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CN-122011028-A - Method for efficiently preparing various substituted chiral phosphoramides

CN122011028ACN 122011028 ACN122011028 ACN 122011028ACN-122011028-A

Abstract

The invention provides a method for efficiently preparing various substituted chiral phosphoramides, which comprises the following steps of reacting nucleoside compounds or alcohols with racemized amino phosphoryl dichloride or alkoxy phosphoryl dichloride in the presence of an organic solvent, alkali, chiral ligands and a catalyst to generate chiral phosphoryl chloride, and then reacting the chiral phosphoryl chloride with a nucleophilic reagent to obtain the chiral phosphoramides. The synthesis method provided by the invention has the characteristics of simple operation, high yield, good diastereoselectivity or enantioselectivity, good compatibility of the obtained target compound with functional groups and wide substrate universality. The obtained product has various structures and good controllability, and has good application potential in the field of medicine synthesis.

Inventors

  • SHANG MING
  • YAO HONGQING

Assignees

  • 上海交通大学

Dates

Publication Date
20260512
Application Date
20241112

Claims (10)

  1. 1. A chiral phosphoryl chloride, characterized in that the chiral phosphoryl chloride has a compound structure represented by the following formula I: Wherein R 1 is derived from any of dimethylamine, diethylamine, diallylamine, bis (2-chloroethyl) amine, diisobutylamine, isopropyl N-benzylglycinate, N-methylbenzylamine, N- [ (trimethylsilicon) methyl ] benzylamine, diethyl iminodiacetate, N- (2-furylmethyl) benzylamine, tetrahydropyrrole, indoline, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine, 4-methylhexahydropyridine, methyl 4-piperidinacetate, morpholine, N-phenylpiperazine, 1- (2-pyrimidinyl) piperazine, cycloheptylamine, 4' -difluoromethylpiperazine, 6-fluoro-3- (4-piperidinyl) -1,2 benzisozole, 4- (1, 2-benzisothiazol-3-yl) -1-piperazine, duloxetine, nortriptyline, vortexin, moxidectin, tolitene; R 2 is 2',3' -isopropylidene uridine, 2',3' -isopropylidene thymidine, 5-fluoro-2 ',3' -isopropylidene uridine, 5-bromo-2 ',3' -isopropylidene uridine, 5-iodo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene adenosine, 6-chloro-2 ',3' -isopropylidene adenosine, zidovudine, 3'-O- (tert-butyldimethylsilyl) thymidine, 3' -O-benzylthymidine, stavudine, 1- ((3 a 'R, 4' R, 6'R, 6a' R) -4'- (hydroxymethyl tetrahydrospiro [ cyclohexane-1, 2' -furo [3,4-d ] [1, 3] dioxol ] -6-yl) pyrimidine-2, 4 (1H, 3H) -dione, (2R, 3S, 5R) -5- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2- (hydroxymethyl) tetrahydrofuran, fructose diacetone, ((2S, 3R, 4S, 5R, 6S) -3,4, 5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-yl) methanol, (2R, 3R, 4R, 5S) -5- (hydroxymethyl) tetrahydrofuran-2, 3, 4-trisbenzoate, (3-phenoxyphenyl) methanol, 4-nitrobenzyl alcohol, methyl 4- (hydroxymethyl) benzoate, any one of 1-naphthalenemethanol, 2-naphthalenemethanol, 3-morpholinophenyl-methanol, (5-nitrofuran-2-yl) methanol, 2-naphthaleneethanol, 1- (2-methoxyphenyl) ethanol, 1- (3-methoxyphenyl) ethanol, 1- (4-methoxyphenyl) ethanol, tert-butyl (4- (2-hydroxyethyl) phenyl) carbamate, metronidazole, 2-thiophenoethanol, 2-thiophenylethanol, N-BOC-2- (4-aminophenyl) ethanol, benzyl 4- (hydroxymethyl) piperidine-1-carboxylate, idebenone.
  2. 2. A process for the preparation of chiral phosphorus oxychloride as claimed in claim 1, comprising the steps of: in the presence of an organic solvent, alkali, chiral ligand and catalyst, nucleoside compounds or alcohols react with racemized amino phosphoryl dichloride or alkoxy phosphoryl dichloride to generate chiral phosphoryl chloride.
  3. 3. The method for preparing chiral phosphoryl chloride according to claim 2, wherein the nucleoside compound is selected from the group consisting of 2',3' -isopropylidene uridine, 5-fluoro-2 ',3' -isopropylidene uridine, 5-bromo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene thymidine, 5-iodo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene adenosine, 6-chloro-2 ',3' -isopropylidene adenosine, zidovudine, 3'-O- (tert-butyldimethylsilyl) thymidine, 3' -O-benzyl thymidine, stavudine, 1- ((3 a 'R, 4' R, 6'R, 6a' R) -4'- (hydroxymethyl tetrahydrospiro [ cyclohexane-1, 2' -furo [3,4-d ] [1, 3] dioxa-pentene ] -6-yl) pyrimidine-2, 4 (1H, 3H) -dione, (2R, 3S, 5R) -5- (4-chloro-7H-pyrrol [2,3-d ] tetrahydropyrimidine, and at least one of fructose-2- (3-methyl) -2-d) furanone; The alcohol is selected from at least one of 4-nitrobenzyl alcohol, (5-nitrofuran-2-yl) methanol, 1- (2-methoxyphenyl) ethanol, 2-thiophenoethanol, N-BOC-2- (4-aminophenyl) ethanol, ((2S, 3R, 4S, 5R, 6S) -3,4, 5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-yl) methanol, (3-phenoxyphenyl) methanol, 1-naphthalenyl methanol, 2-naphthalenyl methanol, 3-morpholinophenyl methanol, 2-naphthalenyl ethanol, 1- (3-methoxyphenyl) ethanol, 1- (4-methoxyphenyl) ethanol, (2R, 3R, 4R, 5S) -5- (hydroxymethyl) tetrahydrofuran-2, 3, 4-tricarbamate, methyl 4- (hydroxymethyl) benzoate, tert-butyl (4- (2-hydroxyethyl) phenyl) carbamate, metronidazole, 4- (hydroxymethyl) piperidine-1-carboxylate and benzoquinone.
  4. 4. The method for preparing chiral phosphoryl chloride according to claim 2, wherein the aminophosphoryl dichloride is at least one selected from dibenzyl amine phosphoryl dichloride, dimethylamine phosphoryl dichloride, bis (2-chloroethyl) phosphoramide dichloride, diallyl phosphoramide dichloride, benzyl (furan-2-ylmethyl) phosphoramide dichloride, (S) -methyl- (3- (1-naphthoxy)) -3- (thiophen-2-yl) propyl) phosphoramide dichloride; the alkoxyphosphoryl dichloride is at least one selected from pyrrolidin-1-yl phosphoryl dichloride, morpholinophosphoryl dichloride, azacyclopentane-1-phosphono dichloride, (4- (6-fluorobenzo [ d ] trimethylandrostadien isoxazol-3-yl)) piperidin-1-yl) phosphine dichloride and ethyl dichlorophosphate.
  5. 5. The method for preparing chiral phosphoryl chloride according to claim 2, wherein the organic solvent is selected from the group consisting of tetrahydrofuran; The base is selected from triethylamine; the catalyst is selected from copper hexafluoroacetylacetonate; The chiral ligand is selected from ligand L1 and ligand L2, and the ligand has the following structure:
  6. 6. The method for preparing chiral phosphoryl chloride according to claim 2, wherein the molar ratio of the nucleoside-containing compound or alcohol to the aminophosphoryl dichloride or alkoxyphosphoryl dichloride is 1:1.0-1.5; The reaction temperature is minus 60 ℃ to minus 30 ℃ and the reaction time is 18-28h.
  7. 7. A preparation method of chiral phosphoramide is characterized by comprising the following steps of reacting chiral phosphoryl chloride according to claim 1 with a nucleophilic reagent to obtain chiral phosphoramide.
  8. 8. The method for preparing chiral phosphoramide according to claim 7, wherein the nucleophilic reagent is selected from any one of sodium phenolate, sodium methoxide, sodium 1-naphtholate, sodium 4-fluorophenol, sodium thiophenate, sodium ethanethiol, cyclohexylamine, benzamide, 4-methoxyaniline, benzylamine, dimethylamine, morpholine, 2-t-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane, L-alanine isopropyl ester, 1,2,3, 4-tetrahydroisoquinoline, methyl magnesium bromide, and lithium amide.
  9. 9. The preparation method of chiral phosphoramide according to claim 7, wherein the reaction temperature is-60 ℃ to-30 ℃ and the reaction time is 2-6 hours.
  10. 10. A chiral phosphoramide prepared according to any one of claims 7 to 9, wherein the chiral phosphoramide comprises a compound having the formula II to X: wherein R 3 is derived from any of dimethylamine, diethylamine, diallylamine, bis (2-chloroethyl) amine, diisobutylamine, isopropyl N-benzylglycinate, N-methylbenzylamine, N- [ (trimethylsilicon) methyl ] benzylamine, diethyl iminodiacetate, N- (2-furylmethyl) benzylamine, tetrahydropyrrole, indoline, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine, 4-methylhexahydropyridine, methyl 4-piperidinacetate, morpholine, N-phenylpiperazine, 1- (2-pyrimidinyl) piperazine, cycloheptylamine, 4' -difluoromethylpiperazine, 6-fluoro-3- (4-piperidinyl) -1,2 benzisozole, 4- (1, 2-benzisothiazol-3-yl) -1-piperazine, duloxetine, nortriptyline, vortexin, moxidectin, tolitene; R 4 is any one of methyl, 1-naphthol, 4-fluorophenol, phenol, methoxy, thiophenol, ethylthio, cyclohexylamine, benzylamine, benzamide, 4-methoxyaniline, dimethylamine, morpholine, tert-butyloxy, 2-tert-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane; r 5 is any one of 2',3' -isopropylidene thymidine, 5-fluoro-2 ',3' -isopropylidene uridine, 5-bromo-2 ',3' -isopropylidene uridine, 5-iodo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene adenosine, (2R, 3S, 5R) -5- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2- (hydroxymethyl) tetrahydrofuran; R 6 is any one of hydrogen, acetoxy, tert-butyldimethylsilyloxy and azido; R 7 is any one of thymidine and uridine; R 8 is derived from any of fructose diacetone, ((2S, 3R, 4S, 5R, 6S) -3,4, 5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-yl) methanol, (2R, 3R, 4R, 5S) -5- (hydroxymethyl) tetrahydrofuran-2, 3, 4-trisbenzoate, (3-phenoxyphenyl) methanol, 4-nitrobenzyl alcohol, methyl 4- (hydroxymethyl) benzoate, 1-naphthalenyl methanol, 2-naphthalenyl methanol, 3-morpholinyl benzyl alcohol, (5-nitrofuran-2-yl) methanol, 2-naphthalenyl ethanol, 1- (2-methoxyphenyl) ethanol, 1- (3-methoxyphenyl) ethanol, 1- (4-methoxyphenyl) ethanol, tert-butyl (4- (2-hydroxyethyl) phenyl) carbamate, metronidazole, 2-thiophenol, 2-thiophenyl ethanol, 4- (hydroxymethyl) piperidine-1-carboxylic acid benzyl ester, idebenone.

Description

Method for efficiently preparing various substituted chiral phosphoramides Technical Field The invention belongs to the technical field of medicines and synthesis of medical intermediates, and particularly relates to a method for efficiently preparing various substituted chiral phosphoramides. Background Compounds having one or more stereocomphosphite atoms in the P (V) oxidation state play a critical role in chemistry, biology and medicine. Including well-known antiviral drugs such as reed west Wei Zuichu designed to combat ebola virus, are also approved for the treatment of SARS-CoV-2. Other related compounds include fosinopril (Fosinopril), a compound useful in the treatment of hypertension and heart failure, and cyclophosphamide, a basic drug chemotherapeutic listed by the World Health Organization (WHO). The synthesis of enantiomerically pure P (V) compounds can be divided into five general classes, (1) chiral resolution strategy of racemic phosphine oxide, (2) chiral prosthetic group induced strategy, (3) strategy of tertiary phosphine oxidation synthesis of P-chiral phosphine oxide, (4) asymmetric catalytic strategy based on phosphine oxide, (5) enantioselective desymmetry by differentiating prochiral groups linked to the phosphorus center by chiral catalysts, with which a number of reactions have been developed. However, a highly efficient and general synthetic method of chiral phosphoramides has not been reported so far. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a method for efficiently preparing various substituted chiral phosphoramides. The invention aims at realizing the following technical scheme: In a first aspect, the present invention provides a chiral phosphoryl chloride having a compound structure represented by formula I: Wherein R 1 is derived from one of dimethylamine, diethylamine, diallylamine, bis (2-chloroethyl) amine, diisobutylamine, isopropyl N-benzylglycinate, N-methylbenzylamine, N- [ (trimethylsilicon) methyl ] benzylamine, diethyl iminodiacetate, N- (2-furylmethyl) benzylamine, tetrahydropyrrole, indoline, 1,2,3, 4-tetrahydroquinoline, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine, 4-methylhexahydropyridine, methyl 4-piperidinacetate, morpholine, N-phenylpiperazine, 1- (2-pyrimidinyl) piperazine, cycloheptylamine, 4' -difluoromethylpiperazine, 6-fluoro-3- (4-piperidinyl) -1,2 benzisozole, 4- (1, 2-benzisothiazol-3-yl) -1-piperazine, duloxetine (3- (1-naphthoxy) -3- (2-thienyl) propyl), vortexin; R 2 is derived from 2',3' -isopropylidene uridine, 2',3' -isopropylidene thymidine, 5-fluoro-2 ',3' -isopropylidene uridine, 5-bromo-2 ',3' -isopropylidene uridine, 5-iodo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene adenosine, 6-chloro-2 ',3' -isopropylidene adenosine, zidovudine, 3'-O- (tert-butyldimethylsilyl) thymidine, 3' -O-benzylthymidine, stavudine, 1- ((3 a 'R, 4' R, 6'R, 6a' R) -4'- (methylol tetrahydrospiro [ cyclohexane-1, 2' -furo [3,4-d ] [1, 3] dioxol ] -6-yl) pyrimidine-2, 4 (1H, 3H) -dione, 1- ((2R, 6S) -6- (hydroxymethyl) -4-trityl morpholin-2-yl) pyrimidine-2, 4 (1H, 3H) -dione, (2R, 3S, 5R) -5- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2- (hydroxymethyl) tetrahydrofuran, diacetone, ((2S, 3R, 4S, 5R, 6S) -3,4, 5-tris (benzyloxy) -6-methoxytetrahydro-2H-pyran-2-yl), (3R, 4R) 4-R, any one of 5S) -5- (hydroxymethyl) tetrahydrofuran-2, 3, 4-trisbenzoate, (3-phenoxyphenyl) methanol, 4-nitrobenzyl alcohol, methyl 4- (hydroxymethyl) benzoate, 1-naphthalenyl methanol, 2-naphthalenyl methanol, 3-morpholinyl benzyl alcohol, (5-nitrofuran-2-yl) methanol, 2-naphthalenyl ethanol, 1- (2-methoxyphenyl) ethanol, 1- (3-methoxyphenyl) ethanol, 1- (4-methoxyphenyl) ethanol, tert-butyl (4- (2-hydroxyethyl) phenyl) carbamate, metronidazole, 2-thiophenoethanol, 2-thiophenylethanol, N-BOC-2- (4-aminophenyl) ethanol, benzyl 4- (hydroxymethyl) piperidine-1-carboxylate, idebenone. In a second aspect, the invention provides a method for preparing chiral phosphoryl chloride, comprising the following steps: in the presence of an organic solvent, alkali, chiral ligand and catalyst, nucleoside compounds or alcohols react with racemized amino phosphoryl dichloride or alkoxy phosphoryl dichloride to generate chiral phosphoryl chloride. Preferably, the nucleoside compound is selected from at least one of 2',3' -isopropylidene uridine, 5-fluoro-2 ',3' -isopropylidene uridine, 5-bromo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene thymidine, 5-iodo-2 ',3' -isopropylidene uridine, 2',3' -isopropylidene adenosine, 6-chloro-2 ',3' -isopropylidene adenosine, zidovudine, 3'-O- (tert-butyldimethylsilyl) thymidine, 3' -O-benzyl thymidine, stavudine, 1- ((3 a 'R, 4' R, 6'R, 6a' R) -4'- (hydroxymethyl tetrahydrospiro [ cyclohexane-1, 2' -furo [3,4-d ] [1, 3] dioxol ] -6-yl) pyrimidine-2, 4 (1H, 3H) -dione, (2R, 3S, 5R) -5- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidine-7-yl) -2- (hydroxymethyl) furane, and difructose. P