CN115093438A - Process for the synthesis of intermediates and intermediates - Google Patents
Process for the synthesis of intermediates and intermediates Download PDFInfo
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- CN115093438A CN115093438A CN202210763920.3A CN202210763920A CN115093438A CN 115093438 A CN115093438 A CN 115093438A CN 202210763920 A CN202210763920 A CN 202210763920A CN 115093438 A CN115093438 A CN 115093438A
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 230000008569 process Effects 0.000 title abstract description 10
- 239000000543 intermediate Substances 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 17
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 8
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 33
- 239000011259 mixed solution Substances 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 21
- -1 cyclopropyl (methylene) isopropyl malonate Chemical compound 0.000 claims description 12
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
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- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 18
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
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- 229940125810 compound 20 Drugs 0.000 description 11
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 11
- 238000010586 diagram Methods 0.000 description 6
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- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- HMSWAIKSFDFLKN-UHFFFAOYSA-N hexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC HMSWAIKSFDFLKN-UHFFFAOYSA-N 0.000 description 4
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- JJKMIZGENPMJRC-UHFFFAOYSA-N 3-oxo-3-propan-2-yloxypropanoic acid Chemical compound CC(C)OC(=O)CC(O)=O JJKMIZGENPMJRC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003518 caustics Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
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- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
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- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000000940 FEMA 2235 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
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- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
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- IUUYANMOEMBTBV-FJXQXJEOSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate;hydron;chloride Chemical compound Cl.CC(C)(C)OC(=O)[C@@H]1CCCN1 IUUYANMOEMBTBV-FJXQXJEOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Embodiments of the present invention provide a method of synthesizing an intermediate, comprising: first compound and I ‑ Reacting to generate a second compound; reacting the second compound with the isopropylidene malonate to generate a third compound; reacting the third compound with tert-butyloxycarbonyl to generate a fourth compound; the fourth compound is an intermediate. According to the synthesis method of the intermediate provided by the embodiment of the invention, the synthesized intermediate can be used for synthesizing F-BPA, and in the process of synthesizing F-BPA by using the synthesized intermediate, only one hydrolysis reaction is needed after fluorinated substitution to obtain the final product F-BPA, so that the synthesis time after fluorinated substitution is shortened, and the yield of the product is improved.
Description
Technical Field
Embodiments of the invention relate to the field of boron compounds, and in particular to methods for synthesizing intermediates and intermediates.
Background
Boron Neutron Capture Therapy (BNCT) is an effective method for treating tumors. In boron neutron capture therapy, BPA (herein referred to as p-dihydroxyboroylphenylalanine or 4-boro-L-phenylalanine) is often used as a drug to treat patients.
For monitoring the distribution of BPA in a patient, radioactive samples are used 18 F atom replaces one hydrogen atom on the benzene ring in the BPA molecule to form a ring 18 F-BPA of F. Because the changed structure has no new functional group introduced, the chemical property is changed little, and the BPA is easy to be recognized and absorbed by cells, so that the activity and the targeting property of the BPA can not be changed by the fluoridation.
Methods exist in the prior art for the synthesis of F-BPA using nucleophilic substitution. However, in the existing method for synthesizing F-BPA by using a nucleophilic substitution method, a plurality of steps of synthesis and separation are still required after fluorinated substitution, so that the total reaction time is long, the yield of the product is low, and the requirements of clinical application are difficult to meet.
Disclosure of Invention
To overcome at least one aspect of the above problems, embodiments of the present invention provide a method of synthesizing an intermediate, comprising:
first compound and I - Reacting to form a second compound, wherein,
the chemical structural formula of the first compound is as follows:
the chemical structural formula of the second compound is as follows:
reacting the second compound with cycloisopropyl malonate to generate a third compound, wherein,
the chemical structural formula of the third compound is as follows:
reacting the third compound with tert-butyloxycarbonyl group to produce a fourth compound, wherein,
the chemical structural formula of the fourth compound is as follows:
the fourth compound is the intermediate.
According to the synthesis method of the intermediate provided by the embodiment of the invention, the synthesized intermediate can be used for synthesizing F-BPA, and in the process of synthesizing F-BPA by using the synthesized intermediate, only one hydrolysis reaction is needed after fluorinated substitution to obtain the final product F-BPA, so that the synthesis time after fluorinated substitution is shortened, and the yield of the product is improved.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a schematic diagram of a process for synthesizing a second compound from a first compound according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of a process for synthesizing a third compound from a second compound according to an embodiment of the present invention;
FIG. 3 is a schematic diagram of a process for synthesizing a fourth compound from a third compound according to an embodiment of the present invention;
FIG. 4 is a schematic diagram of a process for synthesizing a fifth compound from a fourth compound according to an embodiment of the present invention;
FIG. 5 is a schematic diagram of a scheme for synthesizing F-BPA using a fifth compound according to an embodiment of the present invention;
FIG. 6 shows a second compound provided in an embodiment of the present invention 1 HNMR spectrogram;
FIG. 7 shows a third compound provided in an embodiment of the present invention 1 HNMR spectrogram;
FIG. 8 shows a fourth compound provided in an embodiment of the present invention 1 HNMR spectrogram;
FIG. 9 shows a fifth compound provided in an example of the present invention 1 HNMR spectrogram;
FIG. 10 is a drawing of F-BPA provided by an embodiment of the present invention 1 HNMR spectrogram;
FIG. 11 is a schematic diagram of an embodiment of the present invention 18 Radiochemical purity of F-BPA.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
The BPA referred to in the examples of the present invention is herein designated 4-dihydroxyboro-L-phenylalanine. The F-BPA referred to in the examples of the present invention is a compound formed by substituting an F atom for one H atom on the benzene ring of BPA, which is referred to herein as 2-fluoro-4-dihydroxyboron-L-phenylalanine. Embodiments of the invention relate to 18 F-BPA is F-BPA formed by substituting F atoms with relative atomic mass of 18 for one H atom on the benzene ring of BPA. F atoms having a relative atomic mass of 18 are radioactive and result in 18 F-BPA or other substances containing F atoms with a relative atomic mass of 18 carry radioactivity.
Referring to fig. 1-5, embodiments of the invention provide a method of synthesizing F-BPA comprising the steps of:
first compound and I - Reacting to form a second compound, wherein,
the chemical structural formula of the first compound is as follows:
the chemical structural formula of the second compound is as follows:
reacting the second compound with cycloisopropyl malonate to generate a third compound, wherein,
the chemical structural formula of the third compound is as follows:
reacting the third compound with tert-butyloxycarbonyl group to produce a fourth compound, wherein,
the chemical structural formula of the fourth compound is as follows:
the fourth compound and F - The reaction produces a fifth compound in which,
the chemical structural formula of the fifth compound is:
the fifth compound with H + The reaction produces F-BPA, wherein,
the chemical structural formula of the F-BPA is as follows:
the process for the synthesis of F-BPA provided by the examples of the present invention is described in detail below.
See fig. 1. In certain embodiments, first compound 10 is different from I - The reaction produces a second compound 20.
In some embodiments, the first compound 10 is dissolved in diluted hydrochloric acid to obtain a first mixed solution, and the diluted hydrochloric acid serves as a solvent for the first compound 10 and provides an acidic environment for subsequent reactions, but the invention is not limited thereto, and the diluted hydrochloric acid may be replaced by other acids, such as diluted sulfuric acid, acetic acid, and the like. For the purpose of explaining the present invention, dilute hydrochloric acid is exemplified hereinafter. In certain embodiments, the volume of dilute hydrochloric acid may be 10mL, although other suitable volumes are possible. In certain embodiments, the concentration of dilute hydrochloric acid may be 0.1mol/L, although other suitable concentrations are possible, such as 0.09mol/L, 0.11mol/L, for example.
In some embodiments, I will be provided - The compound of (2) and hypochlorite are dissolved in water to obtain a second mixed solution. In certain embodiments, I may be provided - The compound (b) may be a compound of I with an active metal, and illustratively, may beProviding I - The compound can be NaI, KI or other compounds which can be dissolved in water and ionized to obtain I - The compound of (1). In certain embodiments, the hypochlorite can be NaClO, KClO, or other suitable hypochlorite. Below can provide I - The compound (2) is NaI, and the hypochlorite is NaClO, but the mass of NaI may be 134mg, and the mass of sodium hypochlorite may be 58 mg.
In some embodiments, the second mixed solution is added to the first mixed solution to obtain a third mixed solution, but the first mixed solution may also be added to the second mixed solution to obtain the third mixed solution.
In some embodiments, concentrated hydrochloric acid is added to the third mixture to react to form the second compound, and the concentrated hydrochloric acid provides sufficient acidic environment for the reaction to facilitate the reaction.
The reaction mechanism of the step is as follows:
4I - +ClO 2 - +4H + ＝2I 2 +Cl - +2H 2 O；
2I 2 +3ClO 2 - ＝2ICl+2IO 3 - +Cl - ；
ICl is reacted with the first compound to produce a second compound.
In certain embodiments, the concentration of concentrated hydrochloric acid may be 12mol/L, although other concentrations of suitable concentrated hydrochloric acid may be used. In certain embodiments, the volume of concentrated hydrochloric acid may be 0.2mL, although other suitable volumes of concentrated hydrochloric acid may be used. In certain embodiments, concentrated hydrochloric acid is slowly added dropwise to the third mixture. In certain embodiments, concentrated hydrochloric acid may be slowly added dropwise to the third mixed liquor using a dropping funnel. In some embodiments, after adding concentrated hydrochloric acid to the third mixture, stirring may be performed to allow the reaction to proceed sufficiently. In certain embodiments, the reaction temperature is room temperature and the reaction time may be 6 hours.
In some embodiments, after the reaction to form the second compound 20, ether is added to the reaction solution for extraction. In certain embodiments, the volume of diethyl ether may be 30 mL. The organic layer was separated after extraction. In certain embodiments, the organic layer may be washed twice with water, and the two washed organic layers combined. In certain embodiments, the organic layer is evaporated to dryness. In certain embodiments, the organic layer may be evaporated to dryness by rotary evaporation to dryness. After the organic layer is evaporated to dryness, diethyl ether is added for recrystallization, and the volume of the diethyl ether can be 10 mL. The solid obtained from the recrystallization is filtered off and dried under vacuum to isolate the second compound 20.
First Compounds 10 and I - The yield of the reaction to form the second compound 20 was 68%. With reference to the second compound 20 shown in FIG. 6 1 HNMR spectrogram according to 1 The HNMR spectrogram shows that the structure is correct, 1 HNMR(400MHz，TFA)：δ(ppm)2.06(s，2H，-B-OH)，2.15(s，2H，NH 2 )，3.04(2H，-CH 2 ) 3.88(s, 1H, CH), 6.94, 7.29, 7.62(3H, aryl hydrogen), 11.14(s, 1H, -COOH).
See fig. 2. In certain embodiments, the second compound 20 is reacted with the cyclo (isopropylidene) malonate to provide the third compound 30.
In some embodiments, the second compound 20 and m-chloroperoxybenzoic acid (mCPBA) are dissolved in dichloromethane to obtain a fourth mixed solution, m-chloroperoxybenzoic acid can oxidize I on a benzene ring in the second compound 20, and the oxidized product can participate in a subsequent reaction. In certain embodiments, the mass of second compound 20 is 335mg, the volume of methylene chloride is 25mL, and the mass of m-chloroperoxybenzoic acid is 173 mg. In some embodiments, after second compound 20 and m-chloroperoxybenzoic acid (mCPBA) are dissolved in dichloromethane, stirring is performed at room temperature for 0.5h to obtain a fourth mixture.
In some embodiments, the fifth mixture is obtained by dissolving the cyclic isopropyl malonate (Meldrum's Acid) in an alkaline solution, which is used to dissolve the cyclic isopropyl malonate and provide an alkaline environment for the reaction. In certain embodiments, the caustic solution may be KOH, although the caustic solution may also be NaOH, or other suitable caustic solution. In some embodiments, the alkali solution is KOH, the weight of the cyclopropyl (cyclo) isopropyl malonate is 144mg, the concentration of KOH is 5%, and the volume is 1 mL.
In some embodiments, the fifth mixture is added to the fourth mixture and reacts to form the third compound 30. In certain embodiments, the fifth mixed liquor may be slowly added to the fourth mixed liquor through a dropping funnel. In some embodiments, the fifth mixture is added to the fourth mixture, the reaction time may be 5 hours, and the reaction temperature may be room temperature, and the third compound 30 is generated.
In some embodiments, after the reaction to form the third compound 30, a large amount of light yellow solid is generated in the reaction solution, and the light yellow solid is the third compound 30. The pale yellow solid was filtered off, washed with a little water and dried under vacuum, and the third compound 30 was isolated.
In certain embodiments, the second compound 20 is reacted with the isopropyl (ene) malonate to form the third compound 30 in a 58% yield. See fig. 7 for a third compound 30 1 HNMR spectrum according to 1 The HNMR spectrogram shows that the structure is correct, 1 HNMR(400MHz，TFA)：δ(ppm)1.79(s，1H，CH 3 )，2.01s，2H，NH 2 )，2.08(s，2H，-B-OH)，3.04(2H，-CH 2 ) 3.88(1H, -CH), 7.14, 7.26, 7.32(3H, aryl hydrogen), 11.1(s, 1H, -COOH).
See fig. 3. In certain embodiments, the third compound 30 is reacted with a tert-butoxycarbonyl group to form a fourth compound 40.
The english abbreviation of t-butyloxycarbonyl is Boc, and in certain embodiments, the third compound 30 is reacted with a compound that can provide t-butyloxycarbonyl to form the fourth compound 40, and in particular, the third compound 30 is reacted with a t-butyloxycarbonyl of a compound that can provide t-butyloxycarbonyl to form the fourth compound 40. The compound which provides the t-butyloxycarbonyl group can be di-t-butyl dicarbonate (also called t-butyl acetate, chemical formula (Boc) 2 O), of course, the present invention is not limited thereto, and the compound which can provide t-butoxycarbonyl group may also be other compounds such as L-proline tert-butyl ester hydrochloride and the like. For the purpose of explaining the present invention, a compound capable of providing a tert-butoxycarbonyl group will be described hereinafter as an example of di-tert-butyl dicarbonate.
In certain embodiments, the third compound 30, NaHCO 3 And di-tert-butyl dicarbonate are dissolved in dichloromethane and react to generate a fourth compound 40, NaHCO 3 After dissolution in dichloromethane, the solution can be made basic to provide a slightly basic environment for the reaction, of course, NaHCO is used herein 3 Other substances which dissolve in methylene chloride and render the solution alkaline, such as KHCO, may be substituted 3 、K 2 CO 3 、Na 2 CO 3 And so on. In certain embodiments, the third compound 30 has a mass of 481mg, NaHCO 3 The mass of (3) was 168mg, the mass of di-tert-butyl dicarbonate was 202mg, and the volume of methylene chloride was 25 mL. In certain embodiments, the third compound 30, NaHCO 3 And di-tert-butyl dicarbonate are dissolved in dichloromethane, and then the mixture reacts for 1h at 0 ℃, and then the mixture is heated to room temperature and stirred for 5h to react to generate a fourth compound 40.
In certain embodiments, the reaction of third compound 30 with di-tert-butyl dicarbonate produces fourth compound 40 in 88% yield. See the fourth compound 40 shown in FIG. 8 1 HNMR spectrogram according to 1 The HNMR spectrogram shows that the structure is correct, 1 HNMR(400MHz，TFA)：δ(ppm)1.40(s，3H，Boc-CH 3 )，1.79(s，3H，CH 3 )，2.08(s，2H，-B-OH)，3.06(2H，-CH 2 ) 4.85(1H, -CH), 7.19, 7.23, 7.29(3H, aryl hydrogen), 11.6(s, 1H, -COOH).
See fig. 4. In certain embodiments, fourth compound 40 is reacted with F - The reaction produces a fifth compound 50.
In certain embodiments, F may be provided using KF - Of course, NaF or other suitable fluorides may also be used. Hereinafter, KF will be described as an example.
In certain embodiments, 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Hexacosane (English abbreviated as K) 2.2.2 For convenience of writing, K is used in this application 2.2.2 To 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Hexacosane), K 2 CO 3 KF is dissolved in anhydrous dimethyl sulfoxide (DMSO) to obtain a sixth mixed solution, K 2.2.2 As catalyst for the reaction, K 2 CO 3 In solution inAfter the dimethyl sulfoxide is anhydrous, the solution can be made alkaline to provide a weak alkaline environment for the reaction, and of course, K is used 2 CO 3 Can be replaced by other substances which are soluble in anhydrous dimethyl sulfoxide and make the solution alkaline, such as KHCO 3 、NaHCO 3 、Na 2 CO 3 And so on. In certain embodiments, K 2.2.2 Has a mass of 113mg, K 2 CO 3 The mass of (3) was 41.4mg, the mass of KF was 17.4mg, and the volume of anhydrous dimethyl sulfoxide was 10 mL. Will K 2.2.2 ，K 2 CO 3 And after KF is dissolved in anhydrous dimethyl sulfoxide, heating and stirring the mixture for reaction for 0.5h at the temperature of 120-130 ℃ in an oil bath to obtain a sixth mixed solution.
In some embodiments, fourth compound 40 is dissolved in anhydrous dimethyl sulfoxide to obtain a seventh mixed solution. In certain embodiments, the mass of fourth compound 40 is 136mg and the volume of anhydrous dimethylsulfoxide is 5 mL.
In some embodiments, the seventh mixture is added to the sixth mixture and reacted to form the fifth compound 50. In certain embodiments, the seventh mixed liquor may be slowly added to the sixth mixed liquor through a dropping funnel. In some embodiments, the reaction solution becomes dark caramel color with the addition of the seventh mixed solution. In some embodiments, the seventh mixture is added to the sixth mixture, refluxed at 150 ℃, stirred and reacted for 20min to generate the fifth compound 50.
In certain embodiments, after the reaction to form the fifth compound 50, dimethyl sulfoxide is removed by distillation under reduced pressure to provide a first residue. In certain embodiments, after the reaction to form the fifth compound 50, it is cooled to room temperature and the dimethyl sulfoxide is removed by distillation under reduced pressure to give a first residue. In certain embodiments, after dissolving the first residue in methanol, the solution is applied to an activated C18 solid phase extraction column, eluting with diethyl ether and dichloromethane, respectively, to provide a first eluate. In certain embodiments, the first eluate is evaporated to dryness and the fifth compound 50 is isolated, the fifth compound 50 being a tan solid. In some embodiments, the first eluate may be evaporated to dryness by rotary evaporation to dryness. In some embodiments, the C18 solid phase extraction column can be activated by washing the C18 solid phase extraction column with 5mL of acetonitrile to remove excess liquid, washing the column with 10mL of high purity water, and removing excess liquid with air.
In some embodiments, the fourth compound 40 is with F - The reaction yielded the fifth compound 50 in 51% yield. See the fifth Compound 50 shown in FIG. 9 1 HNMR spectrogram according to 1 The HNMR spectrogram shows that the structure is correct, 1 HNMR(400MHz，TFA)：δ(ppm)1.40(s，3H，Boc-CH 3 )，2.06(s，2H，-B-OH)，3.04(2H，-CH 2 ) 4.86(1H, -CH), 6.91, 7.03, 7.1(3H, aryl hydrogen), 10.8(s, 1H, -COOH).
See fig. 5. In certain embodiments, the fifth compound 50 is with H + F-BPA is generated by the reaction.
In some embodiments, hydrochloric acid and dimethyl sulfoxide are mixed to provide an eighth mixed solution. In certain embodiments, the concentration of hydrochloric acid may be 2mol/L, and the volume ratio of hydrochloric acid to dimethyl sulfoxide is 1: 1.
in certain embodiments, a fifth compound 50 is added to the eighth mixed liquor and reacted to form F-BPA. In certain embodiments, the mass of the fifth compound 50 is 129mg and the volume of the eighth mixed solution is 15 mL. In certain embodiments, the fifth compound 50 is added to the eighth mixture at a reaction temperature of 100 ℃ for 0.5h to react to form F-BPA.
In some embodiments, after the reaction to form F-BPA, the reaction solution containing F-BPA is added to an activated silica column (Silican column) and an activated C18 solid phase extraction column, and eluted with hydrochloric acid to obtain a second eluent. In certain embodiments, the hydrochloric acid used for elution may be 50 mmol/L.
In some examples, the silica gel column may be activated by washing the column with 5mL of n-hexane to remove excess liquid, washing the column with 10mL of toluene, and removing excess liquid with air.
In certain embodiments, the second eluate is evaporated to dryness and dried under vacuum to isolate F-BPA. In some embodiments, the second eluate may be evaporated to dryness by rotary evaporation to dryness.
In certain embodiments, the fifth stepCompound 50 and H + The yield of F-BPA produced by the reaction was 60%. With reference to FIG. 10 showing F-BPA 1 HNMR spectrogram according to 1 The HNMR spectrogram shows that the structure is correct, 1 HNMR(400MHz，TFA)：δ(ppm)2.03(s，2H，-B-OH)，2.12(s，2H，-NH 2 )，3.04(2H，-CH 2 ) 3.98(s, 1H, CH), 7.32, 7.51, 8.12(3H, aryl hydrogen), 11.13(s, 1H, -COOH).
In certain embodiments, when synthesized 18 In the case of F-BPA, the step of synthesizing the fourth compound 40 using the first compound 10 is the same as the step of synthesizing the fourth compound 40 using the first compound 10 in the case of F-BPA.
In certain embodiments, when synthesized 18 F-BPA, the fourth compound 40 with 18 The F-reaction produces a fifth compound 50.
In some embodiments of the present invention, the, 18 the F-solution can be produced by using an accelerator using an F-solution without radioactivity. In some embodiments of the present invention, the, 18 the volume of the F-solution was 400. mu.L, and the activity was about 16 mCi.
In some embodiments, the method will comprise 18 F - The solution is added to an activated QMA column (strong anion solid phase extraction column) because 18 The F-solution is formed by passing through an accelerator 18 O(p,n) 18 F is prepared by the nuclear reaction of the F, 18 the F-solution will contain trace impurities and a QMA column is used to remove these trace impurities. In certain embodiments, 0.5mol/LNa may be taken 2 CO 3 10mL of the solution was used to wash the QMA column, air was added to remove excess liquid, the column was washed with 10mL of high purity water, and air was added to drain excess liquid to activate the QMA column.
In some embodiments, the method will comprise 18 Adding the F-solution into the activated QMA column, and adding K 2.2.2 /K 2 CO 3 Eluting with the solution to obtain a third eluate with radioactivity, wherein K is 2 CO 3 The solution can be made alkaline to provide a slightly alkaline environment for the reaction, of course, where K is 2 CO 3 Can be replaced by other substances for rendering the solution alkaline, such as KHCO 3 、NaHCO 3 、Na 2 CO 3 And so on. In some implementationsIn example, K 2.2.2 /K 2 CO 3 The solution is prepared by mixing K 2.2.2 、K 2 CO 3 Dissolving in anhydrous acetonitrile. In certain embodiments, K 2.2.2 /K 2 CO 3 The volume of the solution was 500. mu.L, K 2.2.2 The content was 5.66. mu. mol.
In certain embodiments, after the third eluent having radioactivity is heated to near dryness, acetonitrile is added and heated to near dryness to obtain a second residue having radioactivity. Heating to near dryness (nearly dry) means heating to near dryness but not completely dry. In certain embodiments, after heating the third eluate with radioactivity to near dryness, acetonitrile is added and the third eluate is heated to near dryness, which can be repeated 3 times to substantially remove water.
In some embodiments, after the radioactivity-bearing second residue is cooled to room temperature, the radioactivity-bearing second residue is added to a seventh mixture of fourth compound 40 dissolved in anhydrous dimethyl sulfoxide, and reacted to form a mixture with radioactivity 18 A fifth compound of F50. In some embodiments, a seventh mixture can be obtained by dissolving 2.6mg (3.8. mu. mol) of the fourth compound 40 in 200. mu.L of anhydrous dimethyl sulfoxide. In some embodiments, the second residue with radioactivity is added to a seventh mixture of fourth compound 40 dissolved in anhydrous dimethyl sulfoxide at 150 deg.C for 10min to obtain a mixture with radioactivity 18 A fifth compound of F50.
In some embodiments, a belt is used 18 Fifth Compound 50 Synthesis of F 18 F-BPA. In some embodiments, with 18 Fifth Compound 50 of F with H + Reaction to form 18 F-BPA。
In some embodiments, hydrochloric acid and dimethyl sulfoxide are mixed to provide an eighth mixed solution. In certain embodiments, the concentration of hydrochloric acid may be 2mol/L, and the volume ratio of hydrochloric acid to dimethyl sulfoxide is 1: 1.
in some embodiments, will be provided with 18 Adding the fifth compound 50 of F into the eighth mixed solution to react to generate 18 F-BPA. In some embodiments, will be provided with 18 Adding the fifth compound 50 of F into the eighth mixed solution, reacting at 100 ℃ for 0.5h to generate 18 F-BPA。
In certain embodiments, the reaction produces 18 After F-BPA, will contain 18 Adding the reaction solution of F-BPA into an activated silica gel column and an activated C18 solid phase extraction column, and eluting with hydrochloric acid to obtain a second eluent with radioactivity. In certain embodiments, the hydrochloric acid used for elution may be 50 mmol/L.
In certain embodiments, the second eluate with radioactivity is evaporated to dryness and dried under vacuum, and separated 18 F-BPA. In some embodiments, the second eluate with radioactivity can be evaporated to dryness by rotary evaporation.
In certain embodiments, F-BPA or fourth compound 40 may be synthesized using third compound 30 or fourth compound 40 as an intermediate 18 F-BPA, third compound 30 or fourth compound 40 as an intermediate, the methods provided in the examples of the invention can be used to synthesize third compound 30 or fourth compound 40.
It should be noted that although the synthesis of F-BPA or intermediates is illustrated herein in the form of a number of examples, the various examples herein can be combined with each other without conflict to form a complete example including the specific reactant species, amounts of the various reactants, reaction conditions (temperature, time, etc.).
According to the F-BPA synthesis method provided by the embodiment of the invention, the final product can be obtained by only one hydrolysis reaction after the fluorination substitution, the synthesis time after the fluorination substitution is shortened, and the radiochemical yield and the specific activity of the product are improved.
After the continuous organic reaction, the mixture is subjected to continuous organic reaction, 18 total radiochemical Synthesis of F-BPA (from fourth Compound 40 with 18 F-start to react 18 F-BPA synthesis completed) for about 50min, and the synthesis ended to give 142MBq product (decay corrected) with a radiochemical yield of about 32%. The radiochemical purity of the product is determined by thin-layer chromatography, spotted on silica gel thin-layer plates, washed with 10mmol/L aqueous ammonium acetate: acetonitrile 30: 70 solution isThe starting agent is developed, the radiochemical purity of the solution is measured by a mini-scan radioactive thin-layer scanner after the solution is dried, and the radiochemical purity map is shown in figure 11.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (8)
1. A method of synthesizing an intermediate comprising:
first compound and I - Reacting to form a second compound, wherein,
the chemical structural formula of the first compound is as follows:
the chemical structural formula of the second compound is as follows:
reacting the second compound with cycloisopropyl malonate to form a third compound, wherein,
the chemical structural formula of the third compound is as follows:
reacting the third compound with tert-butyloxycarbonyl group to produce a fourth compound, wherein,
the chemical structural formula of the fourth compound is as follows:
the fourth compound is the intermediate.
2. The method of claim 1, wherein,
the first compound and I - The step of reacting to form the second compound comprises:
dissolving the first compound in dilute hydrochloric acid to obtain a first mixed solution;
will provide I - Dissolving the compound (2) and hypochlorite in water to obtain a second mixed solution, and adding the second mixed solution into the first mixed solution to obtain a third mixed solution;
and adding concentrated hydrochloric acid into the third mixed solution to react to generate the second compound.
3. The method of claim 2, wherein,
after the second compound is generated through the reaction, extracting the reaction liquid to separate an organic layer;
evaporating the organic layer to dryness, and recrystallizing the solid obtained after evaporation to dryness;
and filtering out the solid obtained by recrystallization, and then carrying out vacuum drying to separate out the second compound.
4. The method of claim 1, wherein,
the step of reacting the second compound with the cyclo (isopropylidene) malonate to form a third compound comprises:
dissolving the second compound and m-chloroperoxybenzoic acid in dichloromethane to obtain a fourth mixed solution;
dissolving the cyclopropyl (methylene) isopropyl malonate in the alkali solution to obtain a fifth mixed solution, adding the fifth mixed solution into the fourth mixed solution, and reacting to generate the third compound.
5. The method of claim 4, wherein,
after reacting to produce a third compound, filtering the third compound;
and washing and vacuum drying the third compound obtained by filtering, and separating the third compound.
6. The method of claim 1, wherein,
the step of reacting the third compound with tert-butyloxycarbonyl group to generate a fourth compound comprises:
mixing the third compound, NaHCO 3 And a compound capable of providing the tert-butoxycarbonyl group is dissolved in dichloromethane and reacted to form the fourth compound.
7. An intermediate, wherein the intermediate has the chemical formula:
8. an intermediate according to claim 7, for use in the synthesis of F-BPA.
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