s, 2H), 4.52 (t,J=3.4 Hz, 1H), 3.67 (d,J= 11.0 Hz, 6H), 3.55 – 3.51 (m, 3H), 3.43 (t,J= 6.1Hz, 1H), 2.09 – 2.00 (m, 3H), 1.74 (t,J= 3.6 Hz, 2H), 1.73 – 1.67 (m, 1H),0.84 (d,J= 6.3 Hz, 6H)；
(5) a3 (323 mg, 1 mmol), paraformaldehyde (150 mg, 5 mmol), diethylamine (80 mg, 1 mmol) and anhydrous methanol (1 mL) are added into a reaction flask, the mixture is refluxed for 24h under the protection of argon, after the reaction is finished, the solvent is removed in vacuum, then toluene is added for distillation, methanol is removed, p-toluenesulfonic acid (1.5 mg, 0.01 mmol), anhydrous toluene (5 mL) and a4 Å molecular sieve are added, the mixture is refluxed for 24h under the protection of argon, after the reaction is finished, the crude product is separated by silica gel column chromatography, and the target product A4 (yield is 83%) is obtained, and the analytical data of the product are as follows:1H NMR (400 MHz, CDCl3):δ8.77 (s, 1H),7.16 (s, 1H), 5.11 (s, 2H), 5.07 (s, 2H), 4.59 (t,J= 3.4 Hz, 1H), 3.93 (s,2H), 3.78 (d,J= 10.8 Hz, 6H), 3.54 (s, 2H), 1.88 – 1.83 (m, 1H), 1.67 (dd,J= 4.6, 3.4 Hz, 1H), 1.57 (dd,J= 4.6, 3.4 Hz, 1H), 1.00 (d,J= 6.3 Hz,6H)；
(6) a4 (335 mg, 1 mmol) and concentrated HCl (20 mL) were added to the flask, the mixture was heated under reflux until the reaction was complete, 50 mL of water was added, the mixture was extracted with dichloromethane, concentrated, dried, and the crude product was recrystallized from ethanol/water to give the desired product A (89% yield). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ8.49 (s, 1H), 7.99(s, 1H), 5.12 (s, 2H), 5.07 (s, 2H), 4.57 (t,J= 3.4 Hz, 1H), 4.16 (s, 1H),4.05 (s, 1H), 3.54 (s, 2H), 1.93 (s, 3H), 1.89 (dd,J= 7.3, 3.3 Hz, 1H),1.61 (dd,J= 7.3, 3.5 Hz, 1H), 1.45 – 1.32 (m, 1H), 0.87 (d,J= 6.4 Hz)。
example twenty-six: synthesis of (2-benzamido-1-phenethyl) dimethyl phosphonate
The method takes (2-benzamido-1-styryl) dimethyl phosphonate as a raw material, and comprises the following reaction steps:
to the reaction vessel was added (2-benzamido-1-styryl) dimethylphosphonate (3.3 g, 10 mmol), Raney-Ni (660 mg, 20 mol%), methanol (200 mL) at 40oC and hydrogen (10 atm)
The reaction was carried out for 24 hours. The reaction product was filtered and concentrated to give the product (2-benzamido-1-phenylethyl) dimethylphosphonate (95% yield). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ7.72 (t,J= 5.6 Hz,1H), 7.70–7.65 (m, 2H), 7.40–7.31 (m, 3H), 7.27 (t,J= 7.4 Hz, 4H), 7.24 –7.20 (m, 1H), 4.10–3.98 (m, 1H), 3.97–3.83 (m, 1H), 3.74–3.63 (m, 4H), 3.46(d,J= 10.6 Hz, 3H)。
example twenty-seven: synthesis of 2-amino-1-phenylethylphosphonic acid
The method takes (2-benzamido-1-phenethyl) dimethyl phosphonate as a raw material, and comprises the following reaction steps:
(1) (2-benzamido-1-phenylethyl) dimethylphosphonate (1.33 g, 4 mmol) and 8M hydrochloric acid (50 mL) were added to a reaction flask and the mixture was refluxed;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the reaction solution was cooled to room temperature, washed with dichloromethane, concentrated, and recrystallized to obtain 2-amino-1-phenethylphosphonic acid (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, D2O):δ7.40–7.24 (m, 5H), 3.62–3.36 (m, 2H), 3.30–3.11 (m, 1H)。

Claims (5)

1. a preparation method of β -phosphonoenamine derivative is characterized by comprising the following steps of dissolving enamine derivative, organic phosphine compound, manganese acetate and potassium carbonate in solvent, and reacting at room temperature to obtain β -phosphonoenamine derivative;
the enamine derivative is shown as the following structural general formula:
Figure DEST_PATH_IMAGE001
wherein R is1And R2Adopts one of the following schemes:
(1) R1is one of hydrogen, methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl, R2Is hydrogen;
(2) R2is one of methyl, methoxy, fluorine, chlorine and bromine, R1Is hydrogen;
the organic phosphine compound is shown as the following structural general formula:
Figure DEST_PATH_IMAGE002
r is one of methoxyl, ethoxyl, isopropoxy, tert-butoxy and phenyl.
2. The method of β -phosphonoenamine derivative according to claim 1, wherein the enamine derivative is selected from the group consisting of N- (styryl) benzamide, 2-chloro-N- (styryl) benzamide, 2-fluoro-N- (styryl) benzamide, 3-bromo-N- (styryl) benzamide, 4-methyl-N- (styryl) benzamide, 4-methoxy-N- (styryl) benzamide, 4-trifluoromethyl-N- (styryl) benzamide, N- (2-methylstyryl) benzamide, N- (2-methoxystyryl) benzamide, N- (2-fluorostyryl) benzamide, N- (2-chlorostyryl) benzamide, N- (3-methylstyryl) benzamide, N- (3-chlorostyryl) benzamide, N- (4-methylstyryl) benzamide, N- (4-methoxystyryl) benzamide, N- (4-fluorostyryl) benzamide, N- (4-chlorostyryl) benzamide, and N- (4-bromostyryl) benzamide.
3. The method of claim 1, wherein the organic phosphine compound is selected from the group consisting of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite, and diphenyl phosphine oxide, and the solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and acetic acid.
4. The process for producing β -phosphonoenamine derivatives according to claim 1, wherein the reaction is followed by thin layer chromatography until completion.
5. The process of claim β -phosphonoenamine derivatives according to claim 1, wherein the molar ratio of enamine derivatives, organophosphine compounds, manganese acetate and potassium carbonate is 1: 2: 2.5: 2.
CN201810747025.6A 2018-07-09 2018-07-09 β -phosphonoenamine derivatives and process for their preparation Active CN108864185B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810747025.6A CN108864185B (en) 2018-07-09 2018-07-09 β -phosphonoenamine derivatives and process for their preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810747025.6A CN108864185B (en) 2018-07-09 2018-07-09 β -phosphonoenamine derivatives and process for their preparation

Publications (2)

Publication Number Publication Date
CN108864185A CN108864185A (en) 2018-11-23
CN108864185B true CN108864185B (en) 2020-05-08

Family

ID=64300401

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810747025.6A Active CN108864185B (en) 2018-07-09 2018-07-09 β -phosphonoenamine derivatives and process for their preparation

Country Status (1)

Country Link
CN (1) CN108864185B (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101343289A (en) * 2008-08-25 2009-01-14 苏州大学 Method for synthesis of organo-phosphines acid ester derivant
CN101497632B (en) * 2009-03-04 2012-01-25 苏州大学 Method for synthesizing coumarin-3-phosphonate derivative

Also Published As

Publication number Publication date
CN108864185A (en) 2018-11-23

Similar Documents

Publication Publication Date Title
CN108864185B (en) β -phosphonoenamine derivatives and process for their preparation
CN104803908A (en) Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate
CN105524111B (en) Chiral phosphoramidite monodentate ligand and its synthetic method and application
CN115322157B (en) Letermopevir intermediate compound, preparation method and application thereof
KR101744046B1 (en) Process for preparing an intermediate useful for the synthesis of silodosin
CN108727428B (en) β -aminophosphonic acid derivatives and process for their preparation
WO2017177715A1 (en) Method for preparing chiral ferrocene p, p ligand
CN101693642B (en) Method for synthesizing 1,2-diphenylethylene compounds
CN112707899B (en) Preparation method of quininol
CN110256451B (en) Synthetic method of benzofuro [2,3-b ] quinoline derivative
CN102367216A (en) Preparation method of diselenoaminoformate derivatives
CN116134023A (en) Process for preparing aminofurans
US5856497A (en) Asymmetric synthesis of α-cycloalkylalkyl substituted methanamines
WO2020010587A1 (en) β-PHOSPHONYL-ENAMINE DERIVATIVE AND PREPARATION METHOD THEREFOR
US4231962A (en) 3-Phenoxybenzylideneamines and 3-benzylbenzylideneamines
JP5587350B2 (en) Preparation of ramelteon
CN108821992A (en) A kind of Levetiracetam impurity and synthetic method
US7038091B2 (en) Process for producing acetylene compound
CN113480512B (en) Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone
WO2020010586A1 (en) β-AMINO PHOSPHONIC ACID DERIVATIVE AND PREPARATION METHOD THEREFOR
CN110862385A (en) Application of copper catalyst in preparation of thiazoloquinazolinone derivative through reaction of 1-thiazolylindole compound and tert-butyl nitrite
US9527862B2 (en) Compounds of chiral aromatic spiroketal diphosphine ligands, preparation methods and uses thereof
KR100203457B1 (en) Process for terbinafine
CN114014869B (en) Chiral 2,2' -bipyridine ligand and preparation method and application thereof
CN117720537A (en) Axial chiral indole-furan catalyst and preparation method and application thereof

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
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20220214

Address after: 215311 Room 101, 11 mansion house, Kunshan, Suzhou, Jiangsu

Patentee after: Weng Houke

Address before: No. 8, Xiangcheng District Ji Xue Road, Suzhou, Jiangsu

Patentee before: SOOCHOW University