CN106967083A - The process of preparing of Gadobutrol epoxy side chain intermediate - Google Patents
The process of preparing of Gadobutrol epoxy side chain intermediate Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The invention discloses one kind 4,4 dimethyl 3,5,8 trioxa-l-phosphabicyclos [5,1,0] octane, that is the process of preparing of Gadobutrol epoxy side chain intermediate, process of preparing of the present invention optimizes reaction condition by adjusting charged material weight ratio, improves post processing and purification process, obtained Gadobutrol epoxy side chain intermediate product impurity content is low, the quality of intermediate product is substantially increased while yield is improved, so as to improve the difficulty of technology controlling and process during Gadobutrol production of raw medicine, the quality and qualification rate of Gadobutrol bulk drug is improved；Each step operation method of this preparation technology is simple, and solvent and process conditions are easy safely, realizes environment-friendly and green production, has broad application prospects.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical field, more particularly, it is related in a kind of Gadobutrol epoxy side chain
The synthetic method of mesosome.
Background technology
Magnetic resonance imaging (MRI) diagnostic techniques is the technology for utilizing the radio-frequency radiation reconstruction image in magnetic field, and it is showing
It is better than X-ray in terms of anatomical structure and soft tissue lesionses.However, at the initial stage eighties, MRI in tissues observed configuration aspects simultaneously
Without very high specificity.Mr contrast agent be it is a kind of can influence the compound in its surrounding tissue relaxation time, due to not
Different signal intensities can be produced in same tissue, it is hereby achieved that accurate image.
The central atom or ion outer layer of paramagnetic ion have unpaired electronics, make it to turn into suitable magnetic resonance pair
Compare agent.The outer layer of gadolinium (Gd) has 7 unpaired electronics, so being a kind of strong paramagnetic ion.The gadolinium of non-composite state from
Son is toxic, but with the toxic action of gadolinium can be almost completely eliminated after avirulent organic sequestering agent formation compound to it
Paramagnetic contribution has not significant impact.The various chelating agents that can be injected intravenously of gadolinium have become magnetic resonance imaging (MRI) technology
An indispensable part.
Gadobutrol parenteral solution (Gadavist) is the non-ionic contrast medium based on gadolinium, can be injected intravenously and be used for
The magnetic resonance imaging imaging inspection such as brain, spinal cord, liver.FDA ratifies its listing in March, 2011, for central nervous system
The magnetic resonance imaging (MRI) of patient, it is possible to provide the Contrast enhanced image of central nervous system, to help to detect and visualize destruction
The lesion and central nervous system of barrier cell abnormal blood supply and circulation.
Entitled 10- [(1SR, 2RS) -2,3- dihydroxy -1- (methylol) the propyl group]-Isosorbide-5-Nitrae of Gadobutrol bulk drug chemistry, 7,
10- tetraazacyclododecanands-Isosorbide-5-Nitrae, 7- triacetic acid Gd coordination compounds, structural formula is shown below：
As diagnostic imaging agent, particularly MRI diagnosticums, Gadobutrol is needed higher pure than other common drugs with medicine
Degree, therefore, higher quality standard is proposed to Gadobutrol, and the synthetic method to Gadobutrol is improving purity, improves yield, control
The higher requirement proposed in terms of single miscellaneous content, the need for meet as injection diagnosticum.In the system of existing Gadobutrol
In standby synthetic method, the optimization and improvement of method have had part research report.However, the characteristics of due to Gadobutrol structure, making
The quality of the Gadobutrol obtained with existing preparation method, which is further improved, has reached bottleneck, improves the purity tool of Gadobutrol
There is significant limitation.
The epoxy side chain intermediate of Gadobutrol be Gadobutrol preparation method in key intermediate, entitled 4, the 4- diformazans of chemistry
Base -3,5,8- trioxa-l-phosphabicyclos [5,1,0] octane, the purity and quality extreme influence of epoxy side chain intermediate Gadobutrol most
Finished product quality.In current existing preparation method, or use the concentrated sulfuric acid as catalyst, can not be realized in post-processing stages
Green non-pollution promotes mutual benefit, or the Shortcomings in terms of yield, product purity, or in reduction production cost, Yi Jike
Shortcomings are gone back in terms of green industry production.Therefore, to the process of preparing for the epoxy side chain intermediate for developing Gadobutrol, especially
It is can to carry out workshop amplification and realize that the process for producing method of environment protection requirement has demand.
The content of the invention
High it is an object of the invention to provide a kind of yield in order to solve problems of the prior art, product purity is high,
Impurity is few, and reaction time is short, without using strong acid, easy to operate, steady quality, is adapted to the Gadobutrol epoxy of industrial amplification production
The process of preparing of side chain intermediate.
An aspect of of the present present invention provides the process of preparing of Gadobutrol epoxy side chain intermediate (formula A),
The process of preparing comprises the following steps：
Step 1, compound A-1 and A-2 be subjected to ring-closure reaction in the presence of a catalyst, obtain compound A-3；
Step 2, compound A-3 reacted in the presence of pH buffer reagents, alkali, hydrogen peroxide and mixed solvent, it is raw
Into Gadobutrol epoxy side chain midbody compound (formula A).
Preparation technology route is as follows：
According to the process of preparing of Gadobutrol epoxy side chain intermediate of the present invention, in step 1, the catalyst is pair
Toluenesulfonic acid, p-methyl benzenesulfonic acid hydrate；Preferably p-methyl benzenesulfonic acid monohydrate.
Connect the process of preparing of intermediate, in step 1, A-1 and A-2 weight according to Gadobutrol epoxy side of the present invention
Than (gram:Gram) it is 1:1.5~1:1.9, preferably 1:1.7~1:1.8, more preferably 1:1.77.
Connect the process of preparing of intermediate, in step 1, the addition of catalyst according to Gadobutrol epoxy side of the present invention
For the 0.2%~0.3% of A-1 weight (gram), preferably 0.22%.
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, in step 1, reaction temperature be 70~
90 DEG C, the reaction time is 2~3 hours；Reaction temperature is preferably 80 DEG C.
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, in step 1, in reaction time 2-3
By-product methanol is steamed in hour simultaneously, the methanol amount of steaming and A-1 weight ratio (gram:Gram) it is 0.71:1~0.73:1.
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, in step 1, compound A-3 is used
Distillation mode is purified, and can be air-distillation or vacuum distillation.
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, in step 1, compound A-3's is pure
Spend for more than 96%.
According to some of the preferred embodiment of the invention, step 1 embodiment is as follows：Compound A-1 and A-2 is to toluene
In the presence of sulfonic acid monohydrate, reaction temperature is reaction 2~3 hours at 70~90 DEG C, within 2~3 hours reaction time simultaneously
Steam by-product methanol, the methanol amount of steaming and A-1 weight ratio (gram:Gram) it is 0.71:1~0.73:1；Reaction solution removes excessive
A-2 after again vacuum distillation obtain target compound A-3；
Wherein, A-1 and A-2 charged material weight ratio (gram:Gram) it is 1:1.77, the addition of p-methyl benzenesulfonic acid monohydrate is
The 0.22% of A-1 weight (gram).
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, in step 2, pH buffer reagents are phosphorus
Hydrochlorate, preferably phosphoric acid disodium hydrogen；Alkali is inorganic base, preferably sodium hydroxide；Hydrogen peroxide content is 27%~30%；Mixed solvent
For the mixed solvent of methanol, acetonitrile and water.
Connect the process of preparing of intermediate according to Gadobutrol epoxy side of the present invention, step 2 reaction is divided into three phases：Change
Compound A-3 feeding stages, oxidation reaction stage, post processing purification phase.
Connect the compound A-3 in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention to feed intake rank
Section includes the operation that compound A-3, pH buffer reagent and mixed solvent feed intake and heated up.
Connect the compound A-3 in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention to feed intake rank
Duan Zhong, compound A-3 and pH buffer reagents weight ratio (gram:Gram) it is 120:1~140:1, preferably 126:1~139:1；Mixing
In solvent methanol, acetonitrile and water weight ratio (gram:Gram:Gram) it is 1:(1.0~1.3)：(1.1~1.3), preferably 1：(1.0~
1.2)：(1.22~1.3)；More preferably 1:1.2:1.26、1:1.17:1.22 or 1:1.0:1.3；Compound A-3 is molten with mixing
Agent total amount weight ratio (gram:Gram) it is 1:2~1:4；Preferably 1:2~1:3, more preferably 1:2.7~1:3；Enter after heating
The subsequent oxidation stage.
Connect the oxidation reaction stage bag in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention
Include feeding intake and warming temperature for hydrogen peroxide and alkali.
Connected according to Gadobutrol epoxy side of the present invention in the oxidation reaction stage in the process of preparing of intermediate, step 2,
The inventory of hydrogen peroxide and compound A-3 weight ratio (gram:Gram) it is 1.1:1~1.2:1, preferably 1.16:1~1.18:1；
Alkali feeds intake to be formulated as the 1M aqueous solution, 1M alkali inventory and compound A-3 weight ratio (gram:Gram) it is 0.4:1~
0.6:1, preferably 0.47:1~0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 0.5~2 hour, preferably
1~2 hour；The duration that feeds intake for the aqueous alkali that concentration is 1M is 3~8 hours, preferably 5~6 hours；It is warming up to 60~80
DEG C, it is 6~9 hours, preferably 8~9 hours to continue soaking time；It is 7~9.5 feeding intake with heating and heat preservation elementary reaction liquid pH.
Connect the post processing purification phase in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention
Including following operation：Add saturated sodium-chloride water solution and dichloromethane is post-processed；Organic phase is dried, and concentration removes solvent
Obtain target compound A.
Connect the post processing purification phase in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention
In, the consumption of saturated sodium-chloride water solution and compound A-3 weight ratio (gram:Gram) it is 1.5:1~1.6:1；Dichloromethane
Consumption and compound A-3 weight ratio (gram:Gram) it is 2.7:1~3.5:1.
Connect the post processing purification phase in the process of preparing of intermediate, step 2 according to Gadobutrol epoxy side of the present invention
In, compound A is purified using vacuum distillation mode.
Connect the process of preparing of intermediate, in step 2, compound A purity according to Gadobutrol epoxy side of the present invention
For more than 99.6%.
Connect the process of preparing of intermediate, in step 2, compound A purity according to Gadobutrol epoxy side of the present invention
For more than 99.9%.
According to some of the preferred embodiment of the invention, step 2 embodiment is as follows：
First stage, compound A-3, sodium dihydrogen phosphate feed intake with the mixed solvent comprising methanol, acetonitrile and water and mixed, instead
Liquid is answered to enter next stage after heating up；Compound A-3 and sodium dihydrogen phosphate weight ratio (gram:Gram) it is 126:1~139:1；It is mixed
In bonding solvent methanol, acetonitrile and water weight ratio (gram:Gram:Gram) it is 1：(1.0~1.2)：(1.22~1.3), preferably 1:
1.2:1.26、1:1.17:1.22 or 1:1.0:1.3；Compound A-3 and mixed solvent total amount weight ratio (gram:Gram) it is 1:2.7
~1:3；
Obtain carrying out feeding intake for hydrogen peroxide and sodium hydrate aqueous solution in reaction solution in the first stage, then reaction solution continues
It is warming up to 60~80 DEG C and is kept for 6~9 hours；The inventory of hydrogen peroxide and compound A-3 weight ratio (gram:Gram) it is 1.16:1
~1.18:1；Sodium hydroxide feeds intake to be formulated as the 1M aqueous solution, 1M sodium hydroxide inventory and compound A-3 weight
Than (gram:Gram) it is 0.47:1~0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 1~2 hour；Concentration is
The duration that feeds intake of 1M sodium hydrate aqueous solution is 5~6 hour；Feed intake with heating and heat preservation elementary reaction liquid pH be 7~
9.5；
The reaction solution that above-mentioned second stage is obtained adds saturated sodium-chloride water solution and dichloromethane is post-processed；Have
Machine is mutually dried, and concentration removes solvent and obtains target compound A.The consumption of saturated sodium-chloride water solution and compound A-3 weight ratio
(gram:Gram) it is 1.5:1~1.6:1；The consumption of dichloromethane and compound A-3 weight ratio (gram:Gram) it is 2.7:1~3.5:1；
Compound A is purified using vacuum distillation mode.
Technical parameter feature in present invention process made above can be in any combination.
The process of preparing that the Gadobutrol epoxy side of the present invention connects intermediate is adapted to industry's enlarging production, and production scale is
Kilogram or tonne or tonne more than.
In aforesaid operations, post processing include but is not limited to stirring, the transfer of liquid or solid, washing, alkali cleaning, pickling,
The operation such as filtering, ultrafiltration, loop ultrafiltration, dilution, concentration, drying, lyophilized, or stirring, the transfer of liquid or solid, water
Wash, alkali cleaning, pickling, filtering, ultrafiltration, loop ultrafiltration, dilution, concentration, drying, one or more of groups in the operation such as lyophilized
Close.
In the synthesis field of medicine intermediate organic compound molecule, the purity of midbody compound and wherein maximum list
Miscellaneous content all strong influences the quality of final medical product.Because the reaction of chemical synthesis has reaction site not single
One, the reaction of impurity carry out simultaneously and it is inevitable the characteristics of.Under normal circumstances, reacted by optimum synthesis method and optimization
Condition, medical product compound on the basis of certain purity is reached, then improve its purity to the higher stage be extremely difficult
's.On the other hand, human body or the living individual of other animals are applied to as treating disease, in order to reduce medical product
The middle issuable toxic side effect of impurity, medical product has high requirement in terms of purity and content.So, it can expire
The demand of sufficient industry's enlarging production, can improve medical product purity, reduce maximum single miscellaneous content, and not reduce yield again
On the basis of, the process for producing of different medical products is improved it is not regular follow, also without ready-made warp
Testing and enlightening to use for reference.
Specific to the present invention, Gadobutrol epoxy side connects midbody compound A purity and quality to finished product Gadobutrol matter
Amount influence is larger, and influence of its purity to the purity of end-product Gadobutrol is further amplified in subsequent preparation process.Therefore, change
Compound A as Gadobutrol key intermediate, it is necessary to carry out stricter quality control.
Compared with prior art, Gadobutrol epoxy side of the invention connects the process of preparing of intermediate with following beneficial
Effect：
The Gadobutrol epoxy side of the present invention connects the process of preparing of intermediate in step 1, and Optimal improvements catalyst makes
With without using strong reagents, not only reducing the equipment anticorrosion grade and process equipment cost in production technology, and safety collar
Protect, reduce the potential threat grade endangered production line employee's life；
The Gadobutrol epoxy side of the present invention connects the process of preparing of intermediate in step 1, optimizes ingredient proportion, reduces
The inventory of material A -2, greatly reduces the growing amount of by-product carbinol, so that follow-up methanol is steamed using shorter
Time, the cycle of whole preparation technology flow is shortened.So as to reduce Gadobutrol epoxy side connect intermediate production in material
Cost, time cost and process cycle cost；
Gadobutrol epoxy side prepared by the preparation technology that the Gadobutrol epoxy side of the present invention connects intermediate connects intermediate compound
Impurity is few in thing A products, and especially maximum single miscellaneous content is less than 0.1%, substantially increases intermediate product purity and product matter
Amount；The Gadobutrol epoxy side obtained using this process of preparing connects intermediate as key intermediate to produce medical gadolinium cloth
Alcohol, improves the purity and quality of Gadobutrol, reduces the toxic side effect that Gadobutrol is used；
The present invention process of preparing prepare Gadobutrol epoxy side connect midbody compound A total recoverys bring up to 84% with
On, purity brings up to more than 99.6%, and maximum single miscellaneous content is below 0.1%, and each step intermediate easy purification, post processing is simple
Facilitate easy to operate；
It is good that Gadobutrol epoxy side prepared by the process of preparing of the present invention connects midbody compound A stability, harsh bar
6 months purity is placed under part without obvious change, is easy to store and transports, substantially reduce and carried out instead as Gadobutrol key intermediate
The introducing of seasonable plurality of impurities, is conducive to improving the quality and purity of the Gadobutrol medicine prepared, reduces the medication poison of Gadobutrol
Property, improve drug safety.
In summary, process of preparing of the invention prepares Gadobutrol epoxy side and connects intermediate, without using strong reagents；
Reduce material ratio；Charged material weight ratio and reaction condition are optimized and revised, improves post processing and purification process, obtains
Gadobutrol epoxy side connects that intermediate product impurity content is low, and the purity of intermediate product is substantially increased while yield is improved
And quality so that improve the difficulty of technology controlling and process during Gadobutrol production of raw medicine and improve Gadobutrol bulk drug quality and
Qualification rate；Each step method is simple and easy to apply, and solvent and process conditions are cheap safely, and environment-friendly and green industrialized production, tool can be achieved
Have broad application prospects.
Brief description of the drawings
Fig. 1 is the GC collection of illustrative plates of compound A-3 in 2 according to an exemplary embodiment of the present；
Fig. 2 is the GC collection of illustrative plates of compound A in 2 according to an exemplary embodiment of the present；
The abscissa of GC collection of illustrative plates is the time, and unit is minute；Ordinate is current value, and unit is pico-ampere.
Embodiment
All features disclosed in this specification, or disclosed all methods or during the step of, except mutually exclusive
Feature and/or step beyond, can combine in any way.
Any feature disclosed in this specification, unless specifically stated otherwise, can be equivalent by other or with similar purpose
Alternative features are replaced.I.e., unless specifically stated otherwise, each feature is an example in a series of equivalent or similar characteristics
.
It is below that the process of preparing progress successively to Gadobutrol epoxy side chain intermediate of the present invention is further details of
Explanation.
According to the exemplary embodiment of the present invention, the process of preparing of the Gadobutrol epoxy side chain intermediate is included such as
Lower following steps：
Compound A-1 and A-2 is in the presence of p-methyl benzenesulfonic acid monohydrate, and being warming up to 80 DEG C of reactions must react for 2~3 hours
Liquid, by-product methanol was steamed within 2~3 hours reaction time simultaneously, the methanol amount of steaming and A-1 weight ratio (gram:Gram) be
0.71:1~0.73:1；Wherein, A-1 and A-2 charged material weight ratio (gram:Gram) it is 1:1.77, p-methyl benzenesulfonic acid monohydrate
Addition is the 0.22% of A-1 weight (gram)；
Vacuum distillation obtains target compound A-3 again after the excessive A-2 of reaction solution removing；
Compound A-3, sodium dihydrogen phosphate feed intake with the mixed solvent comprising methanol, acetonitrile and water and mixed, reaction solution heating.
Compound A-3 and sodium dihydrogen phosphate weight ratio (gram:Gram) it is 126:1~139:1；In the mixed solvent methanol, acetonitrile and water
Weight ratio (gram:Gram:Gram) it is 1:1.2:1.26、1:1.17:1.22 or 1:1.0:1.3；Compound A-3 and mixed solvent total amount
Weight ratio (gram:Gram) it is 1:2.7~1:3；
Feeding intake for hydrogen peroxide and sodium hydrate aqueous solution is carried out in the reaction solution of above-mentioned heating, then reaction solution continues to rise
Temperature is to 60~80 DEG C and is kept for 6~9 hours；The inventory of hydrogen peroxide and compound A-3 weight ratio (gram:Gram) it is 1.16:1~
1.18:1；Sodium hydroxide feeds intake to be formulated as the 1M aqueous solution, 1M sodium hydroxide inventory and compound A-3 weight ratio
(gram:Gram) it is 0.47:1~0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 1~2 hour；Concentration is 1M
Sodium hydrate aqueous solution the duration that feeds intake for 5~6 hours；Feed intake with heating and heat preservation elementary reaction liquid pH be 7~
9.5；
Saturated sodium-chloride water solution and dichloromethane are added after the reaction solution cooling that the upper stage is obtained, organic phase is separated simultaneously
Dry, filtering, concentration removes solvent and obtains target compound A.The consumption of saturated sodium-chloride water solution and compound A-3 weight ratio
(gram:Gram) it is 1.5:1~1.6:1；The consumption of dichloromethane and compound A-3 weight ratio (gram:Gram) it is 2.7:1~3.5:1.
Compound A is further purified using vacuum distillation mode.
The total recovery that Gadobutrol epoxy side connects midbody compound A process of preparing is more than 84%, and purity is
More than 99.6%, maximum single miscellaneous content is less than 0.1%.
It is maximum single it is miscellaneous be content highest single component in medical product impurity, in medical synthesis and preparation process method
In, miscellaneous generally maximum list is the crucial quality control index of medical product.
The process of preparing of Gadobutrol epoxy side chain intermediate of the present invention is made into one below in conjunction with specific embodiment
Walk explanation.
The preparation technology route of embodiments of the invention is as follows：
The process of preparing of embodiment 1, Gadobutrol epoxy side chain intermediate
Step 1：
(1) 300g compound A-1 is added in reaction bulb；
(2) 450g compound A-2 is added；
(3) 0.9g p-methyl benzenesulfonic acid monohydrate is added；
(4) 70 DEG C are stirred and heated to, methanol 219g is steamed, heating and steam methanol, the time continues 3 hours simultaneously；
(5) 120 DEG C are warming up to, distillation separates excessive compound A-2；
(6) 170 degrees Celsius are warming up to, air-distillation separates front-end volatiles impurity, it is 80-142 DEG C to collect boiling range；
(7) the compound A-3 (354g, purity 96.2%) that boiling range is 142-147 DEG C of component is collected.
Step 2：
(1) water of the 338g acetonitrile of compound A-3,315g, 270g methanol and 330g is added in reaction bulb, then is added
Enter 2.4g disodium hydrogen phosphate；
(2) agitating and heating reaction solution；
(3) 398g 30% hydrogen peroxide and 1M sodium hydroxide solution 159g are added into reaction bulb at 60-80 DEG C, it is double
Oxygen water time for adding continues 0.5~1 hour, and the dropwise addition sodium hydroxide solution time continues 5 hours, and process reaction hydraulic control pH is added dropwise
Value 7-9.5；
(4) reaction solution is down to room temperature after stirring 6~8 hours in reaction bulb；
(5) 540g saturated aqueous common salt is sequentially added in reaction bulb, 998g dichloromethane stirs and separates organic phase；
(6) 1.7M sodium sulfite solution 911g is continuously added in organic phase, stirs and separates organic phase, sodium sulphate is done
It is dry；
(7) dried organic phase filtering, 40 DEG C of decompression is evaporated off solvent and obtains compound A crude products；
(8) compound A crude products vacuum distillation, obtains product compound A (333g, total recovery 85.8%).
Purity testing is carried out to the compound A obtained and shows that compound A purity is more than 99.6%.
The process of preparing of embodiment 2, Gadobutrol epoxy side chain intermediate
Step 1：
(1) 180g compound A-1 is added in reaction bulb；
(2) 319g compound A-2 is added；
(3) 0.4g p-methyl benzenesulfonic acid monohydrate is added；
(4) 70 DEG C are stirred and heated to, methanol 128g is steamed, heating and steam methanol, the time continues 2 hours simultaneously；
(5) 120 DEG C are warming up to, distillation separates excessive compound A-2；
(6) 170 degrees Celsius are warming up to, air-distillation separates front-end volatiles impurity,；
(7) the compound A-3 (212g purity 96.3%) that boiling range is 142-147 DEG C of component is collected.
Step 2：
(1) water of the 180g acetonitrile of compound A-3,190g, 157g methanol and 198g is added in reaction bulb；Again plus
Enter 1.4g disodium hydrogen phosphate；
(2) agitating and heating reaction solution；
(3) 210g 30% hydrogen peroxide is added dropwise, while 1M sodium hydroxide solution 94g is added dropwise, 60-80 DEG C of temperature control is added dropwise
The hydrogen peroxide time continues 0.5~1 hour, and the dropwise addition sodium hydroxide solution time continues 3-5 hours, and process reaction hydraulic control pH is added dropwise
Value 7-9.5；
(4) reaction solution is down to room temperature after stirring 6~8 hours in reaction bulb；
(5) 300g saturated aqueous common salt is sequentially added in reaction bulb, 599g dichloromethane stirs and separates organic phase；
(6) 1.7M sodium sulfite solution 438g is added in organic phase, stirs and separates organic phase, sodium sulphate is dried；
(7) dried organic phase filtering, 40 DEG C of decompression is evaporated off solvent and obtains compound A crude products；
(8) compound A crude products vacuum distillation, obtains product compound A (178g, total recovery 86%).
Purity testing is carried out to the compound A-3 obtained in step 1, display compound A-3 purity is 96.28%,
Collection of illustrative plates is as shown in Figure 1.
Purity testing is carried out to the finished product compound A obtained in step 2, display compound A purity is
99.86%, collection of illustrative plates is as shown in Figure 2.
Embodiment 3, the workshop amplification preparation technology of Gadobutrol epoxy side chain intermediate
Step 1：
(1) 186kg compound A-1 is added in a kettle.；
(2) 330kg compound A-2 is added；
(3) 372g p-methyl benzenesulfonic acid monohydrate is added；
(4) 80 DEG C are stirred and heated to, methanol is steamed；Heating and separate methanol, the time continues 3 hours simultaneously；
(5) 120 DEG C are warming up to, excessive compound A-2 is distilled out and obtains crude Compound A-3；
(6) by crude Compound A-3 vacuum distillations, compound A-3 (216kg, purity 96.2%) is obtained.
Step 2：
(1) water of the 215kg acetonitrile of compound A-3,208kg, 178kg methanol and 217kg is added in a kettle.,
Add 1.6kg disodium hydrogen phosphates；
(2) agitating and heating reaction solution；
(3) in reactor add 257kg 27% hydrogen peroxide, and 1M sodium hydrate aqueous solution 103kg, temperature control 60-
80℃；The addition hydrogen peroxide time continues 1~2 hour, and the addition sodium hydrate aqueous solution time continues 5~6 hours, process is added dropwise anti-
Answer liquid control ph 7-9.5；
(4) reaction solution is down to room temperature after stirring 8~9 hours in reactor；
(5) 345kg saturated aqueous common salt is sequentially added in reactor, 593kg dichloromethane is stirred and separated organic
Phase；
(6) 1.7M sodium sulfite solution 481kg is added in organic phase, stirs and separates organic phase, sodium sulphate is dried；
(7) dried organic phase filtering, 40 DEG C of decompression is evaporated off solvent and obtains compound A crude products；
(8) to compound A crude product vacuum distillations, product compound A (209kg, total recovery 84.4%) is obtained.To being obtained
Compound A carry out purity testing and show that compound A purity is 99.64%.
1H-NMR analyses are carried out to the compound A obtained, it is as a result as follows：
1H-NMR(400MHz,CDCl3)δ：3.93~4.03 (m, 4H), 3.15~3.17 (m, 2H), 1.28 (s, 3H),
1.33 (s, 3H).
Embodiment 4, the workshop amplification preparation technology of Gadobutrol epoxy side chain intermediate
Step 1：
(1) 1550kg compound A-1 is added in reactor；
(2) 2940kg compound A-2 is added
(3) 3350g p-methyl benzenesulfonic acid monohydrate is added；
(4) 80 DEG C are stirred and heated to, methanol 1120kg is steamed；
(5) 120 DEG C are warming up to, excess compounds A-2 is distilled out and obtains crude Compound A-3；
(6) crude Compound A-3 is subjected to vacuum distillation, obtains compound A-3 (1820kg, purity 96.28%).Step
2：
(1) the 1810kg acetonitrile of compound A-3,1730kg, 1480kg methanol and 1920kg is added in a kettle.
Water, add 15.1kg disodium hydrogen phosphates；
(2) agitating and heating reaction solution；
(3) in reactor add 1990kg 27% hydrogen peroxide, and 1M sodium hydrate aqueous solution 1086kg, temperature control
60-80℃；The process reaction liquid control ph that feeds 7-9.5；
(4) reaction solution is down to room temperature after persistently stirring 8~9 hours in reactor；
(5) 2880kg saturated aqueous common salt is sequentially added in reactor, 6335kg dichloromethane is stirred and separated organic
Phase；
(6) 1.7M sodium sulfite solution 4010kg is added in organic phase, stirs and separates organic phase, sodium sulphate is dried；
(7) dried organic phase filtering, 40 DEG C of decompression is evaporated off solvent and obtains compound A crude products；
(8) crude Compound A vacuum distillations, obtain product compound A (1820kg, total recovery 85.2%).
Purity testing is carried out to the compound A obtained and shows that compound A purity is more than 99.6%.
Test example 1：
The Gadobutrol epoxy side chain midbody compound A prepared to above-described embodiment carries out Stability Determination, by sample
Product are placed six months in normal temperature sealing, sampling observation outward appearance and detection purity, and compound A purity is more than 99.6%.
Compared with the sample before placement, significant change does not occur for outward appearance after Compound A sample is placed 6 months, and purity is not
Significantly reduce.Illustrate that the Gadobutrol epoxy side chain midbody compound A that process of preparing of the present invention is prepared is stable
Property is good, is conducive to storing and transports.
Shown by above example and test example, in the middle of Gadobutrol epoxy side chain prepared by process of preparing of the invention
Body compound A purity is more than 96%, and process total recovery is more than 84%, and product stability is good.Each step operation letter
Just, easy purification, the simple and convenient, environmental protection of post processing is easy to operate, solvent and condition safe and feasible, is conducive to environment-friendly and green industry
Change amplification production, have broad application prospects.
The invention is not limited in foregoing embodiment.The present invention, which is expanded to, any in this manual to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (10)
1. a kind of process of preparing of Gadobutrol epoxy side chain intermediate, it is characterised in that the process of preparing includes
Following preparation technology route and step：
The Gadobutrol epoxy side chain intermediate is as shown in formula A：
Preparation technology route is as follows：
Step 1, compound A-1 and A-2 be subjected to ring-closure reaction in the presence of catalyst p-methyl benzenesulfonic acid hydrate, obtain chemical combination
Thing A-3；
Step 2, compound A-3 reacted in the presence of pH buffer reagents, alkali, hydrogen peroxide and mixed solvent, generate gadolinium
Cloth alcohol epoxy side chain midbody compound A；
Wherein, in step 1, p-methyl benzenesulfonic acid hydrate is preferably p-methyl benzenesulfonic acid monohydrate；A-1 and A-2 weight ratio
For 1:1.5~1:1.9, preferably 1:1.7~1:1.8, more preferably 1:1.77；The addition of catalyst is A-1 weight
0.2%~0.3%, preferably 0.22%.
2. method according to claim 1, it is characterised in that in step 1, reaction temperature is 70~90 DEG C, reaction time
For 2~3 hours；While steaming by-product methanol within reaction time 2-3 hour, the methanol amount of steaming and A-1 weight ratio are
0.71:1~0.73:1.
3. method according to claim 1 or claim 2, it is characterised in that in step 1, compound A-1 and A-2 is to toluene sulphur
In the presence of sour monohydrate, temperature is 70~90 DEG C and reacted 2~3 hours, and methanol was steamed simultaneously within 2~3 hours reaction time
Accessory substance, the methanol amount of steaming and A-1 weight ratio are 0.71:1~0.73:1；Reaction solution depressurizes steaming again after removing excessive A-2
Evaporate and obtain target compound A-3；
Wherein, A-1 and A-2 charged material weight ratio is 1:1.77, the addition of p-methyl benzenesulfonic acid monohydrate is A-1 weight
0.22%.
4. method according to claim 1, it is characterised in that in step 2, reaction is divided into three phases：Compound A-3 is thrown
Material stage, oxidation reaction stage, post processing purification phase.
5. method according to claim 4, it is characterised in that in step 2, compound A-3 feeding stages include chemical combination
The operation that thing A-3, pH buffer reagent and mixed solvent feed intake and heated up；The oxidation reaction stage includes feeding intake for hydrogen peroxide and alkali
And warming temperature；Post-processing purification phase includes following operation：Locate after adding saturated sodium-chloride water solution and dichloromethane progress
Reason；Organic phase is dried, and concentration removes solvent and obtains target compound A.
6. the method according to any one of claim 4 to 5, it is characterised in that in step 2, compound A-3 feeding stages
In, the weight ratio of compound A-3 and pH buffer reagents is 120:1~140:1, preferably 126:1~139:1；In the mixed solvent first
The weight ratio of alcohol, acetonitrile and water is 1:(1.0~1.3):(1.1~1.3), preferably 1：(1.0~1.2)：(1.22~1.3)；
More preferably 1:1.2:1.26、1:1.17:1.22 or 1:1.0:1.3；Compound A-3 and the weight ratio of mixed solvent total amount are 1:
2~1:4；Preferably 1:2~1:3, more preferably 1:2.7~1:3；Enter the subsequent oxidation stage after heating.
7. the method according to any one of claim 4 to 5, it is characterised in that in the step 2 oxidation reaction stage, dioxygen
The inventory of water is 1.1 with compound A-3 weight ratio:1~1.2:1, preferably 1.16:1~1.18:1；Alkali feed intake for
The 1M aqueous solution is made as, 1M alkali inventory is 0.4 with compound A-3 weight ratio:1~0.6:1, preferably 0.47:1~
0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 0.5~2 hour, preferably 1~2 hour；Concentration is 1M's
The duration that feeds intake of aqueous alkali is 3~8 hour, preferably 5~6 hours；60~80 DEG C are warming up to, it is 6 to continue soaking time
~9 hours, preferably 8~9 hours；It is 7~9.5 feeding intake with heating and heat preservation elementary reaction liquid pH.
8. the method according to any one of claim 4 to 5, it is characterised in that in step 2 post processing purification phase, satisfy
It is 1.5 with the consumption of sodium-chloride water solution and compound A-3 weight ratio:1~1.6:1；The consumption and compound of dichloromethane
A-3 weight ratio is 2.7:1~3.5:1.
9. the method according to any one of claim 4 to 5, it is characterised in that in step 2,
First stage, compound A-3, sodium dihydrogen phosphate feed intake with the mixed solvent comprising methanol, acetonitrile and water and mixed, reaction solution
It is warming up to after 50 DEG C and enters next stage.The weight ratio of compound A-3 and sodium dihydrogen phosphate is 126:1~139:1；Mixed solvent
The weight ratio of middle methanol, acetonitrile and water is 1：(1.0~1.2)：(1.22~1.3), preferably 1:1.2:1.26、1:1.17:
1.22 or 1:1.0:1.3；Compound A-3 and the weight ratio of mixed solvent total amount are 1:2.7~1:3；
Obtain carrying out feeding intake for hydrogen peroxide and sodium hydrate aqueous solution in reaction solution in the first stage, then reaction solution continues to heat up
To 60~80 DEG C and keep 6~9 hours.The inventory of hydrogen peroxide is 1.16 with compound A-3 weight ratio:1~1.18:1；Hydrogen
Sodium oxide molybdena feeds intake to be formulated as the 1M aqueous solution, and 1M sodium hydroxide inventory is 0.47 with compound A-3 weight ratio:1
~0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 1~2 hour；Concentration is 1M sodium hydrate aqueous solution
The duration that feeds intake for 5~6 hours；It is 7~9.5 feeding intake with heating and heat preservation elementary reaction liquid pH；
The reaction solution that above-mentioned second stage is obtained adds saturated sodium-chloride water solution and dichloromethane is post-processed；Organic phase
Dry, concentration removes solvent and obtains target compound A.The weight ratio of the consumption of saturated sodium-chloride water solution and compound A-3 is
1.5:1~1.6:1；The consumption of dichloromethane is 2.7 with compound A-3 weight ratio:1~3.5:1；Compound A is using decompression
Distillation mode is purified.
10. method according to claim 1, it is characterised in that including following operation：
Compound A-1 and A-2 is warming up to 80 DEG C of reactions and obtains reaction solution in 2~3 hours in the presence of p-methyl benzenesulfonic acid monohydrate；
While steaming by-product methanol within 2~3 hours reaction time, the methanol amount of steaming and A-1 weight ratio are 0.71:1~0.73:
1；Wherein, A-1 and A-2 charged material weight ratio is 1:1.77, the addition of p-methyl benzenesulfonic acid monohydrate is A-1 weight
0.22%；
Vacuum distillation obtains target compound A-3 again after the excessive A-2 of reaction solution removing；
Compound A-3, sodium dihydrogen phosphate feed intake with the mixed solvent comprising methanol, acetonitrile and water and mixed, reaction solution heating；Chemical combination
The weight ratio of thing A-3 and sodium dihydrogen phosphate is 126:1~139:1；The weight ratio of in the mixed solvent methanol, acetonitrile and water is 1:
1.2:1.26、1:1.17:1.22 or 1:1.0:1.3；Compound A-3 and the weight ratio of mixed solvent total amount are 1:2.7~1:3；
Feeding intake for hydrogen peroxide and sodium hydrate aqueous solution is carried out in reaction solution after heating, then reaction solution is continuously heating to about
60~80 DEG C and keep 6~9 hours；The inventory of hydrogen peroxide is 1.16 with compound A-3 weight ratio:1~1.18:1；Hydrogen-oxygen
Change feeding intake to be formulated as the 1M aqueous solution for sodium, 1M sodium hydroxide inventory is 0.47 with compound A-3 weight ratio:1~
0.52:1；During feeding intake, the duration that feeds intake of hydrogen peroxide is 1~2 hour；Concentration is 1M sodium hydrate aqueous solution
The duration fed intake for 5~6 hours；It is 7~9.5 feeding intake with heating and heat preservation elementary reaction liquid pH；
Saturated sodium-chloride water solution and dichloromethane are added after the reaction solution cooling that the upper stage is obtained, organic phase is separated and does
Dry, filtering, concentration removes solvent and obtains target compound A；The weight ratio of the consumption of saturated sodium-chloride water solution and compound A-3 is
1.5:1~1.6:1；The consumption of dichloromethane is 2.7 with compound A-3 weight ratio:1~3.5:1；
Compound A is optionally further purified using vacuum distillation mode.
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| CN109251209A (en) * | 2018-10-23 | 2019-01-22 | 湖北天舒药业有限公司 | A kind of preparation process of Gadobutrol intermediate |
| CN112409370A (en) * | 2020-12-10 | 2021-02-26 | 四川新迪医药化工有限公司 | Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol |
| CN115724849A (en) * | 2022-11-28 | 2023-03-03 | 安庆朗坤药业有限公司 | Preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane |
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| CN103351396A (en) * | 2013-07-29 | 2013-10-16 | 太仓市茜泾化工有限公司 | Preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5, 1, 0] octane |
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| CN103351396A (en) * | 2013-07-29 | 2013-10-16 | 太仓市茜泾化工有限公司 | Preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5, 1, 0] octane |
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| CN112409370A (en) * | 2020-12-10 | 2021-02-26 | 四川新迪医药化工有限公司 | Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol |
| CN115724849A (en) * | 2022-11-28 | 2023-03-03 | 安庆朗坤药业有限公司 | Preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane |
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