WO2023046046A1 - 用于制备作为荧光示踪剂的吡嗪羧酸类衍生物的氢化合成方法 - Google Patents
用于制备作为荧光示踪剂的吡嗪羧酸类衍生物的氢化合成方法 Download PDFInfo
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- 239000000700 radioactive tracer Substances 0.000 title abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 title abstract description 3
- 238000001308 synthesis method Methods 0.000 title abstract description 3
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical class OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- XHNJXRDGTITISI-QWWZWVQMSA-N (2r)-2-[[3,6-diamino-5-[[(1r)-1-carboxy-2-hydroxyethyl]carbamoyl]pyrazine-2-carbonyl]amino]-3-hydroxypropanoic acid Chemical compound NC1=NC(C(=O)N[C@H](CO)C(O)=O)=C(N)N=C1C(=O)N[C@H](CO)C(O)=O XHNJXRDGTITISI-QWWZWVQMSA-N 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 101
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 52
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 38
- 239000003054 catalyst Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 22
- 235000019253 formic acid Nutrition 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 229910052783 alkali metal Inorganic materials 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 17
- -1 alkali metal formate Chemical class 0.000 claims description 17
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 125000003158 alcohol group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000009466 transformation Effects 0.000 claims description 3
- 239000004280 Sodium formate Substances 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical group [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 239000002360 explosive Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 abstract description 3
- 238000000859 sublimation Methods 0.000 abstract description 3
- 230000008022 sublimation Effects 0.000 abstract description 3
- 230000000903 blocking effect Effects 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000009776 industrial production Methods 0.000 description 8
- 229940125898 compound 5 Drugs 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 5
- 235000011118 potassium hydroxide Nutrition 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- VELGYJCKWFALBF-UHFFFAOYSA-N 3,6-diaminopyrazine-2,5-dicarboxylic acid Chemical compound NC1=NC(C(O)=O)=C(N)N=C1C(O)=O VELGYJCKWFALBF-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/20—Nitrogen atoms
Definitions
- the present invention relates to the preparation of 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxylic acid-2-hydroxyethyl]aminocarbamate for use as a fluorescent tracer in medical diagnosis Acyl ⁇ pyrazine method.
- the second step of this route uses hydrogen as the hydrogen source, which not only requires pressurization but also takes a long time to react in industrial production; moreover, hydrogen is a flammable and explosive gas, which poses a great safety hazard in industrial production.
- the purpose of the present invention is to overcome the problems existing in the prior art, avoid the use of inflammable and explosive hydrogen, and reduce the potential safety hazards in industrial production.
- a further object of the present invention is: while realizing the yield and the quality of compound 1 equivalent to prior art (such as Raghavan Rajagopalan et al., J.Med.Chem., 2011,54,5048-5058.), shorten the reaction time. This is of great significance for industrial production.
- the above object is achieved by providing a preparation method suitable for the industrial production of Compound 1 of the present invention.
- the present invention provides a method for the preparation of 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyridine
- a novel method for oxazine hereinafter also referred to as "compound 1", the method comprising the following steps:
- a compound of formula 5 (hereinafter also referred to as “compound 5”) is subjected to a hydrogen-borrowing reaction with a hydrogen-borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3,6-diamino- 2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine,
- said solvent is selected from alcohol or alcohol aqueous solution.
- hydrophilicity reaction also known as a hydrogen transfer reaction
- a metal catalyst to dehydrogenate a relatively inert organic compound to form a metal hydride while simultaneously activating the organic compound and participating in subsequent reactions An intermediate is formed, which is then reduced by the metal hydride to form a new product.
- Such organic compounds are referred to as "hydrogen-borrowing agents”.
- room temperature means about 20 to 25°C.
- the present invention provides a process for the preparation of 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine of formula 1 , characterized in that the method comprises the following steps:
- the compound of formula 5 is reacted with a hydrogen-borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3,6-diamino-2,5-bis ⁇ N-[(1R )-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine,
- the solvent includes alcohol or alcohol aqueous solution.
- the hydrogen-borrowing reagent used in the method of the present invention is preferably a reagent suitable for industrial production.
- the use of certain reagents may pose production hazards and is therefore not preferred. For example, ammonium formate is prone to sublimation, which can cause clogging problems.
- the hydrogen-borrowing agent is selected from a combination of formic acid and an alkali metal formate, cyclohexadiene, and isopropanol.
- the molar ratio of the compound of formula 5 to the hydrogen-borrowing agent is about 1:2 to 1:20, preferably about 1:2 to 1:10, such as about 1:2.5, about 1:20 4. About 1:5, about 1:6 or about 1:8.
- the metal catalyst is palladium on carbon (Pd/C).
- the mass fraction of palladium in the Pd/C catalyst may be about 5 to 20%, preferably about 10%.
- the Pd/C catalyst may contain about 50 w/w% water.
- the mass ratio of the compound of formula 5 to the metal catalyst is about 10:1 to 10:3, preferably about 10:2.
- the solvent is alcohol
- the solvent is an aqueous alcohol solution.
- the volume ratio of alcohol to water in the aqueous alcohol solution may be about 1:10 to 10:1, preferably about 1:8 to 8:1, more preferably about 4:1 to 8:1.
- the amount of the alcohol may be about 4 to 40 times (v/w) the amount of the compound of formula 5, such as about 10, 15, 25, 30 or 35 times (v/w).
- the alcohol may be selected from methanol, ethanol, isopropanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
- the hydrogen borrowing reaction is performed at a temperature of about 20°C to 100°C, preferably about 20°C to 80°C. In some preferred embodiments, the hydrogen borrowing reaction is performed at a temperature of about 50°C to 70°C. In some preferred embodiments, the hydrogen borrowing reaction is performed at room temperature.
- the hydrogen borrowing reaction is carried out for about 1 to 12 hours, preferably about 2 to 12 hours, more preferably about 2 hours, 10 hours or 12 hours, to complete the conversion of the compound of formula 5 to the formula 1 transformation of the compound.
- the hydrogen borrowing reaction is performed at a temperature of about 70° C. for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1 .
- the conversion to the compound of formula 1 can be monitored by detecting the residual amount of the compound of formula 5 in the reactant, eg, by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the compound of formula 1 generated can be separated and purified by the following steps:
- the aqueous alcohol solution described in step (1) may be, for example, an aqueous ethanol solution.
- the water content of the ethanol aqueous solution may be about 25% to 40% (v/v), preferably about 30% to 36% (v/v).
- the present invention provides the method as described in the first aspect above, wherein the hydrogen-borrowing reagent is a combination of formic acid and an alkali metal formate.
- the molar ratio of the formic acid to the alkali metal formate is about 1:6 to 6:1, preferably about 1:1 to 5:1, more preferably about 1:2 to 5:1 .
- the molar ratio of the compound of formula 5 to the sum of the formic acid and the alkali metal formate is about 1:2 to 1:20, such as about 1:4 to 1:18, about 1:6 to 1:16 or about 1:8 to 1:12. In some preferred embodiments, the molar ratio is about 1:5 to 1:10, such as about 1:6 to 1:8, more preferably about 1:6.
- the alkali metal formate is sodium formate or potassium formate, preferably potassium formate.
- the combination of formic acid and alkali metal formate can be obtained by adding separate formic acid and alkali metal formate or a mixture thereof to the reaction system, or by adding an appropriate amount of formic acid and an appropriate amount of the corresponding alkali metal base in the reaction system. reaction to form in situ.
- the base may be selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate and any combination thereof.
- the solvent is an aqueous alcohol solution.
- the volume ratio of alcohol to water in the aqueous alcohol solution may be about 1:10 to 10:1, preferably about 1:8 to 8:1, more preferably about 4:1 to 8:1.
- the amount of the alcohol can be about 10 to 40 times (v/w), preferably about 10 to 35 times (v/w), such as 15, 25 or 30 times (v/w) the amount of the compound of the formula 5 ).
- the alcohol is selected from methanol, ethanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
- the hydrogen borrowing reaction is performed at a temperature of about 50°C to 80°C, preferably at about 50°C, about 60°C, or more preferably about 70°C.
- the hydrogen borrowing reaction is performed for about 2 to 12 hours, preferably about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
- the method can achieve the same yield and quality of Compound 1 as reported by Raghavan Rajagopalan et al. (J.Med.Chem., 2011, 54, 5048-5058).
- the hydrogen borrowing reaction is performed at a temperature of about 70° C. for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1 .
- the present invention provides a method as described above, wherein the hydrogen-borrowing agent is a combination of formic acid and potassium formate in a molar ratio of about 1:2 to 5:1;
- the molar ratio of the compound of the formula 5 to the sum of the formic acid and the potassium formate is about 1:5 to 1:10, more preferably about 1:6;
- the solvent is an aqueous solution of methanol or ethanol, wherein the volume ratio of the methanol or ethanol to water is about 4:1 to 8:1;
- the amount of the methanol or ethanol is about 15 to 35 times (v/w) the amount of the compound of the formula 5;
- the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (for example, the Pd/C catalyst contains about 50w/w% water);
- the mass ratio of the compound of the formula 5 to the Pd/C catalyst is about 10:2;
- the hydrogen borrowing reaction is carried out at a temperature of about 50°C to 70°C for about 2 to 12 hours, more preferably at a temperature of about 70°C for about 2 hours, to complete the conversion of the compound of the formula 5 to the compound of the formula 1 transformation.
- the resulting compound of formula 1 can be isolated and purified by the steps described in the first aspect above.
- the isolation and purification process may also include adding an appropriate amount of acid (e.g., the same molar amount as the alkali metal base used to form the alkali metal formate in situ) to the combined filtrate and mixing A step of.
- an appropriate amount of acid e.g., the same molar amount as the alkali metal base used to form the alkali metal formate in situ
- the acid is preferably hydrochloric acid. Then, the resulting mixture was concentrated to obtain the crude compound of formula I.
- the present invention provides the method as described in the first aspect above, wherein the hydrogen-borrowing reagent is cyclohexadiene.
- the molar ratio of the compound of formula 5 to the cyclohexadiene is about 1:2 to 1:5; preferably about 1:2 to 1:3.
- the solvent is alcohol, preferably methanol or ethanol, more preferably ethanol.
- the amount of the alcohol is about 4 to 10 times (v/w), such as about 4, about 6 or about 8 times (v/w) the amount of the compound of formula 5.
- the hydrogen borrowing reaction is performed at room temperature for about 10 to 12 hours to complete the conversion of the compound of Formula 5 to the compound of Formula 1 .
- the present invention provides a method as described above, wherein the hydrogen-borrowing reagent is cyclohexadiene;
- the molar ratio of the compound of the formula 5 to the cyclohexadiene is about 1:2 to 1:3;
- the solvent is methanol or ethanol, and the amount of the methanol or ethanol is about 4 to 6 times (v/w) the amount of the compound of formula 5;
- the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (for example, the Pd/C catalyst contains about 50w/w% water);
- the mass ratio of the compound of the formula 5 to the Pd/C catalyst is about 10:2;
- the hydrogen borrowing reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
- the resulting compound of formula 1 can be isolated and purified by the steps described in the first aspect above.
- the method of the invention avoids the use of inflammable and explosive hydrogen, and greatly reduces potential safety hazards in industrialized production.
- the method of the present invention also has the advantages that the debenzylation reaction is carried out completely and there is basically no side reaction. Moreover, by adjusting the reaction conditions (for example, the ratio of reactants and the reaction temperature), the method of the present invention is equivalent to that reported by Raghavan Rajagopalan et al. (J.Med.Chem., 2011,54,5048-5058). While improving the yield and quality of compound 1, the reaction time can be shortened from more than 10 hours reported by Raghavan Rajagopalan et al. to about 2 hours or less, thereby greatly shortening the production time.
- the method of the present invention also avoids the problem of clogged lines caused by sublimation when ammonium formate is used.
- the method of the invention has low requirements on equipment, simple and convenient operation, high yield, high safety and cost-effectiveness, is suitable for industrial production, and has important application value.
- the experimental method that does not indicate specific condition in the embodiment of the present invention is conventional condition usually, or according to the condition suggested by raw material or commodity manufacturer; It can be prepared from known reagents by conventional methods.
- Reagents formic acid, trifluoroacetic acid, acetonitrile, methanol.
- Reagents purified water, acetonitrile.
- the mass spectrum is measured by LC-MS instrument, and the ionization method can be ESI or APCI.
- Thin layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
- the specification of the silica gel plate used is 0.15 mm to 0.2 mm, and the specification of the silica gel plate used for thin layer chromatography separation and purification is 0.4 mm to 0.5 mm.
- Example 1 The operation of Example 1 was repeated except that no KOH was added.
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- Luminescent Compositions (AREA)
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Abstract
涉及用于作为荧光示踪剂的吡嗪羧酸类衍生物的氢化合成方法,具体涉及制备3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的方法,该方法避免使用易燃易爆的氢气,且解决了甲酸铵升华所致的堵塞管路的问题,大大降低了生产中的安全隐患。
Description
本发明涉及用于制备在医学诊断中用作荧光示踪剂的3,6-二氨基-2,5-双{N-[(1R)-1-羧酸-2-羟基乙基]氨基甲酰基}吡嗪的方法。
吡嗪类衍生物作为荧光示踪剂在评估肾功能方面具有潜在的应用前景。作为一种极具临床应用价值的荧光示踪剂,3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪(下文中也称作“式1的化合物”或“化合物1”)的研究得到了广泛的关注,但是目前该化合物的合成路线报道极少。
2011年,Raghavan Rajagopalan等人对化合物1的合成进行了优化,减少了反应步骤(J.Med.Chem.,2011,54,5048-5058)。在该合成方法中,作为原料的3,6-二氨基吡嗪-2,5-二甲酸经酰胺化、钯催化氢化等步骤得到化合物1:
然而,该路线的第2个步骤以氢气作为氢源,在工业生产时不仅需要加压而且反应时间长;而且氢气是易燃易爆气体,在工业化生产中存在极大的安全隐患。
因此,仍然需要开发具有高安全性和高效益的适合3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的工业化生产的方法。
发明内容
本发明的目的在于克服现有技术中存在的问题,避免使用易燃易爆的氢气,降低工业化生产中的安全隐患。
本发明进一步的目的是:在实现与现有技术(例如Raghavan Rajagopalan 等人,J.Med.Chem.,2011,54,5048-5058.)同等的化合物1的收率和质量的同时,缩短反应时间。这对于工业化生产具有重要意义。
通过提供本发明的适合化合物1的工业化生产的制备方法实现了以上目的。
一般而言,本发明提供一种用于制备式1的3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪(下文中也称为“化合物1”)的新方法,所述方法包括以下步骤:
使式5的化合物(下文中也称为“化合物5”)与借氢试剂在溶剂中在适合的金属催化剂的存在下进行借氢反应,以提供所述式1的3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪,
其中所述溶剂选自醇或醇水溶液。
定义
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解,但仍然阐述以下定义以更好地解释本发明。
如本文中所使用,术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的,且不排除其它未列举的元素或方法步骤,尽管其它未列举的元素或方法步骤不一定存在(即,这些术语也涵盖术语“基本上由……组成”和“由……组成”)。
如本文所使用,术语“借氢反应”,也被称为氢转移反应,是指利用金属催化剂从相对惰性的有机化合物中脱氢形成金属氢化物,同时使所述有机化合物活化并参与后续反应生成中间体,之后所述金属氢化物再还原所述中间体以生成新产物。所述有机化合物被称作“借氢试剂”。
如本文中所使用,术语“室温”是指约20至25℃。
术语“约”是指在所述数值的±10%范围内,优选±5%范围内,更优选±2%范围内。
在第一方面,本发明提供制备式1的3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的方法,其特征在于,所述方法包括以下步骤:
使式5的化合物与借氢试剂在溶剂中在适合的金属催化剂的存在下进行借氢反应,以提供所述式1的3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪,
其中所述溶剂包括醇或醇水溶液。
用于本发明的方法的借氢试剂优选地是适于工业化生产的试剂。某些试剂的使用可能会带来生产隐患,因此不是优选的。例如,甲酸铵易于升华,因而会造成堵塞管路的问题。
在一些实施方案中,所述借氢试剂选自甲酸和碱金属甲酸盐的组合、环己二烯和异丙醇。
在一些实施方案中,所述式5的化合物与所述借氢试剂的摩尔比为约1:2至1:20,优选约1:2至1:10,例如约1:2.5、约1:4、约1:5、约1:6或约1:8。
在一些实施方案中,所述金属催化剂为炭载钯(Pd/C)。所述Pd/C催化剂中钯的质量分数可以为约5至20%,优选约10%。例如,所述Pd/C催化剂可以含有约50w/w%的水。
在一些实施方案中,所述式5的化合物与所述金属催化剂的质量比为约10:1至10:3,优选约10:2。
在一些实施方案中,所述溶剂为醇。
在另一些实施方案中,所述溶剂为醇水溶液。所述醇水溶液中醇与水的体积比可以为约1:10至10:1,优选约1:8至8:1,更优选约4:1至8:1。
在一些上文所述的实施方案中,无论所述溶剂是否包括水,所述醇的量可以为所述式5的化合物的量的约4至40倍(v/w),例如约10、15、25、 30或35倍(v/w)。
所述醇可以选自甲醇、乙醇、异丙醇及其混合物,优选为甲醇或乙醇,更优选为乙醇。
在一些实施方案中,所述借氢反应在约20℃至100℃,优选约20℃至80℃的温度下进行。在一些优选的实施方案中,所述借氢反应在约50℃至70℃的温度下进行。在一些优选的实施方案中,所述借氢反应在室温下进行。
在一些实施方案中,所述借氢反应进行约1至12小时,优选约2至12小时,更优选约2小时、10小时或12小时,以完成所述式5的化合物向所述式1的化合物的转化。
在一些优选的实施方案中,所述借氢反应在约70℃的温度下进行约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
可以通过例如薄层色谱法(TLC)检测反应物中式5的化合物的残留量来监测其向所述式1的化合物的转化。
所生成的式1的化合物可以通过以下步骤来分离和纯化:
(1)在所述借氢反应完成后,过滤反应混合物,并用醇水溶液洗涤滤饼至滤液为浅黄色,合并所得的滤液;
(2)浓缩所述滤液,得到所述式I的化合物的粗品;
(3)向所述式I的化合物的粗品加入适量乙腈或水并打浆适合的时间(例如约1至4小时);
(4)过滤,并将滤饼在适合的温度(例如约40至45℃)下减压干燥,得到所述式I的化合物。
步骤(1)中所述的醇水溶液可以是例如乙醇水溶液。所述乙醇水溶液的含水量可以为约25%至40%(v/v),优选约30%至36%(v/v)。
在第二方面,本发明提供如上文第一方面所述的方法,其特征在于,所述借氢试剂为甲酸以及碱金属甲酸盐的组合。
在一些实施方案中,所述甲酸与所述碱金属甲酸盐的摩尔比为约1:6至6:1,优选约1:1至5:1,更优选约1:2至5:1。
在一些实施方案中,所述式5的化合物与所述甲酸和所述碱金属甲酸盐的总和的摩尔比为约1:2至1:20,例如约1:4至1:18、约1:6至1:16或约 1:8至1:12。在一些优选的实施方案中,所述摩尔比为约1:5至1:10,例如约1:6至1:8,更优选约1:6。
在一些优选的实施方案中,所述碱金属甲酸盐为甲酸钠或甲酸钾,优选甲酸钾。
所述甲酸以及碱金属甲酸盐的组合可以通过向反应体系中加入单独的甲酸以及碱金属甲酸盐或其混合物来得到,也可以经由过量的甲酸和适量的相应碱金属碱在反应体系中反应而原位形成。所述碱可以选自氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸氢钾和碳酸氢钠及其任意组合。
在一些优选的实施方案中,所述溶剂为醇水溶液。所述醇水溶液中醇与水的体积比可以为约1:10至10:1,优选约1:8至8:1,更优选约4:1至8:1。所述醇的量可以为所述式5的化合物的量的约10至40倍(v/w),优选约10至35倍(v/w),例如15、25或30倍(v/w)。在一些优选的实施方案中,所述醇选自甲醇、乙醇及其混合物,优选为甲醇或乙醇,更优选为乙醇。
在一些实施方案中,所述借氢反应在约50℃至80℃,优选在约50℃、约60℃或更优选约70℃的温度下进行。
在一些实施方案中,所述借氢反应进行约2至12小时,优选约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
所述方法可以实现与Raghavan Rajagopalan等人(J.Med.Chem.,2011,54,5048-5058)所报道的同等的化合物1的收率和质量。
在一些更优选的实施方案中,所述借氢反应在约70℃的温度下进行约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
在一些特别优选的实施方案中,本发明提供如上文所述的方法,其特征在于,所述借氢试剂为摩尔比为约1:2至5:1的甲酸和甲酸钾的组合;
所述式5的化合物与所述甲酸和所述甲酸钾的总和的摩尔比为约1:5至1:10,更优选约1:6;
所述溶剂为甲醇或乙醇的水溶液,其中所述甲醇或乙醇与水的体积比为约4:1至8:1;
所述甲醇或乙醇的量为所述式5的化合物的量的约15至35倍(v/w);
所述金属催化剂为Pd/C,其中所述Pd/C催化剂中钯的质量分数为约10%(例如,所述Pd/C催化剂含有约50w/w%的水);
所述式5的化合物与所述Pd/C催化剂的质量比为约10:2;并且
所述借氢反应在约50℃至70℃的温度下进行约2至12小时,更优选约70℃的温度下进行约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
所生成的式1的化合物可以通过如上文第一方面所述的步骤来分离和纯化。在一些实施方案中,该分离和纯化过程还可以包括在合并的滤液中加入适量的酸(例如,与用于原位形成所述碱金属甲酸盐的碱金属碱相同的摩尔量)并混合的步骤。例如,当如上文所述原位形成所述甲酸以及碱金属甲酸盐的组合时,可以向合并的滤液中加入与用于原位形成所述碱金属甲酸盐的碱金属碱相同摩尔量的酸。所述酸优选为盐酸。然后,将所得的混合物浓缩,得到所述式I的化合物的粗品。
在第三方面,本发明提供如上文第一方面所述的方法,其特征在于,所述借氢试剂为环己二烯。
在一些实施方案中,所述式5的化合物与所述环己二烯的摩尔比为约1:2至1:5;优选约1:2至1:3。
在一些实施方案中,所述溶剂为醇,优选为甲醇或乙醇,更优选为乙醇。
在一些实施方案中,所述醇的量为所述式5的化合物的量的约4至10倍(v/w),例如约4、约6或约8倍(v/w)。
在一些实施方案中,所述借氢反应在室温下进行约10至12小时,以完成所述式5的化合物向所述式1的化合物的转化。
在一些实施方案中,本发明提供如上文所述的方法,其特征在于,所述借氢试剂为环己二烯;
所述式5的化合物与所述环己二烯的摩尔比为约1:2至1:3;
所述溶剂为甲醇或乙醇,并且所述甲醇或乙醇的量为所述式5的化合物的量的约4至6倍(v/w);
所述金属催化剂为Pd/C,其中所述Pd/C催化剂中钯的质量分数为约10%(例如,所述Pd/C催化剂含有约50w/w%的水);
所述式5的化合物与所述Pd/C催化剂的质量比为约10:2;并且
所述借氢反应在室温下进行约10至12小时,以完成所述式5的化合物向所述式1的化合物的转化。
所生成的式1的化合物可以通过如上文第一方面所述的步骤来分离和 纯化。
本发明的方法避免了使用易燃易爆的氢气,大大降低了工业化生产中的安全隐患。本发明的方法还具有脱苄基反应进行彻底,基本无副反应的优点。而且,通过调整反应条件(例如,反应物的配比和反应温度),本发明的方法在实现与Raghavan Rajagopalan等人(J.Med.Chem.,2011,54,5048-5058)所报道的同等的化合物1的收率和质量的同时,能够将反应时间由Raghavan Rajagopalan等人报道的10多个小时缩短至约2小时或更少,从而大大缩短生产时间。本发明的方法还避免了在使用甲酸铵时由升华所致的堵塞管路的问题。本发明的方法对设备要求不高,操作简便,产率高,安全性和成本效益高,适于工业化生产,具有重要应用价值。
实施例
以下结合实施例进一步描述本发明,但提供这些实施例并非意图限制本发明的范围。
本发明实施例中未注明具体条件的实验方法,通常为常规条件,或按照原料或商品制造厂商所建议的条件;未注明来源的试剂,通常为通过商业途径可购得的常规试剂或者可以由已知的试剂通过常规方法制备得到。
试剂及仪器
1.HRMS
仪器型号:Agilent 1290 Q-TOF-6545A;
试剂:甲酸、三氟乙酸、乙腈、甲醇。
2.LC/MS
仪器:Waters 2767 Sample Manager、Waters 515 HPLC Pump、Waters2489UV/Visible Detector、Waters 3100 Mass Detector;
试剂:纯化水、乙腈。
质谱是用LC-MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析(TLC)使用烟台黄海HSGF254或青岛GF254硅胶板。使用的硅胶板采用的规格是0.15mm~0.2mm,用于薄层层析分离纯化的硅胶板采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海200-300目硅胶为载体。
各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明。
实施例1:3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的制备
往250mL反应瓶中加入20mL纯化水和0.56g KOH,完全溶解后加入2.76g HCOOH和80mL乙醇,搅拌5min后于室温下加入5.00g化合物5和1g10%Pd/C(含水50%),在70℃加热回流2h,TLC监测显示反应完毕,趁热用硅藻土滤除Pd/C。用乙醇水溶液(30%H
2O,V/V)洗涤滤饼至滤液为浅黄色,合并滤液。向滤液中加入10ml的1N盐酸,搅拌15min后减压浓缩至干。将所得的固体用50mL乙腈/水打浆2h,然后过滤。将滤饼于40℃减压干燥12h,得到2.19g固体形式的标题化合物(摩尔收率:65%)。
LC-MS:RT=3.02min,[M-H]=370.9.
HRMS:[M+H
+]=373.1110.
1H NMR[500Hz,DMSO-d6]δ8.47(d,2H),6.78(s,4H),4.47(dt,2H),3.90(dd,2H),3.76(dd,2H).
比较例1:3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的制备
除了不加入KOH以外,重复实施例1的操作。
具体而言,往250mL反应瓶中加入20mL纯化水,然后加入2.76g HCOOH和80mL乙醇,搅拌5min后于室温下加入5.00g化合物5和1g 10%Pd/C(含水50%),在70℃加热回流2h。TLC监测显示目标化合物几乎不可见,原料点有大量残留。
实施例2:3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的制备
往250mL反应瓶中加入20mL纯化水和2.23g KOH,完全溶解后加入2.76g HCOOH和160mL乙醇,搅拌5min后于室温下加入5.00g化合物5、1g 10%Pd/C(含水50%),在60℃加热回流10h,TLC监测显示反应完毕,趁 热用硅藻土滤除Pd/C。用乙醇水溶液(30%H
2O,V/V)洗涤滤饼至滤液为浅黄色,合并滤液。向滤液中加入40ml的1N盐酸,搅拌15min后减压浓缩至干。将所得的固体用30mL水打浆2h,然后过滤。将滤饼于40℃减压干燥12h,得到2.12g固体形式的标题化合物(摩尔收率:63%)。
LC-MS:RT=3.02min,[M-H]=370.9.
HRMS和
1H NMR数据同实施例1。
实施例3:3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的制备
往250mL反应瓶中加入20mL纯化水和2.23g KOH,完全溶解后加入2.76g HCOOH和80mL甲醇,搅拌5min后于室温下加入5.00g化合物5、1g10%Pd/C(含水50%),在50℃加热回流12h,TLC监测显示反应完毕,趁热用硅藻土滤除Pd/C。用乙醇水溶液(36%H
2O,V/V)洗涤滤饼至滤液为浅黄色,合并滤液。向滤液中加入40ml的1N盐酸,搅拌15min后减压浓缩至25mL,然后过滤。将滤饼用50mL水打浆2h,然后过滤。将滤饼于40℃减压干燥12h,得到1.85g红色固体形式的标题化合物(摩尔收率:55%)。
LC-MS:RT=3.02min,[M-H]=370.9.
HRMS和
1H NMR数据同实施例1。
实施例4:3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的制备
往250mL反应瓶中加入20mL乙醇和5.00g化合物5、2g环己二烯和1g10%Pd/C(含水50%),于室温下反应12h,TLC监测显示反应完毕,经硅藻土滤除Pd/C。用乙醇水溶液(36%H
2O,V/V)洗涤滤饼至滤液为浅黄色,合并滤液。将滤液浓缩至干,用20mL水打浆2h,然后过滤。将滤饼于40℃减压干燥12h,得2.20g红色固体形式的标题化合物(摩尔收率:65%)。
LC-MS:RT=3.02min,[M-H]=370.9.
HRMS和
1H NMR数据同实施例1。
除本文中描述的实施方案外,根据前述描述,本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书 的范围内。
本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体通过援引加入本文。
Claims (18)
- 根据权利要求1的方法,其特征在于,所述借氢试剂选自甲酸和碱金属甲酸盐的组合、环己二烯和异丙醇;和/或所述式5的化合物与所述借氢试剂的摩尔比为约1:2至1:20,优选约1:2至1:10,例如约1:2.5、约1:4、约1:5、约1:6或约1:8。
- 根据权利要求1或2的方法,其特征在于,所述金属催化剂为炭载钯(Pd/C);优选地,所述Pd/C催化剂中钯的质量分数为约5至20%,优选约10%(例如所述Pd/C催化剂含有约50w/w%的水)。
- 根据权利要求1至3中任一项的方法,其特征在于,所述式5的化合物与所述金属催化剂的质量比为约10:1至10:3,优选约10:2。
- 根据权利要求1至4中任一项的方法,其特征在于,所述溶剂为醇。
- 根据权利要求1至4中任一项的方法,其特征在于,所述溶剂为醇水溶液;优选地,所述醇水溶液中醇与水的体积比为约1:10至10:1,优选约1:8 至8:1,更优选约4:1至8:1。
- 根据权利要求5至7中任一项的方法,其特征在于,所述醇的量为所述式5的化合物的量的约4至40倍(v/w),例如约10、15、25、30或35倍(v/w)。
- 根据权利要求5至7中任一项的方法,其特征在于,所述醇选自甲醇、乙醇、异丙醇及其混合物,优选为甲醇或乙醇,更优选为乙醇。
- 根据权利要求1至8中任一项的方法,其特征在于,所述借氢反应在约20℃至100℃,优选约20℃至80℃,更优选室温或约50℃至70℃的温度下进行;和/或所述借氢反应进行约1至12小时,优选约2至12小时,更优选约2小时、10小时或12小时,以完成所述式5的化合物向所述式1的化合物的转化。
- 根据权利要求1至9中任一项的方法,其特征在于,所述借氢试剂为甲酸和碱金属甲酸盐的组合;优选地,所述甲酸与所述碱金属甲酸盐的摩尔比为约1:6至6:1,优选约1:1至5:1,更优选约1:2至5:1;和/或优选地,所述式5的化合物与所述甲酸和所述碱金属甲酸盐的总和的摩尔比为约1:2至1:20,优选约1:5至1:10,更优选约1:6。
- 根据权利要求10的方法,其特征在于,所述碱金属甲酸盐为甲酸钠或甲酸钾,优选甲酸钾。
- 根据权利要求10或11的方法,其特征在于,所述溶剂为如权利要求6至8中任一项所述的醇水溶液;和或所述醇的量为所述式5的化合物的量的约10至40倍(v/w),优选约15至35倍(v/w),优选地,所述醇选自甲醇、乙醇及其混合物,优选为甲醇或乙醇,更优选为乙醇。
- 根据权利要求10至12中任一项的方法,其特征在于,所述借氢反应在约50℃至80℃,优选在约50℃、约60℃或更优选约70℃的温度下进行;和/或所述借氢反应进行约2至12小时,优选约2小时,以完成所述式5的化合物向所述式1的化合物的转化;优选地所述借氢反应在约70℃的温度下进行约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
- 根据权利要求1的方法,其特征在于,所述借氢试剂为摩尔比为约1:2至5:1的甲酸和甲酸钾的组合;所述式5的化合物与所述甲酸和所述甲酸钾的总和的摩尔比为约1:5至1:10,更优选约1:6;所述溶剂为甲醇或乙醇的水溶液,其中所述甲醇或乙醇与水的体积比为约4:1至8:1;所述甲醇或乙醇的量为所述式5的化合物的量的约15至35倍(v/w);所述金属催化剂为Pd/C,其中所述Pd/C催化剂中钯的质量分数为约10%(例如,所述Pd/C催化剂含有约50w/w%的水);所述式5的化合物与所述Pd/C催化剂的质量比为约10:2;并且所述借氢反应在约50℃至70℃的温度下进行约2至12小时,更优选约70℃的温度下进行约2小时,以完成所述式5的化合物向所述式1的化合物的转化。
- 根据权利要求1至9中任一项的方法,其特征在于,所述借氢试剂为环己二烯;优选地,所述式5的化合物与所述环己二烯的摩尔比为约1:2至1:5;优选约1:2至1:3。
- 根据权利要求15的方法,其特征在于,所述溶剂为醇,优选为甲醇或乙醇,更优选为乙醇;和/或所述醇的量为所述式5的化合物的量的约4至10倍(v/w),例如约 4、约6或约8倍(v/w)。
- 根据权利要求15或16的方法,其特征在于,所述借氢反应在室温下进行约10至12小时,以完成所述式5的化合物向所述式1的化合物的转化。
- 根据权利要求1的方法,其特征在于,所述借氢试剂为环己二烯;所述式5的化合物与所述环己二烯的摩尔比为约1:2至1:3;所述溶剂为甲醇或乙醇,并且所述甲醇或乙醇的量为所述式5的化合物的量的约4至6倍(v/w);所述金属催化剂为Pd/C,其中所述Pd/C催化剂中钯的质量分数为约10%(例如,所述Pd/C催化剂含有约50w/w%的水);所述式5的化合物与所述Pd/C催化剂的质量比为约10:2;并且所述借氢反应在室温下进行约10至12小时,以完成所述式5的化合物向所述式1的化合物的转化。
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