CN109293592A - A method of preparing Gadobutrol - Google Patents
A method of preparing Gadobutrol Download PDFInfo
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- CN109293592A CN109293592A CN201810797289.2A CN201810797289A CN109293592A CN 109293592 A CN109293592 A CN 109293592A CN 201810797289 A CN201810797289 A CN 201810797289A CN 109293592 A CN109293592 A CN 109293592A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention discloses a kind of compounds by formula G to pass through substitution reaction, deprotection, alkylation, hydrolysis and complex reaction; the method for finally preparing Gadobutrol F; this method further relates to H and J carrying out recrystallization purifying; purity is high, the high income of gained formula H and J can be used as the effective Quality Control point of industrial amplification production；Gadobutrol F uses nanofiltration, recrystallization and ion exchange resin treatment, and consuming energy, low, operating condition is simple, few using resin types, at low cost, and the Gadobutrol that purity is higher than 99.5% finally can be obtained.The present invention for prepare high-purity Gadobutrol bulk pharmaceutical chemicals provide it is a kind of low cost, in high yield, be suitble to industry amplification production technology.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of side to prepare high-purity Gadobutrol in high yield
Method.
Background technique
The mri contrast agent of the trade name Gadovist of Bayer exploitation, is the high concentration Gadobutrol of 1.0mol/L
(Gadobutrol) aqueous solution, Gadobutrol molecular formula C18H31GdN4O9, entitled 10- (2, the 3- dihydroxy -1- hydroxymethyls third of chemistry
Base)-Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands-Isosorbide-5-Nitrae, 7- triacetic acid Gd coordination compound, structure is as follows:
The product is granted in Switzerland for the first time in 2 months 1998, later successively Australia, Canada, European Union, the U.S. and
Other countries' listing.Currently, Gadovist has obtained global more than 100 a state approvals.The indication of U.S.'s listing is adult and youngster
Virgin (including newborn) blood-brain barrier (BBB) and/or central nervous system radiography, malignant galactophore disease radiography.Gadobutrol is Europe
One of 3 low-risk gadolinium class contrast agent that guide is recommended, and effect is non-bad on CNS radiography with contrast agent Gadoteridol, and is
Uniquely obtaining FDA approval can be used for neonatal gadolinium class contrast agent.
Since Gadobutrol is in diagnostic imaging, importance especially in MRI diagnosis has had more document to close it
It is studied at method.
Patent CN201280024781.7 cycleanine (Cyclen) and 4,4- dimethyl-
3,5,8- trioxa-l-phosphabicyclos [5.1.0] octane and lithium chloride react at a higher temperature, then under alkaline condition with monochloro second
Sour sodium is alkylated, and after then being post-processed under acid condition, is removed most of salt by the way that methanol is added, is added oxidation
Gadolinium adjusts pH to neutral or alkalescent with lithium hydroxide, carries out being recrystallized to give Gadobutrol in ethanol after concentration of reaction solution thick
Product, crude product through ion-exchanger cascade purify, active carbon processing, be sterile filtered, ethyl alcohol recrystallization step be finally prepared compared with
Pure Gadobutrol.
But according to inventor the study found that the route of above-mentioned patent there are multiple shortcomings: 1, the first step react cycleanine
Reaction site it is more, can generate polysubstituted by-product, especially 1,7- and Isosorbide-5-Nitrae-disubstitution product, reduce final production yield, together
When make F purification have larger challenge；2, higher using lithium salts price, it needs in a large amount of anionite removal finished product
Free lithium ion, and need to carry out quality inspection and control to the content of lithium ion, increase technology difficulty；3, crude product Gadobutrol is used
A large amount of ion exchange resin cascade purifications, consumptive material is more, and wherein acid ion exchangers can be deviate from from the ligand of target product
Gd reduces the total amount for the Gadobutrol being complexed, and reduces yield；4, a large amount of water are concentrated in Gadobutrol last handling process, energy consumption is big；
5, each intermediate is grease, lacks effective purifying post-processing step, lacks reasonable Quality Control point, the quality of finished product is complete
Post-processing dependent on final step purifies, and risk is big.
Therefore, with lower Material Cost and process costs, high-purity is prepared, the Gadobutrol bulk pharmaceutical chemicals of high yield are still urgently
Problem to be solved.
Summary of the invention
In view of the deficiencies of the prior art, the present invention intends to seek a kind of new Gadobutrol preparation method, lead to
The generation for reducing by-product in reaction process is crossed, intermediate purity is controlled, to reduce the purification load of final product, reduces and relies on most
The risk of failure of latter step purifying technique, reduces the dosage of resin.Finally obtain it is a kind of low cost, in high yield, be suitble to industry put
Big Gadobutrol production technology.
The method that the present invention prepares Gadobutrol, including the following steps:
Formulas I is alkylated to obtain formula J；
Wherein, R C1-C4Alkyl；The C1-C4Alkyl is preferably methyl, ethyl, propyl, isopropyl, normal-butyl or
Tert-butyl.
The method that the present invention prepares Gadobutrol further includes a step or a few steps in the following steps:
Formula A or its salt and N,N-dimethylformamide dimethylacetal or triethyl orthoformate or trimethyl orthoformate is anti-
It answers, formula G is made；
And/or
Formulas I is alkylated to obtain formula J；
And/or
Formula G and formula B occurs substitution reaction and formula H is made；
The method that the present invention prepares Gadobutrol, further includes the following steps:
Formula A or its salt and N,N-dimethylformamide dimethylacetal or triethyl orthoformate or trimethyl orthoformate is anti-
It answers, formula G is made；
Formula G and formula B occurs substitution reaction and formula H is made；
Formula H is deprotected to obtain Formulas I；
Formulas I is alkylated to obtain formula J；
J is deprotected to obtain formula E；
E and gadolinium complex reaction obtain formula F.
The method that the present invention prepares Gadobutrol further includes a step or a few steps in the following steps:
1) under inert gas shielding, by cycleanine (hereinafter referred to as formula A) or its salt and n,N-Dimethylformamide diformazan
Base acetal (hereinafter referred to as DMF-DMA) or the reaction of triethyl orthoformate or trimethyl orthoformate, are made Isosorbide-5-Nitrae, 7,10- tetra- azepines three
Ring [5.5.1.0] tridecane (hereinafter referred to as G) can be directly used for reacting in next step without purification；
2) under inert gas shielding, Isosorbide-5-Nitrae, 7,10- tetra- aza-tricycle [5.5.1.0] tridecanes (hereinafter referred to as G) and 4,4-
Dimethyl -3,5,8- trioxa-l-phosphabicyclo [5.1.0] octane (hereinafter referred to as B) occurs substitution reaction and 1- formoxyl -7- (6- hydroxyl is made
Base -2,2- dimethyl -1,3- cyclic heptane dioxide -5-)-Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands (hereinafter referred to as H), H tied again
It is brilliant；
3) formula H is deprotected under alkaline condition obtains 1- (6- hydroxyl -2,2- dimethyl -1,3- cyclic heptane dioxide -5-) -1,
4,7,10- tetra-
Azepine cyclododecane (hereinafter referred to as I)；
4) Formulas I be alkylated to obtain 1,4,7- tri- (tert-Butoxycarbonylmethyl) -10- (dimethyl -1 6- hydroxyl -2,2-,
3- dioxy cycloheptyl
Alkane -5-)-Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands (hereinafter referred to as J), J is through recrystallizing；
5) J is deprotected to obtain 1,4,7- tri- (carboxymethyl) -10- (6- hydroxyl -2,2- dimethyl -1,3- cyclic heptane dioxide -
5-) -1,4,7,10- four
Azepine cyclododecane (hereinafter referred to as E)；
6) E and gadolinium complex reaction, reaction solution obtain finished product gadolinium by nanofiltration equipment, recrystallization and ion exchange resin
Cloth
Alcohol F.
The present invention creatively uses the compound of formula G to substitute cycleanine in the prior art and carries out substitution reaction, keeps away
Exempt from cycleanine multiple reaction site to generate polysubstituted by-product and then continue to participate in subsequent reactions, influences asking for final product purity
Topic.Specifically, through subsequent reactions, can generate has through inventor the study found that the polysubstituted by-product of cycleanine is once generate
The polysubstituted by-product of essentially identical functional group and similar physicochemical properties with principal product, the polysubstituted by-product are difficult to pass through
Conventional post-processing approach (such as tune pH method, extraction, recrystallization method etc.) removes, it is therefore desirable to targetedly using special
Processing method, such as patent CN201280024781.7 using cation-exchanger adsorb.But inevitably, target product
Ion exchange abjection Gd, and this method higher cost can also occur in this purification process for Gadobutrol, be not appropriate for industry
Production.Therefore, method of the invention all has than the prior art apparent excellent in terms of production cost, yield and concise in technology
Gesture.
The method of the present invention is also avoided in the processing of intermediate and final product simultaneously using column chromatography and a large amount of inhomogeneities
The defect that the ion exchange resin of type is purified, purity with higher and yield are suitble to commercial quantities metaplasia to produce.
H and J has creatively been carried out recrystallization and has handled to have obtained the solid product of high-purity by the method for the present invention, is overcome
It must avoid in purification process and largely wash by the defect of the purification process such as column chromatography or ion exchange adsorption in the prior art
The consuming of de- agent, and the prior art still can only obtain grease after column chromatographs, it is clear that recrystallization method of the present invention obtained
The purity of solid is higher, is more advantageous to quality controllable in technique.Recrystallization method of the invention, on the one hand improves intermediate
Purity, optimize reaction, avoid influence of the excessive impurity to main reaction, on the other hand reasonably set in reaction step appropriate
Quality Control point is set, the total impurities of final step are reduced, reduces the dosage of resin.
The present invention also provides the methods of effective purifying final product Gadobutrol, including recrystallization and resins exchange.It ties again
Crystal bar part is simple, is easy to control, and needs the crude product for different phase to control different water cut with patent CN201280024781.7
Amount and harsh water content ranges are compared, and industrial repeatability, large batch of production are more suitable for；Purifying resin of the invention is only
A kind of weak-base ion-exchange resin is needed, the Gadobutrol of purity > 99.5% can be obtained, avoid patent
The defect that CN201280024781.7 uses acid cation exchange resin to generate simultaneously, also saves cost.Further, originally
Invention has used nanofiltration equipment in last handling process creativeness, has both removed a large amount of salt, has also achieved the purpose that condensed water,
The water for removing nearly 80% at room temperature greatly reduces energy consumption compared with the full technique by being concentrated, and also avoids removing water
Unnecessary impurity is generated in the process.
In above-mentioned preparation method, step 1) the cycleanine salt, wherein salt include but is not limited to hydrochloride, sulfate,
Hydrobromate, hydriodate etc..Reaction dissolvent includes but is not limited to hydrocarbon solvent, alcohols solvent, ether solvent, esters solvent,
Wherein " hydro carbons " is preferably with the hydrocarbon of 1-10 carbon atom comprising but alkyl halide hydro carbons and aromatic hydrocarbons are not limited to, including
But it is not limited to methylene chloride, chloroform (chloroform) and toluene." alcohols " is preferably with the alcohol of 1-10 carbon atom, packet
Include but be not limited to methanol, ethyl alcohol, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and the tert-butyl alcohol.It is described
" ethers " preferably with 2-6 carbon atom ether comprising chain ethers and ring-type ethers, be specifically including but not limited to ether,
Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, methyl phenyl ethers anisole and
Dimethoxy-ethane." esters " are preferably with the ester of 3-10 carbon atom comprising but it is not limited to ethyl acetate, acetic acid third
Ester, isopropyl acetate, isopropyl acetoacetic ester, dimethyl carbonate and butyl acetate.The reaction temperature of step 1) is 50-120 DEG C, preferably
60-100 DEG C, such as 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C, 95 DEG C, 100 DEG C.The cycleanine (formula A) and N, N-
The molar ratio of dimethylformamide dimethyl acetal or triethyl orthoformate or trimethyl orthoformate is 1:(1.0-1.5).
In above-mentioned preparation method, the reaction of step 2), the formula G and 4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo
The molar ratio of [5.1.0] octane is 1.0:(1.0-2.0)；The reaction temperature of step 2) be 50-180 DEG C, preferably 60-150 DEG C, example
Such as 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C, 95 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C, 140 DEG C.
Further, the method that step 2) recrystallizes H includes: that crude product H is added into recrystallization solvent, heating
It stirs to dissolve, gained clear solution (optionally solution can be filtered to obtain clear solution) is stood, slowly drop
Temperature obtains crystal H.Wherein, the recrystallization solvent be esters solvent -ol class solvent-water or esters solvent/alcohols solvent/
Ether solvent-water, the esters solvent include but is not limited to the ester with 3-10 carbon atom comprising but it is not limited to acetic acid second
Ester, propyl acetate, isopropyl acetate, methyl benzoate, gaultherolin, isopropyl acetoacetic ester, dimethyl carbonate or butyl acetate,
More preferably isopropyl acetate, ethyl acetate, methyl benzoate or gaultherolin；The alcohols solvent includes but is not limited to have
There is the alcohol of 1-10 carbon atom comprising but it is not limited to methanol, ethyl alcohol, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), 1- fourth
Alcohol, 2- butanol and the tert-butyl alcohol, preferably isopropanol, methanol, ethyl alcohol；The ether solvent includes but is not limited to former with 2-6 carbon
The ether of son comprising chain ethers and ring-type ethers comprising but it is not limited to ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), four
Hydrogen furans, 2- methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, methyl phenyl ethers anisole and dimethoxy-ethane.Of the invention some
In embodiment, the volume ratio of the esters solvent -ol class solvent-water is (1-200): (1-20): (1-20), preferably (10-
80):(1-10):(1-10)；In some embodiments of the invention, the recrystallization reagent is esters solvent/alcohols solvent/ether
When class solvent-water, the volume ratio of esters solvent or alcohols solvent or ether solvent and water is (1-200): (1-20), preferably
(10-80):(1-5).In some embodiments, the temperature of heating stirring be 30-100 DEG C, preferably 40-90 DEG C, for example, 45 DEG C,
50℃,55℃,60℃,65℃,70℃,75℃,80℃,85℃.The cooling rate of the slow cooling is 0.1-0.5 DEG C/minute
Clock, preferably 0.1-0.3 DEG C/min, more preferable 0.1 DEG C/min.In some embodiments, the temperature at the end of the cooling
For 0 DEG C-room temperature, such as 3 DEG C, 5 DEG C, 7 DEG C, 10 DEG C, 15 DEG C, 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C.In some embodiments
In, the w/v (mg/mL) of the formula H and solvent is 1:(0.2-50), preferably 1:(0.2-30).At of the invention one
In specific embodiment, with isopropyl acetate-isopropanol-water of volume ratio 20:1:1, the w/v of formula H and solvent is 1:10
Ratio to formula H recrystallize.In another specific embodiment of the invention, recrystallization solvent is the acetic acid that volume ratio is 40:1
Ethyl ester-aqueous solution.In another embodiment of the present invention, recrystallization solvent is the isopropyl acetate-that volume ratio is 50:1:1
Isopropanol-water solutions.It can be seen that by the method for the invention, the formula H of solid can be recrystallized to give, formula H's compared with the existing technology
Grease, the present invention has good improvement to the state of formula H, and has carried out effective purification operations, facilitate reaction metering and
The control of inventory, while also assuring the high yield of intermediate.
In above-mentioned preparation method, formula H is first dissolved in organic solvent by the deprotection reaction of step 3), then alkaline reagent is added dropwise,
Then reaction solution is concentrated after completion of the reaction for temperature reaction, adds water and organic solvent, is extracted, and merging concentration has
Machine mutually can be used to react in next step.Wherein, the alkaline reagent includes that ammonium hydroxide, sodium hydrate aqueous solution, calcium hydroxide are water-soluble
One of liquid, potassium hydroxide aqueous solution, triethylamine, pyridine, N-methylmorpholine, tetramethylethylenediamine are a variety of, preferably ammonium hydroxide,
One of sodium hydrate aqueous solution, potassium hydroxide aqueous solution, triethylamine, pyridine are a variety of；Wherein, the organic solvent is hydrocarbon
Class solvent, alcohols solvent, esters solvent, ether solvent, aromatic solvents, preferably methylene chloride, chloroform (chloroform), just oneself
Alkane, normal heptane and toluene, methanol, ethyl alcohol, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and tertiary fourth
Alcohol, ethyl acetate, ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, ring
Amyl methyl ether, methyl phenyl ethers anisole and dimethoxy-ethane, further preferably methanol, toluene, methylene chloride, ethyl acetate or methyl- tert
Butyl ether.The heating temperature of the reaction is 50-120 DEG C, preferably 60-100 DEG C, such as 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85
℃,90℃,95℃.The alkali of the formula H and basic solvent, molar ratio 1:(4-10).
Further, alkylating reagent used in step 4) is
Wherein, X is selected from halogen, TsO- and MsO-, and the halogen is chlorine, bromine or iodine, preferably bromine；R is selected from C1-C4Alkyl；
The C1-C4Alkyl is methyl, ethyl, propyl, isopropyl, normal-butyl or tert-butyl.The molar ratio of the I and alkylating reagent
For 1:(4-10), the alkylated reaction carries out in alkylated reaction solvent, for example, hydrocarbon solvent, amides it is molten etc. or it
Mixed solvent.It in one particular embodiment of the present invention, is solvent with DMF (n,N-Dimethylformamide) and toluene,
TBBA (bromo-acetic acid tert-butyl) is alkylating reagent, and aqueous sodium carbonate is added dropwise, and reaction terminates, and solid, that is, J is precipitated.In order to optimize
Technique, J is put into again after being recrystallized to react in next step, and the recrystallization method includes: to dissolve crude product J in good solvent,
It is formed clear solution (solution can be optionally filtered to obtain clear solution), is then added to the clear solution instead
In solvent, it is (preferably while slow to precipitate crystal or stand (such as placing at room temperature) for stirring under room temperature perhaps heating condition
Slowly solvent flashing) to precipitate crystal, described heat is heated to 30-100 DEG C, preferably 30-80 DEG C, and more preferable 35-65 DEG C,
Such as 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C.Wherein, the good solvent includes one or both of water and organic solvent group
At mixed solvent, the organic solvent includes alcohols, ketone, ethers, nitrile, such as N-Methyl pyrrolidone, ethyl alcohol, third
Ketone, acetonitrile, tetrahydrofuran, methylene chloride, methyl iso-butyl ketone (MIBK), ethyl acetate, 2- methyltetrahydrofuran, toluene etc..It is described anti-
Solvent includes inorganic solvent or organic solvent, and the inorganic solvent includes water, the organic solvent include alkanes, olefines,
Alkynes class, such as hexamethylene, n-hexane, normal heptane etc..Wherein, when the good solvent is the mixed solvent of water and organic solvent,
The volume ratio of organic solvent and water is (1-20): 1, preferably (1-10): 1, the volume ratio of good solvent and anti-solvent is 1:(4-
30), preferably 1:(4-10).The w/v (mg/mL) of the crude product J and good solvent is 1:(1-10), preferably 1:(1-
5).A specific embodiment according to the present invention, the J obtained after recrystallization are solid, purity > 99.5%.Purification effect is good, receives
Rate is higher.
The present invention is before step 4), and 4,4- dimethyl -3,5 of hold mode B, 8- trioxa-l-phosphabicyclo [5.1.0] are pungent always
The non-open loop of group that alkane is formed, compared with the group in the prior art with open loop, yield is higher, as described above, side of the present invention
Two step yields of the method from H to J up to 95%, much higher than be alkylated in the prior art one-step reaction only 80% yield, it is this
The remarkable result embodied on yield is very surprising.
Further, step 5) deprotection reagent used is selected from acid flux material, including trifluoroacetic acid, hydrochloric acid, sulfuric acid, neighbour
Phthalic acid, terephthalic acid (TPA), acetic acid, formic acid, propionic acid, butyric acid, preferably trifluoroacetic acid, acetic acid；The formula J and acid flux material
Molar ratio be 1:(30-80).A specific embodiment according to the present invention, step 4) use trifluoro using methylene chloride as solvent
Acetolysis ester bond and open loop, reaction can cast single step reaction after terminating concentration of reaction solution.
Further, the gadolinium of the step 6) complex reaction exists in the form of gadolinium salt or gadolinium oxide, and the gadolinium salt includes
But it is not limited to gadolinium chloride.It is preferred that the gadolinium of the complex reaction exists in the form of gadolinium oxide.The molar ratio of the formula E and gadolinium reagent is
1:(1-1.5)。
Step 6) the complex reaction makees solvent with water, at 10~15 DEG C, is warming up to after adjusting pH to 2-6 with alkaline reagent
85-95 DEG C, it is cooled to 15-30 DEG C after reaction and is post-processed.The alkaline reagent includes but is not limited to sodium hydroxide, hydrogen
Potassium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, lithium hydroxide.A specific embodiment according to the present invention, E with
The post-processing of gadolinium complex reaction includes: that reaction solution is purified by nanofiltration equipment, and solid then is precipitated through recrystallization, until recrystallization is solid
Then recrystallization solid is passed through weak-base ion-exchange resin after purification by conductivity < 20us/cm of body, concentration is tied again again
Crystalline substance obtains finished product Gadobutrol F.Finished product purity>99.9% obtained according to the method for the present invention, dissociate gadolinium<0.01%, clarification
Degree is qualified, the Gadobutrol F from J to high-purity, two step total recovery > 85%.
Wherein, the step 6) recrystallization operation includes: that crude product F is added into recrystallization reagent, and heating stirring makes it
Dissolution, gained clear solution (optionally solution can be filtered to obtain clear solution) is placed, and slow cooling obtains crystalline substance
Body F.It is described recrystallization reagent be selected from 1-10 carbon atom alcohol or ketone comprising but be not limited to methanol, ethyl alcohol, acetone,
Butanone, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and the tert-butyl alcohol, preferred alcohol, acetone or methanol.
In some embodiments, the heating temperature of the heating stirring is 30-80 DEG C, preferably 40-70 DEG C, such as 45 DEG C, 50 DEG C, 55
DEG C or 60 DEG C.In some embodiments for preparing crystal using slow cooling method, the cooling rate of the slow cooling is
0.1-0.5 DEG C/min, preferably 0.1-0.3 DEG C/min, more preferable 0.1 DEG C/min.In some embodiments, the cooling
At the end of temperature be -10 DEG C of room temperature, such as 3 DEG C, 5 DEG C, 7 DEG C, 10 DEG C, 20 DEG C or 30 DEG C.In some embodiments, described
The w/v (mg/mL) of crude product F and recrystallization reagent is 1:(8-25), preferably 1:(10-15).The weakbase ion is handed over
Changing resin includes containing alkalescent group, such as primary amine groups (also known as level-one amido)-NH2, secondary amine (secondary amine)-NHR or uncle
Amido (three-level amido)-NR2Resin.
The present invention still further provides the key intermediate of formula J for being used to prepare Gadobutrol a kind of, has following knot
Structure:
R=C1-C4 alkyl；The C1-C4 alkyl is preferably methyl, ethyl, propyl, isopropyl, normal-butyl or tert-butyl.
Preferably, R is identical C1-C4 alkyl simultaneously, such as R is simultaneously methyl, ethyl, propyl, isopropyl, normal-butyl or tertiary fourth
Base.
A specific embodiment according to the present invention prepares Gadobutrol using key intermediate J, and reactivity is more preferable, from J to
Two step yield > 85% of final product F, in conjunction with appropriate post-processing approach, purity > 99.9% of final product F.And through the present invention
Inventor the study found that formula J compound can by recrystallization purify, purity is suitable for up to 99.5% after purification
It is post-processed advantageously compared with other intermediates that the prior art uses for a qualifying point in synthesis process,
Yield, purity all significantly improve.
The present invention also provides purposes of the formula J compound in Gadobutrol preparation, can be used as the intermediate or ginseng of Gadobutrol
According to object；Preferably, the formula J compound can also be used in the analysis detection and impurity research of Gadobutrol.
Inert gas of the invention, which refers to, to be played isolation-protective effect to reaction system in the reaction, is not involved in instead
The gas answered, including but not limited to nitrogen, helium, argon gas etc., preferably nitrogen.
Nanofiltration of the present invention is a kind of pressure-driven membrane separating process between reverse osmosis between ultrafiltration, the nanofiltration
Device model: JM1812-1,4040 types and 8040 types, nanofiltration membrane model: PA-NF2-1812 and PA-NF-1812, NF-4040,
NF-8040。
The present invention comprehensively considers from many aspects such as synthetic route, qualifying point, purification process, yield, production costs,
Provide a kind of purity is high, high income, improved Gadobutrol preparation method at low cost, specifically, method of the invention with
The prior art is compared, and is at least had the advantage that
1, in synthetic route design aspect, substitution reaction is carried out with the formula G containing protecting group, avoids the production of polysubstituted by-product
It is raw, dopant species are reduced, the burden of final product removal and the polysubstituted impurity of quality monitoring is mitigated；It is protected always before alkylated reaction
4,4- dimethyl -3,5 is stayed, the group that 8- trioxa-l-phosphabicyclo [5.1.0] octane is formed is in closed loop states, avoids group pair after open loop
The influence of main reaction improves reactivity, increases yield；
2, entire synthetic route designs 3 qualifying points, H, J and final product F altogether, substantially carries out after every two-step reaction
Primary purifying, controls the purity of intermediate, reduces the type and total amount of impurity, avoid impacting reaction, also reduces and produces eventually
The purifying pressure of object F makes the purifying of F be not limited to harsh operating condition and excessive Purification Resin, reduces risk；
3, the method for effectively purifying H, J and final product F is provided, by simply recrystallizing/operating with other, makes each compound
Purity can respectively reach 99.0%, 99.5%, 99.9%, and solidification after the H of oily is purified is chromatographed without column；Every two step is received
Rate respectively reaches 98%, 95%, 95%, and total recovery is about 88%；It wherein purifies resin used in final product F and only needs weak base
Property ion exchange resin, avoid and the de- gadolinium of Gadobutrol ligand acted on using acid-exchange resin, and Purification Resin
Dosage be reduced to 5w/w, production cost is greatly saved；
4, the post-processing of Gadobutrol has used nanofiltration equipment, has both removed a large amount of salt, has also achieved the purpose that condensed water,
The water for removing nearly 80% at room temperature greatly reduces energy consumption.
Specific embodiment
The contents of the present invention are further described below by way of specific embodiment, but should not be construed as model of the invention
It encloses and is only limitted to example below, the features such as all methods disclosed in this specification, step, reagent, temperature, in addition to clearly contradicted
Or it is mutually exclusive except in the case of, can be combined or rationally replace in any way, these belong to the present invention and protect
Scope.
The preparation of 1 G of embodiment
6.50kg toluene is first added into reaction kettle, adds 1.50kg cycleanine (formula A), is eventually adding N, N- diformazan
Base formamide dimethylacetal 1.14kg after the reaction kettle nitrogen protection, is heated to 100 DEG C of reactions, after completion of the reaction, then
Concentration of reaction solution obtains grease G, does not need purification and is directly used in next step.
The preparation of 2 G of embodiment
176kg toluene is first added into reaction kettle, adds 40kg cycleanine (formula A), is eventually adding N, N- dimethyl
Formamide dimethylacetal 31kg after the reaction kettle nitrogen protection, is heated to 100 DEG C of reactions, after completion of the reaction, is then concentrated
Reaction solution obtains grease G, does not need purification and is directly used in next step.
The preparation of 3 H of embodiment
4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo is added into the reaction kettle equipped with the resulting 1.5kg G of embodiment 1
Reaction system is warming up to 120 DEG C, after having reacted by [5.1.0] octane 1.23kg, nitrogen protection, by reaction system Temperature fall
To room temperature, reaction solution is concentrated to get crude product H, isopropyl acetate-isopropanol-water solutions 3L weight of crude product H volume ratio 20:1:1
Crystallization, heating stirring temperature are 75 DEG C, are slowly dropped to room temperature, crystallization obtains solid H, yield 98%.
1HNMR(CDCl3) δ 1.29 (s, 3H), 1.31 (s, 3H), 2.20-2.87 (m, 17H), 3.12 (s, 1H), 3.37-
3.63 (m, 8H), 3.90 (s, 1H), 8.14 (s, 1H)
13CNMR(CDCl3)δ24.55(q),43.13(t),45.24(t),45.76(t),46.19(t),46.58(t),
46.98(t),47.52(t),49.61(t),56.93(t),62.77(t),64.50(t),68.74(d),100.88(s),
164.95(s)
Mass spectrum(EI):m/e 345[(M+H)+].
The preparation of 4 H of embodiment
It is double that 4,4- dimethyl -3,5,8- trioxa is added into the 300L reaction kettle equipped with the resulting 40kg G of embodiment 1
Reaction system is warming up to 120 DEG C, after having reacted by ring [5.1.0] octane 32kg, nitrogen protection, by reaction system Temperature fall
To room temperature, reaction solution is concentrated to get crude product H, isopropyl acetate-isopropanol-water solutions 390L of crude product H volume ratio 50:1:1
Recrystallization, heating stirring temperature are 75 DEG C, are slowly dropped to room temperature, crystallization obtains solid H, yield 95%.
The preparation of 5 H of embodiment
4,4- dimethyl -3,5,8- trioxa-l-phosphabicyclo is added into the reaction kettle equipped with the resulting 1.5kg G of embodiment 1
Reaction system is warming up to 90 DEG C, after having reacted, reaction system is naturally cooling to by [5.1.0] octane 1.23kg, nitrogen protection
Room temperature, reaction solution are concentrated to get crude product H, and crude product H is recrystallized with ethyl acetate-water 3L of volume ratio 40:1, heating stirring temperature
It is 40 DEG C, is slowly dropped to 0 DEG C, crystallization obtains solid H, yield 98%.
Through detecting, the data such as hydrogen spectrum, carbon spectrum and mass spectrum of products therefrom H and embodiment 2 are consistent, show to have obtained embodiment
Solid H described in 2.
The preparation of 6 I of embodiment
Methanol is added into reaction kettle, then 2.20kg H is added in reaction kettle, stirring and dissolving, is added dropwise NaOH (1kg)
Saturated aqueous solution, drop finishes, and system is warming up to 70 DEG C, and after completion of the reaction, concentration is added water and toluene into concentrate, extraction,
Merge organic phase, be concentrated to get I, does not need purifying and be directly used in next step.
The preparation of 7 I of embodiment
Methanol is added into reaction kettle, then 55kg H is added in reaction kettle, stirring and dissolving, NaOH (48kg) is added dropwise
Saturated aqueous solution, drop finish, and system is warming up to 70 DEG C, and after completion of the reaction, water and toluene are added into concentrate for concentration, extract, and close
And organic phase, it is concentrated to get I, purifying is not needed and is directly used in next step.
The preparation of 8 I of embodiment
Ethyl acetate is added into reaction kettle, then 2.20kg H is added in reaction kettle, stirring and dissolving, triethylamine is added dropwise
(2.58kg), drop finish, and system is warming up to 100 DEG C, and after completion of the reaction, water and toluene are added into concentrate for concentration, extract, and close
And organic phase, it is concentrated to get I, purifying is not needed and is directly used in next step.
The preparation of 9 J of embodiment
To being added in reaction kettle after being dissolved equipped with the resulting 1.6kg I of embodiment 6 with DMF (7.70kg), then to reaction
2L toluene is added in kettle, reaction system is cooled to 5-15 DEG C, is added dropwise bromo-acetic acid tert-butyl (3.99kg), system is in 5-15 DEG C of condition
Under after completion of the reaction, be added aqueous sodium carbonate, reaction be gradually increased to room temperature, a large amount of solids are precipitated, solid is collected by filtration, obtain
Crude product J is added in 5L alcohol-water (10:1), then gained mixed solution is added in 20L water, is heated to 60 DEG C by crude product J
Then stirring and dissolving is slowly dropped to room temperature recrystallization, obtains solid J, purity > 99.5%, two step (H → I → J) yield 95%.
1HNMR(CDCl3)δ1.09(s,3H),1.10(s,3H),1.23(s,9H),1.25(s,18H),2.24-2.70(m,
17H),2.96-3.47(m,11H),4.99(s,1H)；
13CNMR(CDCl3)δ24.48(q),24.66(q),28.04(q),48.26(t),51.60(t),51.72(t),
52.66(t),55.26(t),55.80(t),55.88(t),63.26(d),64.88(t),69.27(d),100.61(s),
170.34(s),170.65(s)
Mass spectrum(EI):m/e 659[(M+H)+].
The preparation of 10 J of embodiment
To being added in reaction kettle after being dissolved equipped with the resulting 1.6kg I of embodiment 6 with DMF (7.70kg), then to reaction
2L toluene is added in kettle, reaction system is cooled to 5-15 DEG C, is added dropwise bromo-acetic acid tert-butyl (3.99kg), system is in 5-15 DEG C of condition
Under after completion of the reaction, be added aqueous sodium carbonate, reaction be gradually increased to room temperature, a large amount of solids are precipitated, solid is collected by filtration, obtain
Crude product J is added in 5L acetonitrile-water (10:1), then gained mixed solution is added in 20L water, is heated to 40 DEG C by crude product J
Then stirring and dissolving is slowly dropped to room temperature recrystallization, obtains solid J, purity > 99.5%, two step yield 95%.
Through detecting, the data such as hydrogen spectrum, carbon spectrum and mass spectrum of products therefrom J and embodiment 9 are consistent, show to have obtained embodiment
Product described in 9.
The preparation of 11 J of embodiment
To being added in reaction kettle after being dissolved equipped with the resulting 43kg I of embodiment 6 with DMF (202kg), then to reaction kettle
Middle addition 45L toluene, reaction system are cooled to 5-15 DEG C, are added dropwise bromo-acetic acid tert-butyl (106kg), system is under the conditions of 5-15 DEG C
After completion of the reaction, aqueous sodium carbonate is added, reaction is gradually increased to room temperature, a large amount of solids are precipitated, solid is collected by filtration, and obtains thick
Crude product J is added in 150L acetonitrile-water (10:1), then gained mixed solution is added in 730L water, is heated to 40 by product J
Then DEG C stirring and dissolving is slowly dropped to room temperature recrystallization, obtains solid J, purity > 99.5%, two step yield 95%.
Through detecting, the data such as hydrogen spectrum, carbon spectrum and mass spectrum of products therefrom J and embodiment 9 are consistent, show to have obtained embodiment
Product described in 9.
The preparation of 12 E of embodiment
9.94kg methylene chloride is added in reaction kettle, 3kg J is added to reaction kettle, reaction system is cooled to 5-10
DEG C, trifluoroacetic acid 34.65kg is added dropwise, system is stirred to react under the conditions of 20-25 DEG C, after completion of the reaction, and concentration of reaction solution, concentration
After obtain product E, be directly used in next step.
The preparation of 13 E of embodiment
230kg methylene chloride is added in reaction kettle, 70kg J is added to reaction kettle, reaction system is cooled to 5-10
DEG C, trifluoroacetic acid 710kg is added dropwise, system is stirred to react under the conditions of 20-25 DEG C, after completion of the reaction, concentration of reaction solution, after concentration
Product E is obtained, is directly used in next step.
The preparation of 14 E of embodiment
74kg concentrated hydrochloric acid is added in reaction kettle, 63kg J is added to reaction kettle, system is stirred under the conditions of 40-60 DEG C
Reaction is mixed, after completion of the reaction, concentration of reaction solution obtains product E after concentration, is directly used in next step.
The preparation of 15 final product Gadobutrol F of embodiment
24kg water is added to embodiment 12 is resulting, and in 0.88kg formula E compound, reaction system is cooled to 10-15 DEG C,
PH to 3~4 is adjusted with sodium hydroxide.0.708kg gadolinium oxide is added, is heated to 85-95 DEG C, reaction solution cools to 15-30 DEG C.
Cooling reaction solution is crossed into 0.45um filter membrane, nanofiltration is crossed, 60-70 DEG C of temperature control, 22kg ethyl alcohol, Yu great is added thereto
It is reacted in 75 DEG C, after completion of the reaction, a large amount of solids is precipitated, filtered, be dried to obtain crude product F (2.0kg), resulting crude product F is added
Enter in 20L ethyl alcohol, is heated to 40 DEG C of stirring and dissolvings, slow cooling to -10 DEG C of crystallizations, until conductivity < 20us/cm of formula F.
F after recrystallization is re-dissolved in 5L water, the weak-base ion-exchange resin of 5 times of quality is added, is stirred to react
After, it is filtered to remove resin, is concentrated, second alcohol and water is recrystallized to give solid, dry, obtain 1.2kg product F, purity >
99.9%, dissociate gadolinium < 0.01%, and the clarity for being detected product F is qualified, two step total recoverys 95%.
Mass spectrum(EI):m/e 605[(M+H)+].
The preparation of 16 final product Gadobutrol F of embodiment
500kg water is added in the resulting 48kg formula E compound of embodiment 13, reaction system is cooled to 10-15 DEG C, uses
Sodium hydroxide adjusts pH to 3~4.38.6kg gadolinium oxide is added, is heated to 85-95 DEG C, reaction solution cools to 15-30 DEG C.
Cooling reaction solution is crossed into 0.45um filter membrane, nanofiltration is crossed, 60-70 DEG C of temperature control, 700kg ethyl alcohol is added thereto, in
It is reacted greater than 75 DEG C, after completion of the reaction, a large amount of solids is precipitated, filtered, be dried to obtain crude product F (70kg), resulting crude product F is added
Enter in 840L ethyl alcohol and 90L water, is heated to 40 DEG C of stirring and dissolvings, slow cooling to 20 DEG C of crystallizations, until conductivity < 20us/ of formula F
cm。
F after recrystallization is re-dissolved in water, the weak-base ion-exchange resin of 5 times of quality is added, has been stirred to react
Bi Hou is filtered to remove resin, and concentration, second alcohol and water is recrystallized to give solid, dry, obtains 59kg product F, purity > 99.9%,
Free gadolinium < 0.01%, the clarity for being detected product F is qualified, two step total recoverys 92%.
The preparation of 17 final product Gadobutrol F of embodiment
400kg purified water is added in 1500L reaction kettle, reaction kettle, six chloride hydrates are added in acquired solution in embodiment 14
Gadolinium 36kg is added at one time, and is heated to 80-90 DEG C, adjusts pH to 5~6 with 40% sodium hydroxide, then adjust pH to 7~8, instead
Cooling after having answered, crosses 0.45um precision filtration membranes, and filtered fluid crosses nanofiltration, and crude product is by ethanol/water (volume ratio 15:1) weight after nanofiltration
Crystallization, until conductivity < 20us/cm of formula F.
F after recrystallization is re-dissolved in water, the weak-base ion-exchange resin of 5 times of quality is added, has been stirred to react
Bi Hou is filtered to remove resin, and concentration, second alcohol and water is recrystallized to give solid, dry, obtains 37kg product F, purity > 99.9%,
Free gadolinium < 0.01%, the clarity for being detected product F is qualified, two step total recoverys 90%.
Claims (14)
1. a kind of method for preparing Gadobutrol, comprising steps of
Formulas I is alkylated to obtain formula J；
Wherein, R C1-C4Alkyl；The C1-C4Alkyl is preferably methyl, ethyl, propyl, isopropyl, normal-butyl or tert-butyl.
2. the method according to claim 1 for preparing Gadobutrol, including the following steps:
Formula A or its salt are reacted with n,N-Dimethylformamide dimethylacetal or triethyl orthoformate or trimethyl orthoformate,
Formula G is made；
And/or
Formulas I is alkylated to obtain formula J；
And/or
Formula G and formula B occurs substitution reaction and formula H is made；
3. the method according to claim 1 or 2 for preparing Gadobutrol, including the following steps:
Formula A or its salt are reacted with n,N-Dimethylformamide dimethylacetal or triethyl orthoformate or trimethyl orthoformate,
Formula G is made；
Formula G and formula B occurs substitution reaction and formula H is made；
Formula H is deprotected to obtain Formulas I；
Formulas I is alkylated to obtain formula J；
J is deprotected to obtain formula E；
E and gadolinium complex reaction obtain formula F
4. the method according to claim 1 for preparing Gadobutrol, include the following steps in a step or a few steps:
1) under inert gas protection, by the cycleanine of formula A or its salt and n,N-Dimethylformamide dimethylacetal or original
Formic acid triethyl or trimethyl orthoformate reaction, are made formula G；
2) under inert gas shielding, formula G and formula B occur substitution reaction and formula H are made, and formula H is through recrystallizing；
3) formula H is deprotected obtains Formulas I under alkaline condition；
4) Formulas I is alkylated to obtain formula J, and formula J is through recrystallizing；
5) formula J is deprotected to obtain formula E；
6) formula E and gadolinium complex reaction, reaction solution obtain Gadobutrol formula F by nanofiltration equipment, recrystallization and ion exchange resin
5. preparing the method for Gadobutrol according to claim 2~4 any one, which is characterized in that the salt of A is hydrochloric acid
Salt, sulfate, hydrobromate or hydriodate；A prepare G the step of, reaction dissolvent be selected from hydrocarbon solvent, alcohols solvent,
Ether solvent and esters solvent, wherein the hydrocarbon solvent is selected from the hydrocarbon with 1-10 carbon atom；The alcohols solvent is selected from
The alcohol of 1-10 carbon atom；The ether solvent is selected from the ether with 2-6 carbon atom；The esters solvent, which is selected from, has 3-10
The ester of a carbon atom；The reaction temperature of the step is 50-120 DEG C；A or its salt and N,N-dimethylformamide dimethylacetal or original
The reaction molar ratio of formic acid triethyl or trimethyl orthoformate is 1:(1.0-1.5).
6. preparing the method for Gadobutrol according to claim 2~4 any one, which is characterized in that G prepares the step of H,
The molar ratio of G and B is 1.0:(1.0-2.0)；The step reaction temperature is 50-180 DEG C；The method that H is recrystallized include: by
Crude product H is added into recrystallization solvent, and heating stirring makes it dissolve, slow cooling, obtains crystal H；The recrystallization solvent is
Esters solvent -ol class solvent-water or esters solvent or alcohols solvent or ether solvent-water, the esters solvent, which is selected from, to be had
The ester of 3-10 carbon atom；The alcohols solvent is selected from the alcohol with 1-10 carbon atom；When recrystallization solvent is esters solvent-
When alcohols solvent-water, the volume ratio of the esters solvent -ol class solvent-water is (1-200): (1-20): (1-20)；When tying again
When brilliant reagent is esters solvent or alcohols solvent or ether solvent-water, the esters solvent or alcohols solvent or ether solvent with
The volume ratio of water is (1-200): (1-20)；The w/v of the crude product H and recrystallization solvent is 1:(0.2-50).
7. the method according to claim 3 or 4 for preparing Gadobutrol, which is characterized in that H prepares the step of I, and deprotection is anti-
H first should be dissolved in organic solvent, then alkaline reagent is added dropwise, reaction solution is concentrated after completion of the reaction, adds by then temperature reaction
Water and organic solvent, are extracted, and merging concentration organic phase can be used to react in next step；It is preferred that the alkaline reagent is ammonia
Water, sodium hydrate aqueous solution, calcium hydroxide aqueous solution, potassium hydroxide aqueous solution, triethylamine, pyridine, N-methylmorpholine and tetramethyl
One of base ethylenediamine is a variety of；The organic solvent is hydrocarbon solvent, alcohols solvent, esters solvent, ether solvent or virtue
Fragrant class solvent；The heating temperature of the temperature reaction is 50-120 DEG C；The molar ratio of the alkali of H and alkaline reagent is 1:(4-10).
8. the method according to any one of claims 1-4 for preparing Gadobutrol, which is characterized in that I prepares the step of J,
Alkylating reagent used is
Wherein, X is selected from halogen, TsO- and MsO-, and the halogen is chlorine, bromine or iodine；The I and alkylating reagent
Molar ratio be 1:(4-10)；Method by crude product J recrystallization purifying includes: to dissolve crude product J in good solvent, forms clarification
Solution adds to the clear solution in anti-solvent, and it is brilliant to precipitate crystal or stand precipitation for stirring under room temperature or heating condition
Body；Wherein, the good solvent is the mixed solvent of one or both of water and organic solvent composition, and the organic solvent is selected from
Alcohols, ketone, ethers and nitrile solvents；When the good solvent is the mixed solvent of water and organic solvent, organic solvent and water
Volume ratio be (1-20): 1；The volume ratio of good solvent and anti-solvent is 1:(4-30)；The w/v of crude product J and good solvent
For 1:(1-10).
9. the method according to claim 3 or 4 for preparing Gadobutrol, which is characterized in that J prepares the step of E, and deprotection is anti-
Answering reagent used is acid flux material, and the acid flux material is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, phthalic acid, terephthaldehyde
At least one of acid, acetic acid, formic acid, propionic acid and butyric acid；The molar ratio of J and acid flux material is 1:(30-80).
10. the method according to claim 3 or 4 for preparing Gadobutrol, which is characterized in that E prepares the step of F, described
Gadolinium exists in the form of gadolinium salt or gadolinium oxide, and the gadolinium salt includes gadolinium chloride, and the preferably described gadolinium exists in the form of gadolinium oxide；E with
The molar ratio of the reagent containing gadolinium is 1:(1-1.5).
11. the method according to claim 3 or 4 for preparing Gadobutrol, which is characterized in that E prepares the step of F, and complexing is anti-
Solvent is made using water, at 10~15 DEG C, 85-95 DEG C is warming up to after adjusting pH to 2-6 with alkaline reagent, is cooled to after reaction
The concentration of nanofiltration equipment is passed sequentially through after 15-30 DEG C, solid is precipitated in recrystallization, then conductivity < 20us/cm of obtained solid will
It recrystallizes solid and passes through weak-base ion-exchange resin after purification, concentration recrystallizes again, obtains finished product Gadobutrol F.
12. the method according to claim 11 for preparing Gadobutrol, which is characterized in that the operation of F recrystallization includes: will be thick
Product F is added into recrystallization reagent, and heating stirring makes it dissolve, and gained clear solution is placed, slow cooling, obtains crystal F；
The recrystallization reagent is selected from alcohol or ketone with 1-10 carbon atom；The heating temperature of the heating stirring is 30-80 DEG C；Institute
The cooling rate for stating slow cooling is 0.1-0.5 DEG C/min；The w/v of the crude product F and recrystallization reagent is 1:(8-
25)。
13. a kind of compound of formula J, structure are as follows:
Wherein, R is the alkyl of C1-C4, preferably methyl, ethyl, propyl, isopropyl, normal-butyl or tert-butyl.
14. a kind of purposes of the formula J compound described in claim 13 in Gadobutrol preparation, it is preferred that the formula J compound
It can be used as the intermediate or object of reference of Gadobutrol；Preferably, the formula J compound can also be used in the analysis detection of Gadobutrol and miscellaneous
Matter research.
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| CN114105897A (en) * | 2021-07-29 | 2022-03-01 | 安徽普利药业有限公司 | Preparation method of gadoteridol |
| CN113880850A (en) * | 2021-10-18 | 2022-01-04 | 苏州百灵威超精细材料有限公司 | Gadobutrol intermediate, preparation method and application in gadobutrol preparation |
| CN114685390A (en) * | 2022-04-01 | 2022-07-01 | 苏州美诺医药科技有限公司 | Preparation method of gadobutrol derivative |
| CN114685391A (en) * | 2022-04-01 | 2022-07-01 | 苏州美诺医药科技有限公司 | Preparation method of tetraazacyclododecane derivative |
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