CN108911995A - A kind of stable isotope labeling R- Clorprenaline and preparation method thereof - Google Patents
A kind of stable isotope labeling R- Clorprenaline and preparation method thereof Download PDFInfo
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- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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Abstract
The present invention relates to a kind of stable isotope labeling R- Clorprenalines and preparation method thereof; with methodology of organic synthesis; using stable isotope labeling chlorobenzene as raw material; stable isotope labeling o-chloroacetophenone is generated through F-K reaction; the alpha-brominated o-chloroacetophenone of stable isotope labeling is obtained after bromination; again with stable isotope labeling isopropylamine, reducing agent one pot reaction, stable isotope labeling R- Clorprenaline is obtained.Compared with prior art, stable isotope labeling R- Clorprenaline prepared by the present invention, for chemical purity up to 99% or more, isotope abundance can be used for the metabolic mechanism research and the violated remaining detection of veterinary drug Clorprenaline of field of food safety of drug Clorprenaline 99% or more.
Description
Technical field
The present invention relates to isotope labelling techniques fields, and in particular to a kind of stable isotope labeling R- Clorprenaline and its
Preparation method.
Background technique
Clorprenaline is a kind of common drug for treating respiratory disease, belongs to selective β2Receptor-stimulating drug faces
Bed is widely used in bronchiectasis, bronchial asthma, asthmatic bronchitis etc., and selectivity is high, and functionality is strong.Contain in its molecule
There is an asymmetric carbon atom, be chipal compounds, currently, this drug is still mainly administered in the form of racemates.However it grinds
Study carefully and shows for this kind of β2Receptor-stimulating drug, different enantiomer drug effects may be different.Study the drug activity of enantiomer
It needs to synthesize the stable isotope labeling R- Clorprenaline of single configuration, therefore, stable isotope labeling mapping is carried out to them
Body synthesis and separation are of great significance for further studying its pharmacology and developing less side effects new drug.
Meanwhile Clorprenaline can be with --- promote that animal body is proteins deposited, lipolysis is promoted to inhibit fat deposition,
The lean meat percentage of trunk can be significantly improved, increases weight and improves food conversion ratio, therefore was once used as the rush of the livestock and poultry such as ox, sheep, fowl, pig
Growth stimulator, feed addictive.But this substance has strong harm to human body, can generate palpitaition, headache, nausea, increased heart rate
Etc. poisoning symptoms, even cause life danger when serious.In order to ensure animal-derived food safety, No. 1519 bulletins of the Ministry of Agriculture are
Clorprenaline hydrochloride etc. is forbidden to use in feed and drinking water for animals.Complicated matrix effect in food is needed with stablizing same position
Plain internal standard method is detected.Therefore the stable isotope labeling R- Clorprenaline of single configuration, can be widely applied to chlorine in food
The detection of third that woods content.
Less about stable isotope labeling R- Clorprenaline synthesis open source literature at present, the country has no document report.It
Right Clorprenaline and its hydrochloride is mostly split by racemic modification using Chiral Mobile Phase Additives or chiral stationary phase
It obtains, this kind of method prepares cumbersome, and at high cost, separating effect is poor.Rajesh Kumar Pandey etc. reports natural chiral chlorine
The synthesis of third that woods is first to generate chiral vicinal diamines using expensive ortho-chlorostyrene and chiral reagent reaction, is then being passed through
It crosses three-step reaction to be prepared, the route raw material is expensive, is difficult to obtain, and reaction route is long, and yield is low to be not suitable for surely
Determine the synthesis of isotope labelling R- Clorprenaline.Shanghai metering institute Li Jie et al. disclose in the patent deuterium-labeled phenolethanolamine β by
The synthesis of body agonist, using strong and stimulating, the bromoacetyl chloride bromide reagent of severe toxicity, then amination reduction, which is prepared, disappears
The deuterium-labeled beta receptor agonist of rotation corresponds to isomers (only simple isopropylamine-D6Label), and the not stabilization of single configuration
Isotope labelling R- Clorprenaline also has no the synthesis step of detailed Clorprenaline in patent.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of easily separated purifications, conjunction
At simple stable isotope labeling R- Clorprenaline and preparation method thereof.
The purpose of the present invention can be achieved through the following technical solutions：A kind of stable isotope labeling R- Clorprenaline,
The structural formula of the R- Clorprenaline is as follows：
Wherein, at least one in a, b, c, d, e, f, g, h, i, j, k, m and n is stood alone as13C、D、15N or18O isotope mark
Note.
It is at a13C flag or non-marked；
It is at the b13C flag, one or two kinds of label of D or non-marked；
It is at the c13C flag, one or two kinds of label of D or non-marked；
It is at the d13C flag, one or two kinds of label of D or non-marked；
It is at the e13C flag, one or two kinds of label of D or non-marked；
It is at the f13C flag or non-marked；
It is at the g13C flag, one or two kinds of label of D or non-marked；
It is at the h13C flag, one or two kinds of label of D or non-marked；
It is at the i15N label, one or two kinds of label of D or non-marked；
It is at the j13C flag, one or two kinds of label of D or non-marked；
It is at the k13C flag, one or two kinds of label of D or non-marked；
It is at the m13C flag, one or two kinds of label of D or non-marked；
It is at the n18O label, one or two kinds of label of D or non-marked.
A kind of preparation method of stable isotope labeling R- Clorprenaline as described above, includes the following steps：It will stablize same
The chlorobenzene of position element label generates stable isotope labeling o-chloroacetophenone through F-K reaction, and then bromination obtains stablizing same
Position element marks alpha-brominated o-chloroacetophenone, then with stable isotope labeling isopropylamine and reducing agent reaction to get described steady
Determine isotope labelling R- Clorprenaline.
The synthetic route, using efficient bromide reagent, the alpha-brominated o-chloroacetophenone of intermediate stable isotope labeling is received
Rate is high, purity is high, effective to reduce impurity transmitting；Amination and reduction carry out inside single step reaction, mild condition, by-product
Few, separation is easy；Amination restores among step progress without isolation, reduces and loses, therefore high income, isotope atom utilization rate
It is high.
Preferably, the F-K reaction is the chlorobenzene and stable isotope labeling acetic acid of stable isotope labeling
Acid anhydride catalyzes and synthesizes in the No.1 liquid phase solvent of anhydrous and oxygen-free.It is reacted in the isotope labelling solvent of anhydrous and oxygen-free, is
For the reaction environment provided, the dilution of isotope is avoided.
Preferably, the molar ratio of the chlorobenzene of the stable isotope labeling and stable isotope labeling acetic anhydride is 1：
(0.5~10), it is furthermore preferred that the molar ratio of the chlorobenzene of stable isotope labeling and stable isotope labeling acetic anhydride is 1：(0.5
~5).
Preferably, the No.1 liquid phase solvent is chloroform, methylene chloride, tetrahydrofuran, the acetic acid of stable isotope labeling
One or more of mixing；
The catalyst for catalyzing and synthesizing use includes in titanium tetrachloride, zirconium chloride, bismuth trichloride or antimony trichloride
One or more mixing, the temperature catalyzed and synthesized is -50~200 DEG C, it is furthermore preferred that the temperature catalyzed and synthesized is -20~80 DEG C.
Preferably, the bromination is into stable isotope labeling o-chloroacetophenone and bromide reagent the two of anhydrous and oxygen-free
It is synthesized in number liquid phase solvent, the molar ratio of the stable isotope labeling o-chloroacetophenone and bromide reagent is 1：(1~10), more
Preferably, the molar ratio of the stable isotope labeling o-chloroacetophenone and bromide reagent is 1：(1~3).In anhydrous and oxygen-free
It is reacted in isotope labelling solvent, the reaction environment being to provide for avoids the dilution of isotope
Preferably, the bromide reagent includes one or more of DBBA, DBI, TBAB or C5H6Br2N2O2 mixing；
No. two liquid phase solvents include one of methanol, chloroform, ethyl alcohol or ethyl acetate of stable isotope labeling
Or several mixing；
The brominated temperature is -50~200 DEG C, it is furthermore preferred that bromination temperature is -10~80 DEG C.
Preferably, the alpha-brominated o-chloroacetophenone of the stable isotope labeling and stable isotope labeling isopropylamine and
Reducing agent reacts under anhydrous and oxygen-free environment, and the reducing agent includes the sodium triethylborohydride of stable isotope labeling, isopropyl
The mixing of aluminium alcoholates-one or more of isopropanol or diborane, the alpha-brominated o-chloroacetophenone of the stable isotope labeling, stabilization
The molar ratio of isotope labelling isopropylamine and reducing agent is 1：(1~10)：(1~15), it is furthermore preferred that stable isotope labeling α-
The molar ratio of bromo o-chloroacetophenone, stable isotope labeling isopropylamine and reducing agent is 1：(1~2)：(1~3).
Preferably, the alpha-brominated o-chloroacetophenone of the stable isotope labeling and stable isotope labeling isopropylamine and
The temperature that reducing agent reacts under anhydrous and oxygen-free environment is -50~200 DEG C, it is furthermore preferred that the temperature of reaction is -15~45 DEG C.
The stable isotope labeling mentioned in above-mentioned synthesis process stands alone as at least one13C、D、15N or18The same position O
Element label.
Compared with prior art, the beneficial effects of the present invention are embodied in following several respects：
(1) present invention firstly discloses one kind using stable isotope labeling chlorobenzene as Material synthesis stable isotope labeling R-
The synthetic method of Clorprenaline；
(2) present invention is simple using process route, is readily synthesized, and stable isotope atom utilization is high；
(3) the easily separated purification of product of the present invention, product chemical purity 99% or more, isotope abundance 99% or more,
Can sufficiently meet the needs of research of drug Clorprenaline metabolic mechanism and field of food safety trace detection；
(4) economy and use value of the present invention are good, have preferable promotion prospect.
Detailed description of the invention
Fig. 1 is R- Clorprenaline-D6Mono-crystalline structures figure.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
A kind of stable isotope labeling R- Clorprenaline-13C11Preparation method, this approach includes the following steps：
1, stable isotope labeling o-chloroacetophenone-13C8Preparation
Under anhydrous, anaerobic conditions, by 11.9g chlorobenzene-13C6It is added in 250ml three-necked flask, tetrahydrofuran is added
After being dispersed with stirring, acetic anhydride-is added dropwise in 25ml, titanium tetrachloride 5g13C411.5g after being added dropwise, heats up 80 DEG C and reacts 2 hours,
O-chloroacetophenone-is obtained after washing, dry, recrystallization13C815.6g, yield 94.3%, purity 99.5%, abundance
99.5atom%13C。
2, the alpha-brominated o-chloroacetophenone-of stable isotope labeling13C8Preparation
Under anhydrous, anaerobic conditions, 8.1g o-chloroacetophenone-is added in 250mL three-necked flask13C6, 15g is added
DBBA is added methanol, each 20ml of ethyl acetate, 60 DEG C of temperature control, reacts 4 hours, obtains after washing, dry, recrystallization, 17.3g
Yellow solid, yield 87.8%, purity 99.3%, abundance 99.5atom%13C。
3, stable isotope labeling R- Clorprenaline-13C11Preparation
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-is added in 250mL three-necked flask13C8 6.1g
Anhydrous tetrahydro furan 30ml is added, stirs 10 minutes, isopropylamine-is then added dropwise13C30.65g, after adding, reaction 1
After hour, go back original reagent sodium triethylborohydride 3.5g is added, reacts 1 hour, washing, is recrystallized to give 2.9g R- chlorine at drying
Third Na Lin-13C11, yield 88.8%, purity 99.0%, abundance 99.5atom%13C。
Embodiment 2
A kind of stable isotope labeling R- Clorprenaline-D16Preparation method, this approach includes the following steps：
1, stable isotope labeling o-chloroacetophenone-D7Preparation
Under anhydrous, anaerobic conditions, by 11.7g chlorobenzene-D5It is added in 250ml three-necked flask, deuterated chloroform is added
After being dispersed with stirring, acetic anhydride-D is added dropwise in 35ml, zirconium chloride 3g612.0g after being added dropwise, heats up 60 DEG C and reacts 2 hours,
Heavy water washes, dries, recrystallize after obtain o-chloroacetophenone-D715.4g, yield 95.8%, purity 99.6%, abundance 99.0%
Atom%D.
2, the alpha-brominated o-chloroacetophenone-D of stable isotope labeling7Preparation
Under anhydrous, anaerobic conditions, 8.1g o-chloroacetophenone-D is added in 250mL three-necked flask7, 14g DBI is added,
Deuterated chloroform 20ml is added, 40 DEG C of temperature control, reacts 3 hours, heavy water washes, dries, recrystallize after obtain, 10.8g yellow solid, receipts
Rate 90.1%, purity 99.4%, abundance 99.0atom%D.
3, stable isotope labeling R- Clorprenaline-D16Preparation
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-D is added in 250mL three-necked flask7 12.0g
Deuterated chloroform 15ml is added, stirs 10 points, isopropylamine-D is then added dropwise71.5g, after adding, after reaction 1 hour,
Go back original reagent diborane-D is added63g reacts 1 hour, and heavy water is washed, dried, being recrystallized to give 10.0g R- Clorprenaline-D16,
Yield 86.9%, purity 99.1%, abundance 99.0atom%D.
Embodiment 3
A kind of stable isotope labeling R- Clorprenaline-15N preparation method, this approach includes the following steps：
1, the preparation of o-chloroacetophenone
Under anhydrous, anaerobic conditions, 11.2g chlorobenzene is added in 250ml three-necked flask, methylene chloride 35ml is added,
Antimony trichloride 2g after being dispersed with stirring, is added dropwise acetic anhydride 12.9g, after being added dropwise, heats up 50 DEG C and react 1 hour, wash, is dry,
O-chloroacetophenone 14.6g, yield 94.3%, purity 99.5% are obtained after recrystallization.
2, the preparation of alpha-brominated o-chloroacetophenone
Under anhydrous, anaerobic conditions, 7.5g o-chloroacetophenone is added in 250mL three-necked flask, 10.1g dibromo sea is added
Cause is added methanol 20ml, 40 DEG C of temperature control, reacts 4 hours, obtains after washing, dry, recrystallization, 10.4g yellow solid, yield
89.0%, purity 99.4%.
3, stable isotope labeling R- Clorprenaline-15The preparation of N
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone 11.6g is added in 250mL three-necked flask
Ethyl alcohol 20ml is added, stirs 10 minutes, isopropylamine-is then added dropwise15N 1.3g after adding, after reaction 1 hour, adds
Enter isopropanol-aluminium isopropoxide 5.2g, react 1 hour, washing, is recrystallized to give 9.6g R- Clorprenaline-at drying15N, yield
89.3%, purity 99.2%, abundance 99.3atom%15N。
Embodiment 4
A kind of stable isotope labeling R- Clorprenaline-18O preparation method, this approach includes the following steps：
1, o-chloroacetophenone-18The preparation of O
Under anhydrous, anaerobic conditions, 5.6g chlorobenzene is added in 100ml three-necked flask, be added tetrahydrofuran 15ml, three
After being dispersed with stirring, acetic anhydride-is added dropwise in bismuth chloride 2g18O36.6g after being added dropwise, heats up 40 DEG C and reacts 5 hours,18O washing,
O-chloroacetophenone-is obtained after dry, recrystallization18O 7.6g, yield 95.3%, purity 99.3%, abundance 99.0atom%18O。
2, the preparation of alpha-brominated o-chloroacetophenone
Under anhydrous, anaerobic conditions, 7.5g o-chloroacetophenone-is added in 250mL three-necked flask1812.2g is added in O
TBAB is added ethyl acetate 20ml, 60 DEG C of temperature control, reacts 2 hours,18It is obtained after O washing, dry, recrystallization, 10.2g yellow is solid
Body, yield 88.8%, purity 99.4%, abundance 99.0atom%18O。
3, stable isotope labeling R- Clorprenaline-18The preparation of O
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-is added in 250mL three-necked flask18O 5.9g
Tetrahydrofuran 20ml is added, stirs 10 minutes, isopropylamine 1.0g is then added dropwise, after adding, after reaction 1 hour, adds
Enter diborane 3.2g, react 1 hour, drying is recrystallized to give 4.8g R- Clorprenaline-18O, yield 88.2%, purity
99.1%, abundance 99.0atom%18O。
Embodiment 5
A kind of stable isotope labeling R- Clorprenaline-D6Preparation method, this approach includes the following steps：
1, the preparation of o-chloroacetophenone
Under anhydrous, anaerobic conditions, 11.2g chlorobenzene is added in 250ml three-necked flask, addition methylene chloride 15ml,
After being dispersed with stirring, acetic anhydride 13.5g is added dropwise in acetic acid 10ml, antimony trichloride 1g, bismuth trichloride 1g, after being added dropwise, is heated up 50 DEG C
Reaction 3 hours, washing, drying obtain o-chloroacetophenone 14.8g, yield 95.3%, purity 99.5% after recrystallizing.
2, the preparation of alpha-brominated o-chloroacetophenone
Under anhydrous, anaerobic conditions, 7.5g o-chloroacetophenone is added in 250mL three-necked flask, 5.1g dibromo sea is added
Cause, 5.1gTBAB are added ethyl alcohol 10ml, ethyl acetate 10ml, 65 DEG C of temperature control, react 3 hours, after washing, is dry, recrystallizing
It arrives, 11.4g yellow solid, yield 92.5%, purity 99.4%.
3, stable isotope labeling R- Clorprenaline-D6Preparation
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone 12.0g is added in 250mL three-necked flask
Deuterated chloroform 15ml is added, stirs 10 points, isopropylamine-D is then added dropwise61.3g, after adding, after reaction 1 hour,
Go back original reagent diborane 3.5g is added, reacts 1 hour, heavy water is washed, dried, being recrystallized to give 11.0g R- Clorprenaline-D6, receive
Rate 88.9%, purity 99.1%, abundance 99.0atom%D.Its mono-crystalline structures figure is as shown in Figure 1.
Embodiment 6
A kind of stable isotope labeling R- Clorprenaline-13C11D16 18O15N preparation method, this approach includes the following steps：
1, stable isotope labeling o-chloroacetophenone-13C8D7 18The preparation of O
Under anhydrous, anaerobic conditions, chlorobenzene-13C6D5It is added in 250ml three-necked flask, addition anhydrous tetrahydro furan, four
After being dispersed with stirring, acetic anhydride-is added dropwise in titanium chloride 4.5g13C4D6 18O after being added dropwise, heats up 70 DEG C and reacts 2 hours, heavy water washes,
O-chloroacetophenone-is obtained after dry, recrystallization13C8D7 18O。
2, the alpha-brominated o-chloroacetophenone-of stable isotope labeling13C8D6 18The preparation of O
Under anhydrous, anaerobic conditions, o-chloroacetophenone-is added in 250mL three-necked flask13C8D7 18O, addition DBBA,
TBAB is added ethyl acetate 30ml, 70 DEG C of temperature control, reacts 2 hours, heavy water washes, dries, recrystallize after obtain alpha-brominated neighbour's chlorobenzene
Ethyl ketone-13C8D6 18O。
3, stable isotope labeling R- Clorprenaline-13C11D16 18O15The preparation of N
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-is added in 250mL three-necked flask13C8D6 18Nothing is added in O
Water tetrahydrofuran stirs 10 minutes, isopropylamine-is then added dropwise13C3D7 15After adding, after reaction 1 hour, go back original reagent is added in N
Deuterated sodium triethylborohydride reacts 1 hour, and heavy water is washed, dried, being recrystallized to give R- Clorprenaline-13C11D16 18O15N。
Embodiment 7
A kind of stable isotope labeling R- Clorprenaline-D6 15N preparation method, this approach includes the following steps：
1, stable isotope labeling o-chloroacetophenone-D7Preparation
Under anhydrous, anaerobic conditions, chlorobenzene-D5It is added in 250ml three-necked flask, addition deuterated chloroform, antimony trichloride,
After being dispersed with stirring, acetic anhydride-D is added dropwise6, after being added dropwise, heat up 50 DEG C and react 3 hours, heavy water obtains after washing, dry, recrystallizing
To o-chloroacetophenone-D7。
2, the alpha-brominated o-chloroacetophenone-D of stable isotope labeling6Preparation
Under anhydrous, anaerobic conditions, o-chloroacetophenone-D is added in 250mL three-necked flask7, TBAB is added, deuterium is added
For ethyl alcohol 30ml, 50 DEG C of temperature control, react 2 hours, heavy water washes, dries, recrystallize after obtain alpha-brominated o-chloroacetophenone-13C8D6 18O。
3, stable isotope labeling R- Clorprenaline-D6 15The preparation of N
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-D is added in 250mL three-necked flask6Anhydrous second is added
Ether stirs 10 minutes, isopropylamine-is then added dropwise15After adding, after reaction 1 hour, go back original reagent diborane is added, reaction 1 is small in N
When, heavy water is washed, is dried, being recrystallized to give R- Clorprenaline-D6 15N。
Embodiment 8
A kind of stable isotope labeling R- Clorprenaline-18O 15N preparation method, this approach includes the following steps：
1, stable isotope labeling o-chloroacetophenone-18The preparation of O
Under anhydrous, anaerobic conditions, chlorobenzene is added in 250ml three-necked flask, and tetrahydrofuran is added, and bismuth trichloride stirs
After mixing dispersion, acetic anhydride-is added dropwise18O after being added dropwise, heats up 60 DEG C and reacts 2 hours,18It is obtained after O washing, dry, recrystallization
O-chloroacetophenone-18O。
2, the alpha-brominated o-chloroacetophenone-of stable isotope labeling18The preparation of O
Under anhydrous, anaerobic conditions, o-chloroacetophenone-is added in 250mL three-necked flask18TBAB is added in O, and second is added
Alcohol, reacts 4 hours by 20 DEG C of temperature control,18O washing, is recrystallized to give alpha-brominated o-chloroacetophenone-at drying18O。
3, stable isotope labeling R- Clorprenaline-18O15The preparation of N
Under anhydrous, anaerobic conditions, alpha-brominated o-chloroacetophenone-is added in flask18Anhydrous ether, stirring 10 is added in O
Minute, isopropylamine-is then added dropwise15After adding, after reaction 1 hour, go back original reagent sodium triethylborohydride is added, reaction 1 is small in N
When,18O washing, is recrystallized to give R- Clorprenaline-at drying18O 15N。
Claims (10)
1. a kind of stable isotope labeling R- Clorprenaline, which is characterized in that the structural formula of the R- Clorprenaline is as follows：
Wherein, at least one in a, b, c, d, e, f, g, h, i, j, k, m and n is stood alone as13C、D、15N or18O isotope labelling.
2. a kind of stable isotope labeling R- Clorprenaline according to claim 1, which is characterized in that be at a13C
Label or non-marked；
It is at the b13C flag, one or two kinds of label of D or non-marked；
It is at the c13C flag, one or two kinds of label of D or non-marked；
It is at the d13C flag, one or two kinds of label of D or non-marked；
It is at the e13C flag, one or two kinds of label of D or non-marked；
It is at the f13C flag or non-marked；
It is at the g13C flag, one or two kinds of label of D or non-marked；
It is at the h13C flag, one or two kinds of label of D or non-marked；
It is at the i15N label, one or two kinds of label of D or non-marked；
It is at the j13C flag, one or two kinds of label of D or non-marked；
It is at the k13C flag, one or two kinds of label of D or non-marked；
It is at the m13C flag, one or two kinds of label of D or non-marked；
It is at the n18O label, one or two kinds of label of D or non-marked.
3. a kind of preparation method of stable isotope labeling R- Clorprenaline as claimed in claim 1 or 2, which is characterized in that packet
Include following steps：The chlorobenzene of stable isotope labeling is generated into stable isotope labeling neighbour chlorobenzene second through F-K reaction
Ketone, then bromination obtains the alpha-brominated o-chloroacetophenone of stable isotope labeling, then with stable isotope labeling isopropylamine and
Reducing agent reacts to get the stable isotope labeling R- Clorprenaline.
4. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 3, which is characterized in that institute
The chlorobenzene and stable isotope labeling acetic anhydride that the F-K reaction stated is stable isotope labeling are the one of anhydrous and oxygen-free
It is catalyzed and synthesized in number liquid phase solvent.
5. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 4, which is characterized in that institute
The chlorobenzene for the stable isotope labeling stated and the molar ratio of stable isotope labeling acetic anhydride are 1：(0.5~10).
6. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 4, which is characterized in that institute
State one or more of mixing of chloroform, methylene chloride, tetrahydrofuran, acetic acid that No.1 liquid phase solvent is stable isotope labeling；
The catalyst for catalyzing and synthesizing use includes one of titanium tetrachloride, zirconium chloride, bismuth trichloride or antimony trichloride
Or several mixing, the temperature catalyzed and synthesized are -50~200 DEG C.
7. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 3, which is characterized in that institute
The bromination stated is to synthesize in No. two liquid phase solvents of anhydrous and oxygen-free at stable isotope labeling o-chloroacetophenone and bromide reagent,
The molar ratio of the stable isotope labeling o-chloroacetophenone and bromide reagent is 1：(1~10).
8. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 7, which is characterized in that institute
The bromide reagent stated includes one or more of DBBA, DBI, TBAB or C5H6Br2N2O2 mixing；
No. two liquid phase solvents include one of methanol, chloroform, ethyl alcohol or ethyl acetate of stable isotope labeling or several
Kind mixing；
The brominated temperature is -50~200 DEG C.
9. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 3, which is characterized in that institute
The alpha-brominated o-chloroacetophenone of the stable isotope labeling stated and stable isotope labeling isopropylamine and reducing agent are in anhydrous and oxygen-free
It is reacted under environment, the reducing agent includes the sodium triethylborohydride, aluminium isopropoxide-isopropanol or second boron of stable isotope labeling
The mixing of one or more of alkane, the alpha-brominated o-chloroacetophenone of the stable isotope labeling, stable isotope labeling isopropylamine
And the molar ratio of reducing agent is 1：(1~10)：(1~15).
10. a kind of preparation method of stable isotope labeling R- Clorprenaline according to claim 9, which is characterized in that
The alpha-brominated o-chloroacetophenone of the stable isotope labeling and stable isotope labeling isopropylamine and reducing agent are in anhydrous nothing
The temperature reacted under oxygen environment is -50~200 DEG C.
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