WO2021088223A1 - 一种在水相溶剂中合成氘代化合物的方法 - Google Patents

一种在水相溶剂中合成氘代化合物的方法 Download PDF

Info

Publication number
WO2021088223A1
WO2021088223A1 PCT/CN2019/127457 CN2019127457W WO2021088223A1 WO 2021088223 A1 WO2021088223 A1 WO 2021088223A1 CN 2019127457 W CN2019127457 W CN 2019127457W WO 2021088223 A1 WO2021088223 A1 WO 2021088223A1
Authority
WO
WIPO (PCT)
Prior art keywords
deuterated
salt
acid
compound
formula
Prior art date
Application number
PCT/CN2019/127457
Other languages
English (en)
French (fr)
Inventor
万谦
宋泽金
曾静
孟令奎
Original Assignee
华中科技大学
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 华中科技大学 filed Critical 华中科技大学
Publication of WO2021088223A1 publication Critical patent/WO2021088223A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/58—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by elimination of halogen, e.g. by hydrogenolysis, splitting-off
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/20—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
    • C07C33/22—Benzylalcohol; phenethyl alcohol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/24—Preparation of ethers by reactions not forming ether-oxygen bonds by elimination of halogens, e.g. elimination of HCl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/32—Phenylacetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/70—Monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/80—Phthalic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of isotope labeling chemical synthesis, and more specifically, relates to a method for synthesizing a deuterated compound in an aqueous solvent.
  • Deuterium (D, also known as heavy hydrogen) is one of the two stable isotopes of hydrogen. Deuterium accounts for only about 0.02% (or 0.03% based on mass) of all naturally occurring hydrogen.
  • deuterated solvents which are widely used in spectroscopy, are used in nuclear magnetic resonance spectroscopy (NMR) to overcome the interference of solvent signals from the signal of the test substance; in the field of analytical chemistry, deuterium-labeled compounds can be used as non-interfering internal standard substances.
  • deuterated compounds are mainly prepared by methods such as dehalogenation, deoxydeuteration, hydrogen deuterium exchange, and reduction and deuteration of unsaturated bonds.
  • This exchange reaction is also used to prepare D from H 3 PO 2 3 PO 2 , such as Oshima (Bull.Chem.Soc.Jpn.,2001,74,225), prepared on site by HD exchange between NaH 2 PO 2 and D 2 O under extremely acidic conditions (DCl/D 2 O, pH less than 1) D 3 PO 2 .
  • D 3 PO 2 will also exchange with H 2 O due to the HD exchange reaction to generate H 3 PO 2 or HD 2 PO 2 .
  • the purpose of the present invention is to provide a method for synthesizing deuterated compounds in an aqueous solvent, in which the types of raw materials used to construct the reaction system are studied and improved, using formula (II).
  • the phosphorus-deuterium bond-containing material shown in) is a deuterium source.
  • it can effectively solve the severe reaction conditions in the preparation process of deuterated compounds, the serious excess of deuterium source used, and the strict anhydrous ( 1 H 2 O) and/or the problem that the reaction needs to be carried out in a deuterated solvent.
  • compounds containing phosphorus-deuterium bonds are used as deuterium sources, and are preferably initiated by free radical initiators to realize reduction deuteration reactions of organic halogenated compounds, diazonium compounds, and xanthate compounds, etc.
  • the reaction conditions are simple and controllable, the operation is convenient, the cost is low, the applicability of the substrate is good, and the yield and deuteration rate are high.
  • the labeling reaction is simple and safe, and can be efficiently performed in non-deuterated solvents including water (1 H 2 O), and the deuterium source used can be equivalent.
  • a method for synthesizing deuterated compounds in an aqueous solvent which is characterized in that the chemical reaction equation based on the method is as follows:
  • the solvent is water ( 1 H 2 O), or a mixed solvent composed of water (1 H 2 O) and an organic solvent;
  • R 1 is selected from at least one of an alkyl group, an aromatic group, and an acyl group;
  • X is selected At least one of iodine atom, bromine atom, chlorine atom, diazo group, and xanthate group;
  • Z is selected from any one of oxygen atom and sulfur atom;
  • R 2 and R 3 are independently selected from deuterium atom, At least one of an alkyl group, an aromatic group, a hydroxyl group, an alkoxy group, a phenol group, and an oxygen anion O - ;
  • D is a deuterium atom.
  • the organic solvent is an alkane solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ester solvent, a nitrile solvent, At least one of ether solvents, ketone solvents, and alcohol solvents.
  • the compound represented by formula (I) undergoes a reduction reaction under the action of a free radical initiator to produce a free radical represented by formula (IV), which further obtains the phosphorus-deuterium-containing compound represented by formula (II)
  • the deuterium atom in the bonded material thus obtains the reduced deuterated compound as shown in formula (III).
  • the deuterated hypophosphorous acid (D 3 PO 2 ) compound includes at least one of deuterated hypophosphorous acid (D 3 PO 2 ), deuterated hypophosphorous acid inorganic salt, deuterated hypophosphorous acid organic salt, and deuterated hypophosphorous acid ester ;
  • the deuterated phosphorous acid (D 3 PO 3 ) compound includes at least one of deuterated phosphorous acid (D 3 PO 3 ), deuterated phosphorous acid inorganic salt, deuterated phosphorous acid organic salt, and deuterated phosphorous acid ester ;
  • the inorganic salt is lithium salt, sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt, ammonium salt, aluminum salt, copper salt, ferrous salt, iron salt, barium salt, chromium salt At least one of salt, lead salt, manganese salt, cobalt salt, nickel salt;
  • the organic salt is at least one of amine salt, pyridine salt, aniline salt, piperidine salt and other nitrogen heterocyclic salt;
  • the deuterated hypophosphite includes at least one of alkyl alcohol esters of deuterated hypophosphorous acid, esters formed by deuterated hypophosphorous acid and aryl phenol, and at least one of phosphine oxides directly formed by phosphorous-carbon bonds of deuterated hypophosphorous acid.
  • the deuterated thiohypophosphite is an alkyl alcohol ester of deuterated thiohypophosphorous acid, an ester formed by deuterated thiohypophosphorous acid and an aryl phenol, and deuterated thiohypophosphorous acid is directly formed by a phosphorus-carbon bond
  • the deuterated phosphorous acid ester is at least one of alkyl alcohol esters of deuterated phosphorous acid, esters formed by deuterated phosphorous acid and aryl phenol, and phosphine oxides directly formed by phosphorous-carbon bond of deuterated phosphorous acid.
  • Species preferably deuterated methyl phosphite, deuterated phenol phosphite, phenyl deuterated phosphine oxide;
  • the deuterated thiophosphite is an alkyl alcohol ester of deuterated thiophosphite, an ester formed by deuterated thiophosphite and an arylphenol, and a phosphine oxide formed directly by a phosphorus-carbon bond of deuterated phosphorous acid At least one of the group of substances; preferably, methyl deuterated thiophosphite, phenol deuterated thiophosphite, and phenyl deuterated phosphine.
  • the free radical initiator is a fat-soluble initiator, a water-soluble initiator or an amphoteric initiator.
  • the free radical initiator is azobisisobutylamidine dihydrochloride (AIBA), azobisisobutyronitrile (AIBN), azobisisobuimidazoline hydrochloride (VA044), and Azoisobutylcyanoformamide (VA30), triethylborane (Et 3 B), benzoyl peroxide (BPO), or azobisisoheptonitrile (ABVN).
  • AIBA azobisisobutylamidine dihydrochloride
  • AIBN azobisisobutyronitrile
  • VA044 azobisisobuimidazoline hydrochloride
  • VA30 Azoisobutylcyanoformamide
  • Et 3 B triethylborane
  • BPO benzoyl peroxide
  • ABSVN azobisisoheptonitrile
  • the base is at least one of an organic base and an inorganic base
  • the organic base is selected from alkyl amines, imidazole, pyridine, piperidine, ethyl piperidine, 2,6-lutidne (2,6-Lutidne), 1,8-diaza two Cycloundec-7-ene (DBU), tetrabutylammonium acetate (TBAOAc), triphenylphosphorus (Ph 3 P), triethyl phosphine (Et 3 P), potassium tert-butoxide (t-BuOK) , At least one of sodium methoxide (NaOCH 3 ), sodium ethoxide (NaOEt), sodium formate (COONa), potassium formate (COOK), sodium acetate (NaOAc), and potassium acetate (KOAc);
  • the inorganic base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH) 2 ), calcium carbonate (CaCO 3 ), potassium carbonate (K 2 CO 3 ), sodium carbonate ( At least one of Na 2 CO 3 ), potassium bicarbonate (KHCO 3 ), sodium bicarbonate (NaHCO 3 ), cesium carbonate (CsCO 3 ), and ammonia.
  • the amount of the phosphorus-deuterium bond substance contained in the phosphorus-deuterium bond-containing material represented by formula (II) is the same as that of the compound represented by formula (I)
  • the ratio of the amount is greater than or equal to 1:1.
  • the amount of the base must be such that at least 90% of the phosphorus-deuterium bond-containing material represented by formula (II) will not undergo HD exchange with H 2 O in the reaction system;
  • the amount of the alkali needs to satisfy the pH value of the reaction system to be between 2-13.
  • the method for synthesizing deuterated compounds provided by the present invention has simple operation, good substrate applicability and high efficiency.
  • the amount of the deuterium source used in the present invention can be the equivalent level of the substrate, and the deuterium source used is simple and easy to obtain, low in cost, stable and safe, and easy to store for a long time.
  • the reaction solvent of the present invention is environmentally friendly. Compared with the traditional deuteration method, it uses near-neutral deuterated reagents. The reaction conditions are mild, and the HD exchange of the deuterated reagents with water and other solvents under the reaction conditions is avoided. Water ( 1 H 2 O), no need for deuterated solvents. This method can obtain the target deuterated product with high yield and high deuteration rate in the water phase (H 2 O).
  • the method for synthesizing deuterated compounds provided by the present invention can efficiently realize the multi-deuteration of substrates, and provides new ideas and methods for the preparation of multi-deuterated compounds.
  • the deuteration method provided by the present invention can be carried out in the water phase and can maintain a high deuteration rate.
  • H 2 O Hydrogen-deuterium exchange only occurs under very strong acidic (such as pH ⁇ 1) or very strong alkaline (such as pH>13) conditions, and under weaker acid or weaker base reaction conditions (2 ⁇ pH ⁇ 13), With the phosphorus-deuterium bond-containing substance as the deuterium source, the HD exchange reaction in water can be completely or most (>90%) inhibited.
  • the present invention uses the easily available phosphorus-deuterium bond-containing substance as the deuterium source, and efficiently realizes the deuterium labeling of the compound through a simple reduction reaction.
  • the deuterium source reagent is low in cost, stable and safe. It is compatible with water (1 H 2 O) and easy to store for a long time; the operation is simple and environmentally friendly.
  • no deuterated solvent is required. This method can obtain the target deuterated product with high yield and high deuteration rate in the water phase (H 2 O).
  • the HD is exchanged through hydrogen to remove Coupling 31 P NMR monitoring spectrum.
  • the pH range where HD exchange does not occur at all is 2.5-11.7
  • the pH range where most (>90%) hydrogen-deuterium exchange does not occur is 2.5-12.8 (where the pH value is detected by a pH meter).
  • the method for synthesizing the deuterated compound of the present invention includes the following steps:
  • R 1 is selected from at least one of alkyl, aromatic, and acyl
  • X is selected from at least one of iodine, bromine, chlorine, diazonium, and xanthate (formula I is Halide, diazonium salt or Xanthate)
  • Z is selected from at least one of oxygen atom and sulfur atom
  • R 2 and R 3 are selected from deuterium atom, alkyl group, aromatic group, hydroxyl group, alkoxy group At least one of the salt compounds corresponding to the phenolic group and hydroxyl group forming acid, R 2 and R 3 may be the same or different.
  • the water refers to ordinary non-deuterated water, namely 1 H 2 O;
  • the solvent is water or a mixed solvent formed by water and other solvents; wherein, the other solvent is At least one of alkane solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ester solvents, nitrile solvents, ether solvents, ketone solvents, and alcohol solvents.
  • reaction process can be as follows:
  • the compound represented by formula (I) generates a free radical represented by formula (IV) under the action of a free radical initiator, and the free radical further obtains the phosphorus-deuterium bond-containing compound represented by formula (II)
  • the deuterium atom thus obtains the deuterated compound represented by formula (III).
  • the above-mentioned initiator is an initiator that can generate free radicals, and includes at least one of fat-soluble, water-soluble and amphoteric initiators.
  • the initiator is AIBA (azobisisobutylamidine dihydrochloride), AIBN (azobisisobutyronitrile), VA044 (azobisisobuimidazoline hydrochloride), VA30 (azo Isobutyl cyanoformamide), Et 3 B (triethylborane), BPO (benzoyl peroxide), ABVN (azobisisoheptonitrile), etc.
  • organic bases include alkyl amines, imidazole, pyridine, piperidine, ethyl piperidine, 2,6-lutidne (2,6-Lutidne ), 1,8-diazabicycloundec-7-ene (DBU), tetrabutylammonium acetate (TBAOAc), triphenylphosphorus (Ph 3 P), triethyl phosphine (Et 3 P) , Potassium tert-butoxide (t-BuOK), sodium methoxide (NaOCH 3 ), sodium ethoxide (NaOEt), sodium formate (COONa), potassium formate (COOK), sodium acetate (NaOAc), potassium acetate (KOAc), etc.; inorganic alkali Including sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH), etc.
  • organic bases include alkyl amines, imidazole,
  • the ratio of the amount of the substance containing the phosphorus-deuterium bond in the compound containing the phosphorus-deuterium bond represented by the formula (II) to the amount of the substance of the compound represented by the formula (I) is greater than or equal to 1:1 It should be understood that, theoretically, only when the amount of deuterium source is greater than or equal to the amount of deuterium label, the label can be completely reacted, and the deuterium label can achieve satisfactory results.
  • the amount of base needs to be such that the substance containing the phosphorus-deuterium bond does not undergo HD exchange or most (>90%) do not undergo HD exchange in the reaction system, that is, the pH value of the reaction system is between 2 and 13, different For phosphorus-deuterium bond substances, the pH range of the reaction system may have a certain difference.
  • the pH range of hydrogen deuterium exchange is 2.5-12.8, as shown in Figure 1.
  • the above reaction can be carried out effectively at room temperature and heating conditions, and the temperature is related to the half-life of the selected initiator at this temperature.
  • Te 3 B triethylborane
  • VA044 azobisisobuimidazoline hydrochloride
  • AIBA azobisisobutylamidine dihydrochloride Salt
  • AIBN azobisisobutyronitrile
  • step (2) The raw material mixture system obtained in step (1) is reacted under corresponding conditions until the starting raw materials are consumed, and the reaction is terminated. After post-treatment, column chromatography separation and purification or recrystallization, the target product is obtained.
  • iodo compound 1a (152mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 69.6 mg, 0.8 equiv), sodium bicarbonate (NaHCO 3 , 84.0 mg, 2.0 equiv), initiator Azobisisobutylamidine hydrochloride (AIBA, 27 mg, 0.2 equiv) was weighed into a 10 mL reaction flask, then water (H 2 O, 2.0 ml) was added, and the reaction was carried out at 80 degrees Celsius. After the iodine compound 1a was consumed, the reaction was terminated (5h), and the solvent water was distilled off under reduced pressure.
  • AIBA Azobisisobutylamidine hydrochloride
  • the obtained crude product was acetylated under the conditions of acetic anhydride and triethylamine. After acylation, the crude product was extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, washed with saturated sodium thiosulfate solution, and dried with anhydrous sodium sulfate. Concentration to obtain a crude product, column chromatography separation and purification to obtain compound 2a (142.0 mg), the yield was 93%, and the deuteration rate was 98%.
  • Iodine compound 1a 152mg
  • deuterated sodium hypophosphite monohydrate NaD 2 PO 2 ⁇ H 2 O, 86.5 mg, 1.6 equiv
  • sodium bicarbonate NaHCO 3 , 50.4 mg, 1.2 equiv
  • the initiator azobisisobuimidazoline hydrochloride VA044, 32 mg, 0.2 equiv
  • water H 2 O, 2.0 ml
  • iodo compound 1ab (215mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 104.5 mg, 1.2 equiv), sodium bicarbonate (NaHCO 3 , 84.0 mg, 2.0 equiv), initiator Azobisisobutylamidine dihydrochloride (AIBA, 27 mg, 0.2 equiv) was weighed into a 10 mL reaction flask, and then water and acetonitrile (H 2 O, 1.0 ml each of acetonitrile) were added and reacted at 80 degrees Celsius.
  • AIBA Azobisisobutylamidine dihydrochloride
  • the iodo compound 1ab (215mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 104.5 mg, 1.2 equiv), sodium bicarbonate (NaHCO 3 , 84.0 mg, 2.0 equiv), initiator Azobisisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) was weighed into a 10mL reaction flask, and then the solvent water and tert-butanol (H 2 O, tert-butanol 1.0ml each) were added to the reaction flask at 80 Reaction in degrees Celsius.
  • AIBA Azobisisobutylamidine dihydrochloride
  • iodo compound 1ab (215mg), deuterated sodium hypophosphite monohydrate (NaD 2 PO 2 ⁇ H 2 O, 108.0 mg, 2.0 equiv), imidazole (Imidazole, 40.9 mg, 1.2 equiv), initiator Azobisisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) was weighed into a 10mL reaction flask, and then water and tert-butanol (H 2 O, t-BuOH 1.0ml each) were added at 80 degrees Celsius Next response.
  • AIBA Azobisisobutylamidine dihydrochloride
  • the iodo compound 1ab (215mg), deuterated sodium hypophosphite monohydrate (NaD 2 PO 2 ⁇ H 2 O, 108.0mg, 2.0equiv), 2,6-lutidine (2,6- Lutidine, 70uL, 1.2equiv), the initiator azobisisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) were weighed into a 10mL reaction flask, and then the solvent water and tert-butanol (H 2 O, t-BuOH each 1.0ml), react at 80 degrees Celsius.
  • AIBA initiator azobisisobutylamidine dihydrochloride
  • Compound 2a is a white solid.
  • Iodine compound 1b (173.1mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 104.5 mg, 1.2 equiv), sodium bicarbonate (NaHCO 3 , 84.0 mg, 2.0 equiv), initiator azo Diisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) was weighed into a 10mL reaction flask, and then water and tert-butanol (H 2 O, tert-butanol 1.0ml each) were added and reacted at 80 degrees Celsius After the iodine compound 1b is consumed, the reaction is terminated (5h), the crude product is extracted with ethyl acetate 3 times, the organic phases are combined, washed with saturated brine, washed with saturated sodium thiosulfate solution, dried with anhydrous sodium sulfate, and concentrated to obtain the crude product Column chromatography was separated and purified to obtain compound 2b
  • Compound 2b is a colorless oily substance.
  • the iodo compound 1c (185.1 mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 104.5 mg, 1.2 equiv), sodium bicarbonate (NaHCO 3 , 84.0 mg, 2.0 equiv), initiator azo Diisobutylamidine dihydrochloride (AIBA, 27mg, 0.2equiv) was weighed into a 10mL reaction flask, and then the solvent water and tert-butanol (H 2 O, tert-butanol each 1.0ml) were added, and the temperature was kept at 80 degrees Celsius.
  • deuterated calcium hypophosphite Ca(D 2 PO 2 ) 2
  • sodium bicarbonate NaHCO 3
  • AIBA initiator azo Diisobutylamidine dihydrochloride
  • Compound 2c is a colorless oily substance.
  • Iodine compound 1d (249.0mg), deuterated calcium hypophosphite (Ca(D 2 PO 2 ) 2 , 217.5mg, 2.5equiv), sodium bicarbonate (NaHCO 3 , 168.0mg, 4.0equiv), initiator azo Diisobutylamidine dihydrochloride (AIBA, 54mg, 0.4equiv) was weighed into a 10mL reaction flask, and the solvent water and tert-butanol (H 2 O, tert-butanol each 1.0ml) were added, and the temperature was kept at 80 degrees Celsius.
  • AIBA initiator azo Diisobutylamidine dihydrochloride
  • Compound 2d is a colorless oily substance.
  • Compound 2e is a white solid.
  • Iodine compound 1f (117mg), sodium bicarbonate (NaHCO 3 , 105.0 mg, 2.5 equiv), deuterated sodium hypophosphite monohydrate (NaD 2 PO 2 ⁇ H 2 O, 270.0 mg, 5.0 equiv), initiator Azobisisobutylamidine dihydrochloride (AIBA, 81 mg, 0.6 equiv) was weighed into a 10 mL reaction flask, and then the solvent water (H 2 O, 2.0 ml) was added to the reaction at 80 degrees Celsius, and the compound 1f was expected to be iodinated.
  • AIBA Azobisisobutylamidine dihydrochloride
  • Compound 2f is a colorless liquid.
  • Compound 2g is a white solid.
  • Compound 2h is a white solid.
  • Compound 2i is a white solid.
  • the iodine compound 1j (250mg), sodium bicarbonate (NaHCO 3 , 252mg, 6.0equiv) were weighed into a 10mL reaction flask, and then the solvent water (H 2 O, 3.0ml) was added.
  • Compound 2j is a white solid.
  • Compound 2k is a white solid.
  • Compound 21 is a white solid.
  • reaction product ie, the structural formula of compound 2m-2w
  • yield ie, the structural formula of compound 2m-2w
  • reaction time ie, the reaction time
  • deuteration rate in each example are shown in the following table (the percentage of D in the table indicates the deuteration rate of the corresponding deuterated site):
  • the water in the present invention refers to ordinary non-deuterated water, namely 1 H 2 O.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明属于同位素标记化学合成技术领域，公开了一种在水相溶剂中合成氘代化合物的方法，该方法基于如下化学反应方程式，将如式（I）所示的卤代物、重氮盐或黄原酸酯（Xanthate），如式（II）所示的含磷-氘键的物料、引发剂、碱及溶剂混合，反应得到如式（III）所示的还原氘代产物；其中，所述溶剂为水（1H2O）或水与有机溶剂组成的混合溶剂。本发明通过对构建反应体系的原料种类进行研究和改进，采用如式（II）所示的含磷-氘键的物料为氘源，与现有技术相比能够有效解决氘代化合物制备过程中反应条件严苛、所采用的氘源严重过量、需严格无水（1H2O）和/或反应需要在氘代溶剂中进行的问题。

Description

一种在水相溶剂中合成氘代化合物的方法 【技术领域】
本发明属于同位素标记化学合成技术领域，更具体地，涉及一种在水相溶剂中合成氘代化合物的方法。
【背景技术】
氘(D，也称为重氢)是氢的两种稳定同位素之一。氘仅占所有天然存在的氢的约0.02％(或基于质量的0.03％)。但是，氘标记化合物的使用在波谱学、分析化学、有机化学、药学等多个科学领域有着重要的意义。具体的，波谱学方面广泛使用的氘代溶剂在核磁共振波谱(NMR)中用于克服溶剂信号对待测试物质信号的干扰；在分析化学领域氘标记的化合物可用作为非干扰性的内标物质使用；而在有机化学领域对反应机理的研究中，特别是涉及反应氢源问题时，常常伴随着氘代化合物的使用；在药学方面，在代谢位点引入氘元素对药物在体代谢过程可产生重要影响，以达到延长药物半衰期、降低剂量的目的，继而获得具有更好疗效的药物。(J.Med.Chem.2019,62,5276)
鉴于氘代化合物的广泛应用，氘代化合物的制备显得尤为重要。目前，氘代化合物主要是通过脱卤氘代、脱氧氘代、氢氘交换以及不饱和键的还原氘代等方法制得。但这些方法大都有以下缺点：需要用到昂贵、有毒和/或性质不稳定，易燃易爆的试剂(例如：NaBD 4,LiAlD 4,DCOONa,n-Bu 3SnD)，氘源不易获取且需要大过量(Si-D类物质、氘气)，反应需要在昂贵的氘代溶剂中(例如：氘代丙酮、氘代四氢呋喃、氘代醇、氘代酸类)进行等。Oshima(Bull.Chem.Soc.Jpn.,2001,74,225),Gainger(Org.Biomol.Chem.2012,10,4752),Oba(J.Label Compd.Radiopharm.2015,58,215)等也报道了氘代次磷酸(D 3PO 2)参与的自由基氘代反应。这一方法 使用的氘代试剂价格便宜，性质稳定，毒性低，且反应条件温和，因而具有较好的应用潜力。
但是这些方法必须在重水中进行。例如：Oba的反应中使用到Pd/C(J.Label Compd.Radiopharm.2015,58,215),由于反应的氘源实际上是D 3PO 2与D 2O在Pd/C催化下产生的D 2,而D 3PO 2与H 2O在同样条件下会产生H 2或者HD，(Tetrahedron Lett,1984,25,4565.以及Org.Lett.2004,6,3521.)可以预见在水相中该反应氘代率不高；另一方面，众所周知，次磷酸或者亚磷酸的P-H键可以和D 2O发生可逆的交换反应生成P-D键，这一交换反应也被用于从H 3PO 2制备D 3PO 2，如Oshima(Bull.Chem.Soc.Jpn.,2001,74,225)利用极强酸性条件(DCl/D 2O，pH小于1)下NaH 2PO 2与D 2O的H-D交换现场制备D 3PO 2。同样D 3PO 2也会由于H-D交换反应的存在和H 2O发生交换生成H 3PO 2或HD 2PO 2。因此同样可以预见H 2O的引入会导致D 3PO 2参与的自由基氘代反应的氘代率严重下降(J.Org.Chem.2015,80,10025以及J.Phys.Chem.1964,68,544)。所以已报道的氘代次磷酸(D 3PO 2)或其盐参与的氘代方法均需严格避免水( 1H 2O)的存在，且需消耗大量氘水，因而也导致操作不易，经济性较差。
【发明内容】
针对现有技术的以上缺陷或改进需求，本发明的目的在于提供一种在水相溶剂中合成氘代化合物的方法，其中通过对构建反应体系的原料种类进行研究和改进，采用如式(II)所示的含磷-氘键物料为氘源，与现有技术相比能够有效解决氘代化合物制备过程中反应条件严苛、所采用的氘源严重过量、反应需严格无水( 1H 2O)和/或反应需要在氘代溶剂中进行的问题。本发明利用含磷-氘键的化合物为氘源，并优选通过自由基引发剂引发，可以实现有机卤代化合物、重氮化合物、黄原酸酯类(Xanthate)化合物等的还原氘代反应，反应条件简单可控、操作便捷、成本低、底物适用性好、产率及氘代率高。与现有技术相比，该标记反应简单、安全，可以在包括 水( 1H 2O)在内的非氘代溶剂中高效进行，使用的氘源可以是当量的。
为实现上述目的，按照本发明，提供了一种在水相溶剂中合成氘代化合物的方法，其特征在于，该方法所基于的化学反应方程式如下：
Figure PCTCN2019127457-appb-000001
是将如式(I)所示的化合物、如式(II)所示的含磷-氘键的物料与引发剂、碱及溶剂混合反应得到如式(III)所示的还原氘代产物；
其中，所述溶剂为水( 1H 2O)，或者为水( 1H 2O)与有机溶剂构成的混合溶剂；R 1选自烷基、芳香基、酰基中的至少一种；X选自碘原子、溴原子、氯原子、重氮基、黄原酸酯基中的至少一种；Z选自氧原子、硫原子中任意一种；R 2、R 3独立的选自氘原子、烷基、芳香基、羟基、烷氧基、酚基、氧负离子O -中的至少一种；D为氘原子。
作为本发明的进一步优选，在水 1H 2O与有机溶剂构成的混合溶剂中，所述有机溶剂为烷烃类溶剂、卤代烃类溶剂、芳香烃类溶剂、酯类溶剂、腈类溶剂、醚类溶剂、酮类溶剂、醇类溶剂中的至少一种。
作为本发明的进一步优选，所述反应的具体反应历程如下：
Figure PCTCN2019127457-appb-000002
具体是如式(I)所示的化合物在自由基引发剂作用下发生还原反应产生如式(IV)所示的自由基，该自由基进一步获取如式(II)所示的含磷-氘键的物料中的氘原子从而得到如式(III)所示的还原氘代化合物。
作为本发明的进一步优选，所述如式(II)所示的含磷-氘键的物料包括氘代次磷酸(D 3PO 2)类化合物、氘代亚磷酸(D 3PO 3)类化合物、氘代硫代次磷酸(D 3P(＝S)O)类化合物、氘代硫代亚磷酸(D 3P(＝S)O 2)类化合 物中的至少一种，其中，
所述氘代次磷酸(D 3PO 2)类化合物包括氘代次磷酸(D 3PO 2)、氘代次磷酸无机盐、氘代次磷酸有机盐、氘代次磷酸酯中的至少一种；
所述氘代硫代次磷酸(D 3P(＝S)O)类化合物包括氘代硫代次磷酸(D 3P(＝S)O)、氘代硫代次磷酸无机盐、氘代硫代次磷酸有机盐、氘代硫代次磷酸酯中的至少一种；
所述氘代亚磷酸(D 3PO 3)类化合物包括氘代亚磷酸(D 3PO 3)、氘代亚磷酸无机盐、氘代亚磷酸有机盐、氘代亚磷酸酯中的至少一种；
所述氘代硫代亚磷酸(D 3P(＝S)O 2)类化合物包括氘代硫代亚磷酸(D 3P(＝S)O 2)、氘代硫代亚磷酸无机盐、氘代硫代亚磷酸有机盐、氘代硫代亚磷酸酯中的至少一种。
作为本发明的进一步优选，所述无机盐为锂盐、钠盐、钾盐、钙盐、锌盐、镁盐、铵盐、铝盐、铜盐、亚铁盐、铁盐、钡盐、铬盐、铅盐、锰盐、钴盐、镍盐、中的至少一种；
所述有机盐为胺盐、吡啶类盐、苯胺类盐、哌啶类盐以及其他氮杂环类盐中的至少一种；
所述氘代次磷酸酯包括氘代次磷酸烷基醇酯，氘代次磷酸与芳基酚形成的酯，以及氘代次磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代次磷酸甲酯、氘代次磷酸苯酚酯、二苯基氘代氧膦(DP(＝O)Ph 2)；
所述氘代硫代次磷酸酯为氘代硫代次磷酸烷基醇酯，氘代硫代次磷酸与芳基酚形成的酯，以及氘代硫代次磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代硫代次磷酸甲酯、氘代硫代次磷酸苯酚酯、二苯基氘代硫膦(DP(＝S)Ph 2)；
所述氘代亚磷酸酯为氘代亚磷酸烷基醇酯，氘代亚磷酸与芳基酚形成的酯，以及氘代亚磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代亚磷酸甲酯、氘代亚磷酸苯酚酯、苯基氘代氧膦；
所述氘代硫代亚磷酸酯为氘代硫代亚磷酸烷基醇酯，氘代硫代亚磷酸与芳基酚形成的酯，以及氘代亚磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代硫代亚磷酸甲酯、氘代硫代亚磷酸苯酚酯、苯基氘代硫膦。
作为本发明的进一步优选，所述自由基引发剂为脂溶性引发剂、水溶性引发剂或两性引发剂。
优选的，所述自由基引发剂为偶氮二异丁基脒二盐酸盐(AIBA)、偶氮二异丁腈(AIBN)、偶氮二异丁咪唑啉盐酸盐(VA044)、偶氮异丁氰基甲酰胺(VA30)、三乙基硼烷(Et 3B)、过氧化苯甲酰(BPO)、或偶氮二异庚腈(ABVN)。
作为本发明的进一步优选，所述碱为有机碱和无机碱中的至少一种；
优选的，所述有机碱选自烷基胺类、咪唑、吡啶、哌啶、乙基哌啶、2,6-二甲基吡啶(2,6-Lutidne)、1,8-二氮杂二环十一碳-7-烯(DBU)、四丁基醋酸铵(TBAOAc)、三苯基磷(Ph 3P)、三乙基膦(Et 3P)、叔丁醇钾(t-BuOK)、甲醇钠(NaOCH 3)、乙醇钠(NaOEt)、甲酸钠(COONa)、甲酸钾(COOK)、醋酸钠(NaOAc)、醋酸钾(KOAc)中的至少一种；
所述无机碱选自氢氧化钠(NaOH)、氢氧化钾(KOH)、氢氧化钙(Ca(OH) 2)、碳酸钙(CaCO 3)、碳酸钾(K 2CO 3)、碳酸钠(Na 2CO 3)、碳酸氢钾(KHCO 3)、碳酸氢钠(NaHCO 3)、碳酸铯(CsCO 3)、氨类中的至少一种。
作为本发明的进一步优选，所述如式(II)所示的含磷-氘键的物料中所含的磷-氘键的物质的量与所述如式(I)所示的化合物的物质的量之比大于等于1：1。
作为本发明的进一步优选，所述碱的用量需满足使至少90％的所述如式(II)所示的含磷-氘键的物料在反应体系中不会和H 2O发生H-D交换；优选的，所述碱的用量需满足使反应体系pH值处于2～13之间。
总体而言，通过本发明所构思的以上技术方案与现有技术相比，利用简单、廉价、安全、性质稳定易于存放的如式(II)所示的含磷-氘键化合物为氘源，通过还原反应高效实现了化合物的氘代标记，实现了在水相溶剂中氘代化合物的合成，能够取得下列有益效果：
1、本发明提供的氘代化合物的合成方法，操作简单、底物适用性好、效率高。
2、本发明氘源使用量可以为底物等当量级别，且使用的氘源简单易得，成本低廉，稳定安全，易于长期储存。
3、本发明反应溶剂环保，与传统氘代方法相比，采用近中性氘代试剂，反应条件温和，避免了氘代试剂在反应条件下与水及其他溶剂的H-D交换，因此无需严格无水( 1H 2O)，无需要求氘代溶剂。此法可以在水相(H 2O)中高产率、高氘代率的得到目标氘代产物。
4、本发明提供的氘代化合物的合成方法，可以高效的实现底物的多氘代化，为多氘代化合物的制备提供了新的思路和方法。
5、本发明提供的氘代方法能够在水相进行且能保持高的氘代率，通过系统的对H-D交换速率进行研究发现，对于含磷-氘键的物质，其与H 2O的快速氢氘交换只发生于极强的酸性(如pH<1)或极强碱性(如pH>13)条件下，而在较弱酸或较弱碱的反应条件(2≤pH≤13)下，以含磷-氘键的物质作为氘源，其在水中的H-D交换反应可以完全或绝大部分(>90％)被抑制。
综上，本发明利用简单易得的含磷-氘键物质为氘源，通过一个简单的还原反应高效实现了化合物的氘代标记，与现有技术相比，氘源试剂成本低廉，稳定安全，可以和水( 1H 2O)兼容，易于长期储存；操作简单环保，与传统氘代方法相比，无需要求氘代溶剂。此法可以在水相(H 2O)中高产率、高氘代率的得到目标氘代产物。
【附图说明】
图1是以一种磷氘键物质：Ca(D 2PO 2) 2(99.0％D-inc.c＝0.12mol/L)为例，在不同pH溶液下放置一天后，H-D交换通过氢去耦 31P NMR监测的图谱。此例下，完全不发生H-D交换的pH范围为2.5-11.7，绝大多数(>90％)不发生氢氘交换的pH范围为2.5-12.8(其中，pH值由pH计检测)。
【具体实施方式】
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
总体来说，本发明氘代化合物的合成方法，包括以下步骤：
(1)将式(I)所示化合物、式(II)所示含磷-氘键的氘源、引发剂、碱及水相溶剂混合，获得反应原料混合体系进行反应；反应通式为：
Figure PCTCN2019127457-appb-000003
其中，R 1均选自烷基、芳香基、酰基中的至少一种；X选自碘，溴、氯、重氮基、黄原酸酯基中的至少一种(式I所示即为卤代物、重氮盐或黄原酸酯(Xanthate))；Z选自氧原子、硫原子中至少一种；R 2、R 3选自氘原子、烷基、芳香基、羟基、烷氧基、酚基、羟基形成酸所对应的盐类化合物中至少一种，R 2和R 3可以相同也可以不同。
上述水相溶剂中合成氘代化合物的方法，所述水指普通非氘代水，即 1H 2O；所述溶剂为水或水与其它溶剂形成的混合溶剂；其中，所述其它溶剂为烷烃类溶剂、卤代烃类溶剂、芳香烃类溶剂、酯类溶剂、腈类溶剂、醚类溶剂、酮类溶剂、醇类溶剂中的至少一种。
进一步的，反应历程可以如下所示：
Figure PCTCN2019127457-appb-000004
其中，式(I)所示的化合物在自由基引发剂作用下产生如式(IV)所示的自由基，该自由基进一步获取如式(II)所示的含磷-氘键化合物中的氘原子从而得到如式(III)所示的氘代化合物。
更具体的，含P-D键物质可以为含氘代次磷酸及氘代硫代次磷酸类化合物包括氘代次磷酸(D 3PO 2)、氘代硫代次磷酸(D 3P(＝S)O)、氘代次磷酸无机盐(包括氘代次磷酸的锂盐、钠盐、钾盐、钙盐、锌盐、镁盐、铵盐、铝盐、铜盐、亚铁盐、铁盐、钡盐、铬盐、铅盐、锰盐、钴盐、镍盐等)、氘代次磷酸有机盐(包括氘代次磷酸的各种胺盐、吡啶类盐、苯胺类盐、哌啶类，以及其他氮杂环类盐)、氘代次磷酸酯(包括次磷酸烷基醇酯、氘代次磷酸与芳基酚形成的酯，以及氘代次磷酸以磷-碳键直接形成的氘代氧膦)、氘代硫代次磷酸无机盐、氘代硫代次磷酸有机盐、氘代硫代次磷酸酯。
以及含氘代亚磷酸类化合物包括氘代亚磷酸(D 3PO 3)氘代硫代亚磷酸(D 3P(＝S)O 2)、氘代亚磷酸无机盐(包括氘代亚磷酸的锂盐、钠盐、钾盐、钙盐、锌盐、镁盐、铵盐、铝盐、铜盐、亚铁盐、铁盐、钡盐、铬盐、铅盐、锰盐、钴盐、镍盐等)、氘代亚磷酸的各种胺盐、吡啶类盐、苯胺类盐、哌啶类，以及其他氮杂环类盐)、氘代亚磷酸酯(包括亚磷酸烷基醇酯、氘代亚磷酸与芳基酚形成的酯，以及氘代亚磷酸以磷-碳键直接形成的氘代硫膦)、氘代硫代亚磷酸无机盐、氘代硫代亚磷酸有机盐、氘代硫代亚磷酸酯。
上述引发剂为可产生自由基的引发剂，包括脂溶性、水溶性及两性引 发剂中的至少一种。例如，所述引发剂为AIBA(偶氮二异丁基脒二盐酸盐)、AIBN(偶氮二异丁腈)、VA044(偶氮二异丁咪唑啉盐酸盐)、VA30(偶氮异丁氰基甲酰胺)、Et 3B(三乙基硼烷)、BPO(过氧化苯甲酰)、ABVN(偶氮二异庚腈)等。
上述碱为各种有机碱和无机碱中的至少一种：有机碱包括烷基胺类、咪唑、吡啶、哌啶、乙基哌啶、2,6-二甲基吡啶(2,6-Lutidne)、1,8-二氮杂二环十一碳-7-烯(DBU)、四丁基醋酸铵(TBAOAc)、三苯基磷(Ph 3P)、三乙基膦(Et 3P)、叔丁醇钾(t-BuOK)、甲醇钠(NaOCH 3)、乙醇钠(NaOEt)、甲酸钠(COONa)、甲酸钾(COOK)、醋酸钠(NaOAc)、醋酸钾(KOAc)等；无机碱包括氢氧化钠(NaOH)、氢氧化钾(KOH)、氢氧化钙(Ca(OH) 2)、碳酸钙(CaCO 3)、碳酸钾(K 2CO 3)、碳酸钠(Na 2CO 3)、碳酸氢钾(KHCO 3)、碳酸氢钠(NaHCO 3)、碳酸铯(CsCO 3)、氨类等。
上述如式(II)所示的含磷-氘键的化合物中所含的磷-氘键的物质的量与上述如式(I)所示的化合物的物质的量之比大于等于1：1；应当理解，理论上，仅当氘源的量大于或等于待氘标记物的量时，待标记物才可完全反应，氘标记才可达到满意效果。
碱的用量需满足使所含磷-氘键的物质在反应体系中不发生H-D交换或绝大多数(>90％)不发生H-D交换，即反应体系pH值处于2～13之间，不同的磷-氘键物质，反应体系pH范围可能会有一定的差异。H-D交换通过氢去耦 31P NMR监测，pH值由pH计检测。例如：以Ca(D 2PO 2) 2(99.0％D-inc.c＝0.12mol/L)为例，不发生H-D交换的pH范围为2.5-11.7，绝大多数(>90％)不发生氢氘交换的pH范围为2.5-12.8，如图1所示。
上述反应能在室温、加热条件下有效进行，其温度与选用引发剂在该温度下的半衰期相关。如选用三乙基硼烷(Et 3B)可在室温进行，选用偶氮二异丁咪唑啉盐酸盐(VA044)可在40摄氏度左右进行，而选用偶氮二异丁基脒二盐酸盐(AIBA)、偶氮二异丁腈(AIBN)可在80摄氏度下进行。
(2)将步骤(1)制得的原料混合体系，在相应条件下反应至起始原料消耗完，终止反应。经过后处理，柱层析分离纯化或重结晶后得到目标产物。
以下为具体实施例：
实施例1：化合物2a的合成
Figure PCTCN2019127457-appb-000005
a)、将碘代化合物1a(152mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,69.6mg，0.8equiv)、碳酸氢钠(NaHCO 3，84.0mg，2.0equiv)、引发剂偶氮二异丁基脒盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入水(H 2O，2.0ml)，于80摄氏度下反应。待碘代化合物1a消耗完后终止反应(5h)，减压蒸馏除去溶剂水。所得粗产物在醋酐、三乙胺条件下乙酰化，酰化后粗品用乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2a(142.0mg)，产率为93％，氘代率为98％。
b)、将碘代化合物1a(152mg)、氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,86.5mg，1.6equiv)、碳酸氢钠(NaHCO 3，50.4mg，1.2equiv)、引发剂偶氮二异丁咪唑啉盐酸盐(VA044，32mg，0.2equiv)称量于10mL反应瓶中，然后加入水(H 2O，2.0ml)，于45摄氏度下反应。待碘代化合物1a消耗完后终止反应(16h)，减压蒸馏除去水，并在醋酐、三乙胺条件下乙酰化，酰化后粗品经乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩并经柱层析分离纯化得到化合物2a(139.0mg)，产率为91％，氘代率为98％。
Figure PCTCN2019127457-appb-000006
c)、将碘代化合物1ab(215mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,104.5mg，1.2equiv)、碳酸氢钠(NaHCO 3，84.0mg，2.0equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入水和乙腈(H 2O，乙腈各1.0ml)，于80摄氏度下反应。待碘代化合物1ab消耗完后终止反应(5h)，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2a(138.8mg)，产率为91％，氘代率为94％。
d)、将碘代化合物1ab(215mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,104.5mg，1.2equiv)、碳酸氢钠(NaHCO 3，84.0mg，2.0equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入溶剂水和叔丁醇(H 2O，叔丁醇各1.0ml)，于80摄氏度下反应。待碘代化合物1ab消耗完后终止反应(5h)，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩柱层析分离纯化得到化合物2a(140.1mg)，产率为92％，氘代率为99％。
e)、将碘代化合物1ab(215mg)、氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,108.0mg，2.0equiv)、咪唑(Imidazole，40.9mg，1.2equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入水和叔丁醇(H 2O，t-BuOH各1.0ml)，于80摄氏度下反应。待碘代化合物1ab消耗完后终止反应(5h)，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2a(141.8mg)，产率为93％，氘代率为97％。
f)、将碘代化合物1ab(215mg)、氘代次磷酸钠一水合物(NaD 2PO 2·H 2O, 108.0mg，2.0equiv)、2,6-二甲基吡啶(2,6-Lutidine，70uL，1.2equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入溶剂水和叔丁醇(H 2O，t-BuOH各1.0ml)，于80摄氏度下反应。待碘代化合物1ab消耗完后终止反应(5h)，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2a(138.3mg)，产率为91％，氘代率为96％。
化合物2a为白色固体。
1H NMR(600MHz,CDCl 3)δ5.40(t,J＝9.6Hz,1H,H-3),4.86–4.81(m,2H,H-1,H-2),4.76(t,J＝9.6Hz,1H,H-4),3.84(dt,J＝10.2,6.0Hz,1H,H-5),3.36(s,3H,-OMe),2.04(s,3H,-OAc),2.00(s,3H,-OAc),1.97(s,3H,-OAc),1.14(d,J＝6.0Hz,2H,H-6).
13C NMR(151MHz,CDCl 3)δ170.4,170.3,170.1,96.8,74.0,71.4,70.3,65.1,55.5,21.0,20.9,17.22(t,J C-D＝19.6Hz).
HRMS calcd for C 13H 19DNaO 8[M+Na] +：328.1113,found 328.1113.
实施例2：化合物2b的合成
Figure PCTCN2019127457-appb-000007
将碘代化合物1b(173.1mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,104.5mg，1.2equiv)、碳酸氢钠(NaHCO 3，84.0mg，2.0equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，然后加入水和叔丁醇(H 2O，叔丁醇各1.0ml)，于80摄氏度下反应，待碘代化合物1b消耗完后终止反应(5h)，粗品乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2b(102.4mg)，产率为93％，氘代率为 99％。
化合物2b无色油状物质。
1H NMR(600MHz,CDCl 3)δ7.39–7.25(m,5H),4.78(d,J＝12.0Hz,1H),4.65(s,1H),4.57(d,J＝12.0Hz,1H),4.48(t,J＝4.8Hz,1H),4.06–3.93(m,3H),3.83(t,J＝7.8Hz,1H),3.69(t,J＝8.4Hz,1H),2.09–1.96(m,1H).
13C NMR(101MHz,CDCl 3)δ138.2,128.6,128.1,128.0,83.5,81.4,79.7,72.6,70.8,69.6,35.0(t,J C-D＝19.9Hz).
HRMS calcd for C 13H 15DNaO 3[M+Na] +：244.1054,found 244.1055.
实施例3：化合物2c的合成
Figure PCTCN2019127457-appb-000008
将碘代化合物1c(185.1mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,104.5mg，1.2equiv)、碳酸氢钠(NaHCO 3，84.0mg，2.0equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，27mg，0.2equiv)称量于10mL反应瓶中，后加入溶剂水和叔丁醇(H 2O，叔丁醇各1.0ml)，于80摄氏度下反应，待碘代化合物1c消耗完后终止反应(10h)，粗品乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2c(108.6mg)，产率为89％，氘代率为97％。
化合物2c无色油状物质。
1H NMR(400MHz,CDCl 3)δ5.50(d,J＝4.8Hz,1H,H-1),4.57(dd,J＝8.0,2.4Hz,1H,H-3),4.27(dd,J＝4.8,2.4Hz,1H,H-2),4.06(dd,J＝7.6,1.6Hz,1H,H-4),3.89(t,J＝6.4Hz,1H),1.50(s,3H,-CH 3),1.45(s,3H,-CH 3),1.33(s,3H,-CH 3),1.31(s,3H,-CH 3),1.22(d,J＝6.8Hz,2H,H-6).
13C NMR(101MHz,CDCl 3)δ109.2,108.5,96.8,73.8,71.2,70.6,63.7, 26.3,25.1,24.7,15.9(t,J C-D＝19.6Hz).
HRMS calcd for C 12H 19DNaO 5[M+Na] +：268.1266,found 268.1268.
实施例4：化合物2d的合成
Figure PCTCN2019127457-appb-000009
将碘代化合物1d(249.0mg)、氘代次磷酸钙(Ca(D 2PO 2) 2,217.5mg，2.5equiv)、碳酸氢钠(NaHCO 3，168.0mg，4.0equiv)、引发剂偶氮二异丁基脒二盐酸盐(AIBA，54mg，0.4equiv)称量于10mL反应瓶中，后加入溶剂水和叔丁醇(H 2O，叔丁醇各1.0ml)，于80摄氏度下反应，待碘代化合物1d消耗完后终止反应(5h)，粗品乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2d(116.2mg)，产率为94％，氘代率为4-D:98％,6-D:98％。
化合物2d无色油状物质。
1H NMR(400MHz,CDCl 3)δ5.23(t,J＝10.0Hz,1H,H-3),4.86–4.79(m,2H,H-1,H-2),3.99–3.90(m,1H,H-5),3.35(s,3H,-OMe),2.11(dd,J＝4.8,1.6Hz,0.5H,H-4eq),2.06(s,3H),1.99(s,3H),1.40(t,J＝11.6Hz,0.5H,H-4ax),1.16(d,J＝6.4Hz,2H,H-6).
13C NMR(101MHz,CDCl 3)δ170.7,170.4,97.8,72.4,68.2,63.2,55.2,39.4–37.0(m,C-D),21.2,21.1,20.5(t,J C-D＝19.3Hz).
HRMS calcd for C 11H 16D 2NaO 6[M+Na] +：271.1121,found 271.1129.
实施例5：化合物2e的合成
Figure PCTCN2019127457-appb-000010
将碘代化合物1e(124mg)、碳酸氢钠(NaHCO 3，105.0mg，2.5equiv)、称量于10mL反应瓶中，后加入溶剂水(H 2O，2.0ml)，溶解后，加入氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,216.0mg，4.0equiv)，引发剂偶氮二异丁基脒二盐酸盐(AIBA，40.6mg，0.3equiv)于80摄氏度下反应，待碘代化合物1e消耗完后终止反应(5h)，稀盐酸酸化反应体系至pH 2-3，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2e(57.8mg)，产率为94％，氘代率为97％。
化合物2e为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.13(d,J＝7.8Hz,2H),7.51(d,J＝8.4Hz,2H).
HRMS calcd for C 7H 4DO 2[M-H] -：122.0358,found 122.0358.
实施例6：化合物2f的合成
Figure PCTCN2019127457-appb-000011
将碘代化合物1f(117mg)、碳酸氢钠(NaHCO 3，105.0mg，2.5equiv)、氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,270.0mg，5.0equiv)，引发剂偶氮二异丁基脒二盐酸盐(AIBA，81mg，0.6equiv)称量于10mL反应瓶中，后加入溶剂水(H 2O，2.0ml)于80摄氏度下反应，待碘代化合物1f消耗完后终止反应(12h)，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2f(39.4mg)，产率为73％，氘代率为99％。
化合物2f为无色液体。
1H NMR(600MHz,CD 2Cl 2)δ7.27(s,1H),4.57(d,J＝5.4Hz,1H,-CH 2),1.79(t,J＝5.4Hz,1H,-OH).
HRMS calcd for C 7H 7DNaO[M+Na] +：132.0530,found 132.0529.
实施例7：化合物2g的合成
Figure PCTCN2019127457-appb-000012
将碘代化合物1g(131mg)、碳酸氢钠(NaHCO 3，105.0mg，2.5equiv)、称量于10mL反应瓶中，后加入溶剂水(H 2O，2.0ml)，溶解后，加入氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,216.0mg，4.0equiv)，引发剂偶氮二异丁咪唑啉盐酸盐(VA044，48.5mg，0.3equiv)于80摄氏度下反应，待碘代化合物1g消耗完后终止反应(8h)，稀盐酸酸化反应体系至pH 2-3，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2g(62.4mg)，产率为92％，氘代率为97％。
化合物2g为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.11–7.92(m,2H),7.31(d,J＝8.4Hz,1H),2.44(s,3H,-CH 3).
13C NMR(151MHz,CD 2Cl 2)δ172.5,145.5,130.7,130.6,129.8,129.6(t,J C-D＝24.5Hz),127.0,22.0.
HRMS calcd for C 8H 6DO 2[M-H] -：136.0514,found 136.0514.
实施例8：化合物2h的合成
Figure PCTCN2019127457-appb-000013
将碘代化合物1h(132mg)、碳酸氢钠(NaHCO 3，168.0mg，4.0equiv)、称量于10mL反应瓶中，后加入溶剂水(H 2O，2.0ml)，加入氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,270.0mg，5.0equiv)，引发剂偶氮二异丁腈(AIBN，50.4mg，0.3equiv)于回流温度下反应，待碘代化合物1h消耗 完后终止反应(8h)，稀盐酸酸化反应体系至pH 2-3，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，重结晶分离纯化得到化合物2h(49.3mg)，产率为72％，氘代率为96％。
化合物2h为白色固体。
1H NMR(600MHz,CD 3OD-d 4)δ7.78(s,1H),7.34(d,J＝8.4Hz,1H),6.81(d,J＝8.4Hz,1H).
13C NMR(151MHz,CDCl 3)δ174.3,163.1,135.8,131.5,119.53(t,J C-D＝24.8Hz),117.9,115.4.
HRMS calcd for C 7H 4DO 3[M-H] -：138.0307,found 138.0315.
实施例9：化合物2i的合成
Figure PCTCN2019127457-appb-000014
将碘代化合物1i(187mg)、碳酸氢钠(NaHCO 3，210.0mg，5.0equiv)、称量于10mL反应瓶中，后加入溶剂水(H 2O，2.0ml)，溶解后，加入氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,432.0mg，8.0equiv)，引发剂偶氮二异丁基脒二盐酸盐(AIBA，81mg，0.6equiv)于80摄氏度下反应，待碘代化合物1i消耗完后终止反应(5h)，稀盐酸酸化反应体系至pH 2-3，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2i(51.8mg)，产率为84％，氘代率为2-D:97％,5-D:99％。
化合物2i为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.12(s,1H),7.65(d,J＝7.2Hz,1H),7.51(d,J＝7.2Hz,1H).
13C NMR(151MHz,CD 2Cl 2)δ172.6,134.4,130.5,130.4(t,J C-D＝25.1Hz),129.7,129.0,128.9(t,J C-D＝24.9Hz).
HRMS calcd for C 7H 3D 2O 2[M-H] -：123.0421,found 123.0431.
实施例10：化合物2j的合成
Figure PCTCN2019127457-appb-000015
将碘代化合物1j(250mg)、碳酸氢钠(NaHCO 3，252mg，6.0equiv)、称量于10mL反应瓶中，后加入溶剂水(H 2O，3.0ml)，50摄氏度加热溶解后，加入氘代次磷酸钠一水合物(NaD 2PO 2·H 2O,648.0mg，12.0equiv)，引发剂偶氮二异丁腈(AIBN，82.0mg，1.0equiv)于回流温度下反应，待碘代化合物1j消耗完后终止反应(8h)，稀盐酸酸化反应体系至pH 2-3，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2j(50.1mg)，产率为81％，氘代率为2-D:97％,3-D:99％,5-D:92％。
化合物2j为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.16(s,1H),7.69(s,1H),7.55(t,J＝6.6Hz,0.08H).
13C NMR(151MHz,CD 2Cl 2)δ172.5,134.2,130.5,130.3(t,J C-D＝24.9Hz),129.7,128.8(t,J C-D＝24.9Hz),128.7(t,J C-D＝24.8Hz).
HRMS calcd for C 7H 2D 3O 2[M-H] -：124.0483,found 124.0485.
实施例11：化合物2k的合成
Figure PCTCN2019127457-appb-000016
将咪唑(340.5mg,5mmol)称量于10mL反应瓶中，搅拌下加入水0.1mL,冰浴下，剧烈搅拌，缓慢加入10.0mol/L的氘代次磷酸氘水溶液(0.4mL,4mmol)，完毕后，加入叔丁醇1.5mL,加入碘代化合物1k(155mg,0.5 mmol)，引发剂偶氮二异丁腈(AIBN，82.0mg，1.0equiv)于80摄氏度下反应，待碘代化合物1k消耗完后终止反应(10h)，乙酸乙酯/饱和食盐水萃取3次，合并有机相，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2k(50.7mg)，产率为92％，氘代率为75％。
化合物2k为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ7.46–7.42(m,2H),7.41–7.36(m,2H),7.35–7.26(m,3H),6.99–6.93(m,2.25H),5.06(s,2H).
实施例12：化合物2l的合成
Figure PCTCN2019127457-appb-000017
a)将碘代化合物1l(160mg,0.5mmol)、咪唑(136mg，4.0equiv)、称量于10mL反应瓶中，后加入溶剂二甲基亚砜(DMSO,2mL)，50摄氏度加热溶解后，加入氘代次磷酸对甲氧基苯胺盐(p-Anisidine·D 3PO 2,385mg，4.0equiv)，引发剂偶氮二异庚腈(ABVN，124.0mg，1.0equiv)于70摄氏度下反应12h，稀盐酸酸化反应体系，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2l(61mg)，产率为63％，氘代率为33％。
b)将碘代化合物1l(160mg,0.5mmol)、咪唑(136mg，4.0equiv)、称量于10mL反应瓶中，后加入溶剂乙腈2mL，50摄氏度加热溶解后，加入氘代次磷酸对甲氧基苯胺盐(p-Anisidine·D 3PO 2,385mg，4.0equiv)，引发剂偶氮二异丁腈(AIBN，82.0mg，1.0equiv)于80摄氏度下反应12h，稀盐酸酸化反应体系，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤， 饱和硫代硫酸钠溶液洗涤，无水硫酸钠干燥，浓缩得粗产物，柱层析分离纯化得到化合物2l(16.5mg)，产率为17％，氘代率为44％。
化合物2l为白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.65–8.63(m,1H),8.23–8.20(m,2H),7.55(t,J＝7.8Hz,0.56H),3.92(s,6H).
实施例13～23：化合物2m～2w的合成
反应通式如下：
Figure PCTCN2019127457-appb-000018
各实施例中的反应产物(即，化合物2m～2w的结构式)、产率、反应时间及氘代率如下表所示(表格中D配合百分数，表示对应氘代位点的氘代率)：
Figure PCTCN2019127457-appb-000019
[a]合成步骤按照实施例2中2a的合成步骤进行；
[b]合成步骤按照实施例1中例a所示2a的合成步骤进行
[c]合成步骤按照实施例5中2e的合成步骤进行。
实施例13～23中产物2m～2w的性质如下：
产物2m.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ7.61(d,J＝8.4Hz,2H),7.34(d,J＝7.8Hz,2H),2.92(t,J＝6.0Hz,4H),2.43(s,3H),1.61(dt,J＝11.4,6.0Hz,4H),1.44–1.31(m,1H).
13C NMR(101MHz,CD 2Cl 2)δ144.1,133.9,130.1,128.2,47.6,25.8,23.7(t,J C-D＝19.6Hz),21.8.
HRMS calcd for C 12H 16DNNaO 2S[M+Na] +：263.0935,found 263.0935.
产物2n.无色糖稀状物质。
1H NMR(600MHz,CD 2Cl 2)δ5.52(s,1H),4.83(s,1H),4.68(s,1H),4.54(d,J＝6.0Hz,1H),4.18(dd,J＝7.8,0.6Hz,1H),3.74(dd,J＝7.8,6.0Hz,1H),2.11(s,3H),2.06(s,3H),1.78(s,0.8H),1.64(s,0.2H).
13C NMR(101MHz,CD 2Cl 2)δ170.3,170.1,100.2,74.0,71.4,67.7,65.3,33.47(t,J C-D＝19.5Hz),21.5,21.4
HRMS calcd for C 10H 13DNaO 6[M+Na] +：254.0745,found 254.0750.
产物2o.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ6.30(dd,J＝6.0,1.8Hz,1H,H-1),4.69(dd,J＝6.0,1.8Hz,1H,H-2),4.17(d,J＝7.2Hz,1H,H-3),3.82(dt,J＝9.6,6.0Hz,1H,H-5),3.37(dd,J＝9.0,8.4Hz,1H,H-4),3.08(s,1H,-OH),2.61(s,1H,-OH),1.33(dt,J＝6.0,1.8Hz,2H,H-6).
13C NMR(101MHz,CD 2Cl 2)δ145.1,103.4,75.9,75.0,70.8,17.3(t,J C-D＝19.5Hz).
HRMS calcd for C 6H 9DNaO 3[M+Na] +：154.0585,found 154.0585.
产物2p.无色糖稀状物质。
1H NMR(600MHz,CDCl 3)δ7.39–7.25(m,5H),4.78(d,J＝12.0Hz,1H),4.65(s,1H),4.57(d,J＝12.0Hz,1H),4.48(t,J＝4.8Hz,1H),4.06–3.93(m,3H),3.83(t,J＝7.8Hz,1H),3.69(t,J＝8.4Hz,1H),2.09–1.96(m,1H).
13C NMR(101MHz,CDCl 3)δ138.2,128.6,128.1,128.0,83.5,81.4,79.7,72.6,70.8,69.6,35.0(t,J C-D＝19.9Hz).
HRMS calcd for C 13H 15DNaO 3[M+Na] +：244.1054,found 244.1055.
产物2q.白色固体。
1H NMR(600MHz,CDCl 3)δ5.25(dd,J＝10.2,3.6Hz,1H,H-3),5.20(dd,J＝3.6,1.8Hz,1H,H-2),5.04(t,J＝9.6Hz,1H,H-4),4.60(d,J＝1.8Hz,1H,H-1),3.83(dt,J＝10.2,6.6Hz,1H,H-5),3.36(s,3H,-OMe),2.13(s,3H,-OAc),2.02(s,3H,-OAc),1.96(s,3H,-OAc),1.19(d,J＝6.0Hz,2H,H-6).
13C NMR(101MHz,CDCl 3)δ170.3,170.2,170.2,98.7,71.3,70.0,69.3,66.4,55.3,21.1,21.0,20.9,17.4(t,J C-D＝19.5Hz).
HRMS calcd for C 13H 19DNaO 8[M+Na] +：328.1113,found 328.1112.
产物2r.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.15–8.10(m,1H),7.65(td,J＝7.5,0.9Hz, 1H),7.53–7.49(m,2H).
HRMS calcd for C 7H 4DO 2[M-H] -：122.0358,found 122.0358.
产物2s.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ7.36–7.32(m,2H),7.30–7.27(m,2H),3.67(s,2H).
13C NMR(151MHz,CD 2Cl 2)δ177.9,134.0,130.0,129.7(t,J C-D＝24.2Hz),129.1,129.0,127.8,41.3.
HRMS calcd for C 8H 6DO 2[M-H] -：136.0514,found 136.0513.
产物2t.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.40(s,1H),7.91(d,J＝7.8Hz,1H),7.68(d,J＝7.8Hz,1H).
13C NMR(151MHz,CD 2Cl 2)δ171.2,133.7(t,J C-D＝25.2Hz),131.6(q,J F＝33.0Hz),131.0(q,J F＝3.4Hz),130.6,129.9,127.57(q,J F＝3.8Hz),124.30(q,J F＝272.3Hz).
HRMS calcd for C 8H 3DF 3O 2[M-H] -：190.0232,found 190.0233.
产物2u.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ7.67(s,1H),7.45(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),3.91(s,3H).
13C NMR(151MHz,CD 2Cl 2)δ172.7,160.3,131.0,130.0,122.8(t,J C-D＝25.2Hz),120.8,115.1,56.0.
HRMS calcd for C 8H 6DO 3[M-H] -：152.0463,found 152.0465.
产物2v.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ8.15–8.11(m,2H).(d,J＝5.6Hz,1H),7.65(d,J＝7.8Hz,1H),7.51(t,J＝7.8Hz,1H).
HRMS calcd for C 7H 4DO 2[M-H] -：122.0358,found 122.0358.
产物2w.白色固体。
1H NMR(600MHz,CD 2Cl 2)δ7.71–7.59(m,1H),7.32(d,J＝7.4Hz,1H),7.28–7.21(m,1H).
HRMS calcd for C 7H 3DFO 2[M-H] -：140.0264,found 140.0268.
上述实施例中，仅以碘代化合物为例对氘代化合物的合成进行了介绍，依据反应原理，氯代、溴代、重氮盐、黄原酸酯(Xanthate)类化合物按照该方法同样可以制备得到氘代化合物。
本发明中的水均是指普通非氘代水，即 1H 2O。
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (9)

  1. 一种在水相溶剂中合成氘代化合物的方法，其特征在于，该方法所基于的化学反应方程式如下：
    Figure PCTCN2019127457-appb-100001
    是将如式(I)所示的化合物、如式(II)所示的含磷-氘键的物料与引发剂、碱及溶剂混合反应得到如式(III)所示的还原氘代产物；
    其中，所述溶剂为水( 1H 2O)，或者为水( 1H 2O)与有机溶剂构成的混合溶剂；R 1选自烷基、芳香基、酰基中的至少一种；X选自碘原子、溴原子、氯原子、重氮基、黄原酸酯基中的至少一种；Z选自氧原子、硫原子中任意一种；R 2、R 3独立的选自氘原子、烷基、芳香基、羟基、烷氧基、酚基、氧负离子O -中的至少一种；D为氘原子。
  2. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，在水 1H 2O与有机溶剂构成的混合溶剂中，所述有机溶剂为烷烃类溶剂、卤代烃类溶剂、芳香烃类溶剂、酯类溶剂、腈类溶剂、醚类溶剂、酮类溶剂、醇类溶剂中的至少一种。
  3. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述反应的具体反应历程如下：
    Figure PCTCN2019127457-appb-100002
    具体是如式(I)所示的化合物在自由基引发剂作用下发生还原反应产生如式(IV)所示的自由基，该自由基进一步获取如式(II)所示的含磷-氘键的物料中的氘原子从而得到如式(III)所示的还原氘代化合物。
  4. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述如式(II)所示的含磷-氘键的物料包括氘代次磷酸(D 3PO 2)类化合物、氘代亚磷酸(D 3PO 3)类化合物、氘代硫代次磷酸(D 3P(＝S)O)类化合物、氘代硫代亚磷酸(D 3P(＝S)O 2)类化合物中的至少一种，其中，
    所述氘代次磷酸(D 3PO 2)类化合物包括氘代次磷酸(D 3PO 2)、氘代次磷酸无机盐、氘代次磷酸有机盐、氘代次磷酸酯中的至少一种；
    所述氘代硫代次磷酸(D 3P(＝S)O)类化合物包括氘代硫代次磷酸(D 3P(＝S)O)、氘代硫代次磷酸无机盐、氘代硫代次磷酸有机盐、氘代硫代次磷酸酯中的至少一种；
    所述氘代亚磷酸(D 3PO 3)类化合物包括氘代亚磷酸(D 3PO 3)、氘代亚磷酸无机盐、氘代亚磷酸有机盐、氘代亚磷酸酯中的至少一种；
    所述氘代硫代亚磷酸(D 3P(＝S)O 2)类化合物包括氘代硫代亚磷酸(D 3P(＝S)O 2)、氘代硫代亚磷酸无机盐、氘代硫代亚磷酸有机盐、氘代硫代亚磷酸酯中的至少一种。
  5. 如权利要求4所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述无机盐为锂盐、钠盐、钾盐、钙盐、锌盐、镁盐、铵盐、铝盐、铜盐、亚铁盐、铁盐、钡盐、铬盐、铅盐、锰盐、钴盐、镍盐、中的至少一种；
    所述有机盐为胺盐、吡啶类盐、苯胺类盐、哌啶类盐以及其他氮杂环类盐中的至少一种；
    所述氘代次磷酸酯包括氘代次磷酸烷基醇酯，氘代次磷酸与芳基酚形成的酯，以及氘代次磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代次磷酸甲酯、氘代次磷酸苯酚酯、二苯基氘代氧膦(DP(＝O)Ph 2)；
    所述氘代硫代次磷酸酯为氘代硫代次磷酸烷基醇酯，氘代硫代次磷酸与芳基酚形成的酯，以及氘代硫代次磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代硫代次磷酸甲酯、氘代硫代次磷酸苯酚酯、二 苯基氘代硫膦(DP(＝S)Ph 2)；
    所述氘代亚磷酸酯为氘代亚磷酸烷基醇酯，氘代亚磷酸与芳基酚形成的酯，以及氘代亚磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代亚磷酸甲酯、氘代亚磷酸苯酚酯、苯基氘代氧膦；
    所述氘代硫代亚磷酸酯为氘代硫代亚磷酸烷基醇酯，氘代硫代亚磷酸与芳基酚形成的酯，以及氘代亚磷酸以磷-碳键直接形成的氧膦类物质中的至少一种；优选为氘代硫代亚磷酸甲酯、氘代硫代亚磷酸苯酚酯、苯基氘代硫膦。
  6. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述自由基引发剂为脂溶性引发剂、水溶性引发剂或两性引发剂。
    优选的，所述自由基引发剂为偶氮二异丁基脒二盐酸盐(AIBA)、偶氮二异丁腈(AIBN)、偶氮二异丁咪唑啉盐酸盐(VA044)、偶氮异丁氰基甲酰胺(VA30)、三乙基硼烷(Et 3B)、过氧化苯甲酰(BPO)、或偶氮二异庚腈(ABVN)。
  7. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述碱为有机碱和无机碱中的至少一种；
    优选的，所述有机碱选自烷基胺类、咪唑、吡啶、哌啶、乙基哌啶、2,6-二甲基吡啶(2,6-Lutidne)、1,8-二氮杂二环十一碳-7-烯(DBU)、四丁基醋酸铵(TBAOAc)、三苯基磷(Ph 3P)、三乙基膦(Et 3P)、叔丁醇钾(t-BuOK)、甲醇钠(NaOCH 3)、乙醇钠(NaOEt)、甲酸钠(COONa)、甲酸钾(COOK)、醋酸钠(NaOAc)、醋酸钾(KOAc)中的至少一种；
    所述无机碱选自氢氧化钠(NaOH)、氢氧化钾(KOH)、氢氧化钙(Ca(OH) 2)、碳酸钙(CaCO 3)、碳酸钾(K 2CO 3)、碳酸钠(Na 2CO 3)、碳酸氢钾(KHCO 3)、碳酸氢钠(NaHCO 3)、碳酸铯(CsCO 3)、氨类中的至少一种。
  8. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在 于，所述如式(II)所示的含磷-氘键的物料中所含的磷-氘键的物质的量与所述如式(I)所示的化合物的物质的量之比大于等于1：1。
  9. 如权利要求1所述在水相溶剂中合成氘代化合物的方法，其特征在于，所述碱的用量需满足使至少90％的所述如式(II)所示的含磷-氘键的物料在反应体系中不会和H 2O发生H-D交换；优选的，所述碱的用量需满足使反应体系pH值处于2～13之间。
PCT/CN2019/127457 2019-11-07 2019-12-23 一种在水相溶剂中合成氘代化合物的方法 WO2021088223A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911082310.1A CN112778379B (zh) 2019-11-07 2019-11-07 一种在水相溶剂中合成氘代化合物的方法
CN201911082310.1 2019-11-07

Publications (1)

Publication Number Publication Date
WO2021088223A1 true WO2021088223A1 (zh) 2021-05-14

Family

ID=75747951

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/127457 WO2021088223A1 (zh) 2019-11-07 2019-12-23 一种在水相溶剂中合成氘代化合物的方法

Country Status (2)

Country Link
CN (1) CN112778379B (zh)
WO (1) WO2021088223A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113788733A (zh) * 2021-08-19 2021-12-14 五邑大学 一种反式烯烃的氘代方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666821A (en) * 1968-08-29 1972-05-30 Merck & Co Inc Deuterated methylene chloride
JP2014111561A (ja) * 2012-08-10 2014-06-19 Wako Pure Chem Ind Ltd 芳香族化合物の重水素化方法
CN110054541A (zh) * 2019-05-16 2019-07-26 安徽秀朗新材料科技有限公司 一种氘代芳香族化合物的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102234502B (zh) * 2010-04-21 2013-03-27 华中科技大学 一种缓蚀剂及其制备方法
WO2015121802A1 (en) * 2014-02-12 2015-08-20 Isagro S.P.A. Benzoylphenyl-formamidines having a fungicidal activity, their agronomic compositions and relative use
CN107056611B (zh) * 2017-03-31 2020-05-19 华中科技大学 一种聚酯类化合物的反应型增塑剂、其制备方法和应用
CN107629039B (zh) * 2017-10-12 2019-09-20 河南真实生物科技有限公司 氘代丙烯酰胺的制备方法和中间体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666821A (en) * 1968-08-29 1972-05-30 Merck & Co Inc Deuterated methylene chloride
JP2014111561A (ja) * 2012-08-10 2014-06-19 Wako Pure Chem Ind Ltd 芳香族化合物の重水素化方法
CN110054541A (zh) * 2019-05-16 2019-07-26 安徽秀朗新材料科技有限公司 一种氘代芳香族化合物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAKOTO OBA: "A Convenient Method for Palladium-catalyzed Reductive Deuteration of Organic Substrates Using Deuterated Hypophosphite in D2O", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 58, no. 5, 15 May 2015 (2015-05-15), pages 215 - 219, XP055810720, ISSN: 0362-4803, DOI: 10.1002/jlcr.3277 *

Also Published As

Publication number Publication date
CN112778379A (zh) 2021-05-11
CN112778379B (zh) 2022-10-14

Similar Documents

Publication Publication Date Title
CN102127092B (zh) 依维莫斯的制备
CN102206178B (zh) 制备艾瑞昔布的方法
CN104876995A (zh) 鹅去氧胆酸衍生物的制备方法
CN103265420A (zh) 一种芳香二酮化合物的制备方法
WO2021088223A1 (zh) 一种在水相溶剂中合成氘代化合物的方法
CN111925381A (zh) 一种巴洛沙韦关键中间体的合成方法
WO2015012110A1 (ja) Ｃ－グリコシド誘導体の製造方法
CN102690194B (zh) 3-环丙基甲氧基-4-二氟甲氧基苯甲酸的制备方法
JP2006151946A (ja) ジアリール誘導体の製造方法
Couri et al. Microwave-assisted efficient preparation of novel carbohydrate tetrazole derivatives
CN104803882B (zh) 一种化合物及其制备方法和应用
JP5157154B2 (ja) ４’−（アルコキシカルボニル）ビシクロヘキシル−４−イルカルボン酸及びその製造方法
CN107118088A (zh) 一种间羟基苯乙酮的制备方法
ITMI20010936A1 (it) Processo per la produzione di acidi 2-4-(2,2-dialociclopropil)fenossi|-alcanoici e loro esteri
JP2013503115A (ja) ２−ブロモ−６−フルオロナフタレンの調製方法
EP4262887A1 (en) Trans-cyclooctenes with high reactivity and favorable physiochemical properties
CN109232316B (zh) 一类α-三级腈结构β-二羰基化合物的合成方法
CN102093247B (zh) 一种2-甲基-4-n-(2-甲基苯甲酰)苯甲酸的制备方法
CN101113138A (zh) 二茂铁亚胺环钯配合物催化下芳基腈类衍生物的合成方法
CN105330633A (zh) 一种制备联苯二酐混合物的方法
CN102557941B (zh) 一种螺环丙基甲酰衍生物的中间体化合物的制备方法
CN101602760A (zh) 一种奥美沙坦酯的制备方法
CN104119289B (zh) 一种合成氧化呋咱化合物的方法
CN106631824B (zh) 一种(1-环丙基-1-甲基)乙基胺盐酸盐的合成方法
CN105399739A (zh) 1,8-萘啶-2-胺的合成方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19951935

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19951935

Country of ref document: EP

Kind code of ref document: A1