CN115925586A - Preparation method of parent of targeting PSMA and derivative thereof - Google Patents
Preparation method of parent of targeting PSMA and derivative thereof Download PDFInfo
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- CN115925586A CN115925586A CN202211358929.2A CN202211358929A CN115925586A CN 115925586 A CN115925586 A CN 115925586A CN 202211358929 A CN202211358929 A CN 202211358929A CN 115925586 A CN115925586 A CN 115925586A
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- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
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- 150000002306 glutamic acid derivatives Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a PSMA matrix, which breaks through the original liquid phase organic synthesis method, amino acid is bonded on a resin carrier, and a matrix compound is constructed in a solid phase organic synthesis mode, so that the purification of an intermediate can be completed only by simply washing resin. The method fully utilizes the advantages of simple purification, self pseudo-dilution effect and quick and efficient reaction of the solid-phase organic synthesis intermediate, and ensures that the construction of the compound becomes simple and convenient.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a PSMA-targeted parent and a preparation method of a derivative thereof.
Background
Prostate Cancer (PCa) is the most common malignancy of the male genitourinary system, accounting for the second-most incidence of Cancer in men. Among them, the incidence of males in developed countries is higher than in developing countries. However, in recent years, the incidence of prostate cancer in men in developing countries including china has been on the rise year by year with the progress of medical measures and changes in living environments. Aiming at the treatment of cancer, early diagnosis and accurate treatment are good means for improving the survival rate and the cure rate of cancer patients. Therefore, research and development of an early diagnosis and treatment means for prostate cancer are the current research hotspots.
Pluvicotom (lutetium Lu 177 vipivotede tetraxeta, formerly 177 Lu-PSMA-617) was approved for the treatment of prostate specific membrane antigen positive metastatic castration resistant prostate cancer (PSMA positive mCRPC) previously receiving other anticancer therapies (androgen receptor pathway inhibition and taxane chemotherapy), along with concurrent therapy
(68 Ga-PSMA-11) was approved for diagnosis to identify PSMA-positive lesions, and thus research with PSMA-617 as a parent would be a future research hotspot.
177Lu-PSMA-617 is a PSMA-targeted radioligand therapy developed to treat metastatic castration resistant prostate cancer (mCRPC). The drug is an accurate cancer treatment method combining a targeting compound (ligand) and a therapeutic radioisotope (radioactive particle). After blood injection, 177Lu-PSMA-617 binds to prostate cancer cells expressing PSMA, a transmembrane protein, and thus the uptake rate of the drug by the tumor is high compared to normal tissues. Once bound, radiation (beta particles) from the radioisotope can damage tumor cells, destroy their replicative capacity and/or trigger cell death. The radiation of the radioisotope only works for a short distance to limit damage to surrounding cells.
The traditional PSMA-617 basic matrix is mainly synthesized by a traditional liquid phase organic method in the synthesis process, wherein dangerous catalytic hydrogenation and harsh feeding proportion and anhydrous and anaerobic environment are involved, so that the difficulty of synthesis and the cost of raw materials are not increased, and the traditional PSMA-617 basic matrix is not favorable for large-scale production in the later period. Selecting raw material H-Glu (otbu) -otbu. Hcl on segment 1, mainly selecting triphosgene and p-nitrophenyl chloroformate in the process of urea group construction, constructing an active intermediate by controlling strict feeding proportion and harsh reaction conditions, then reacting the active intermediate with H-Lys (Z) -otbu to form a parent precursor of PSMA-617, and finally removing benzyl under the condition of Pd/H2 to obtain a basic parent of PSMA-617. The method has the defects of strict control of feeding proportion, harsh reaction conditions and certain potential safety hazard.
Therefore, the development of suitable production processes to enable the synthesis of molecular probes to realize industrial production is imminent. According to the invention, through the synthesis research of the parent of the target PSMA, an efficient, safe and simple synthesis process is designed, and the method has general adaptability to the synthesis of the parent of the PSMA and derivatives thereof, and has great development and application values.
Disclosure of Invention
The invention designs and synthesizes a new synthetic route by carrying out inverse synthesis analysis on a parent compound, and under the new process condition, the synthesis of the PSMA-617 does not need a strict operation environment and a high-level reaction solvent, the whole operation is safe and efficient, the source of the required raw materials is wide, the price is low, and the large-scale production can be realized.
The parent compound is synthesized by adopting a solid-phase organic synthesis mode. The commercial amino acid is bonded to the resin carrier, and the process utilizes the 'pseudo-dilution' effect of the resin, so that the feeding ratio is not controlled deliberately, and the generation of dimer can be avoided by the 'pseudo-dilution' effect of the resin even if the feeding ratio is high. In addition, the solid phase synthesis has the advantages that repeated purification of intermediates is avoided, the purification of the intermediates can be realized only by simply cleaning resin, and the purification steps of the intermediates are greatly simplified.
The synthesis operation of the PSMA parent substance is extremely simple and convenient. The method breaks through the original liquid phase organic synthesis method, amino acid is bonded on a resin carrier, and the parent compound is constructed in a solid phase organic synthesis mode, so that the purification of an intermediate can be completed only by simply washing resin.
In the construction process of the ureido module, the construction of the ureido module is carried out by using CDI, DSC and the like with simple raw material sources without using harsh reaction solvents such as triphosgene, anhydrous solvent, nitrogen protection and the like and complex reaction conditions, and the reaction is simple and efficient. In addition, the 'pseudo-dilution' effect of the resin is utilized, so that the feeding proportion is not required to be strictly controlled, dimer byproducts cannot be generated even if the feeding proportion is larger, and the later purification work is greatly saved.
In the PSMA parent body cracking process, the parent body with protection is firstly cracked from resin by weak acid (2 percent TFA), and then concentrated acid cutting is carried out, so that the use amount of TFA can be greatly saved, the synthesis cost is reduced, the waste liquid amount is greatly reduced, and the post-treatment is also simplified.
The present invention provides a process for preparing a compound of formula 1:
the method is characterized in that glutamic acid or derivatives thereof are used as starting materials and are prepared by a solid-phase synthesis method;
the method comprises the following steps:
(1) Preparation of resin Carrier
Glutamic acid or derivatives thereof are used as initial raw materials, and resin is used as a solid phase carrier to prepare a compound shown in a formula 2;
(2) Preparation of ureido moieties
After the compound shown in the formula 2 is subjected to deamination protection, a compound shown in a formula 3 is prepared;
(3) Preparation of Module K
Reacting the compound of formula 3 with lysine (lys) or a derivative thereof to prepare a compound of formula 4;
(4) Modification of the PSMA precursor
Sequentially coupling a compound of formula 4 with naphthylalanine (Nal) or a derivative thereof, and 4-aminomethyl-cyclohexylcarboxylic acid or a derivative thereof to obtain a compound of formula 5;
(5) Cleavage and purification of PSMA precursors
Cracking and purifying the compound shown in the formula 5 to obtain a compound shown in the formula 1;
wherein the groups Z1 and Z2 each independently represent a protecting group;
R 1 and R 2 Each of which is independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkenyl, substituted or unsubstituted C1-C8 alkynyl, substituted or unsubstituted C1-C8 alkyl-keto, substituted or unsubstituted C1-C8 alkyl-amino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl;
or R 1 And R 2 Together with the N atom to which they are attached form a substituted or unsubstituted 3-10 membered heterocyclic ring or 3-10 membered heteroaryl group;
the substituent can be H, OH, NH 2 Halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxy, C1-C8 alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl;
the preparation method is characterized in that the resin is Wang resin or dichlorotrityl chloride resin.
The preparation method is characterized in that the queen resin or dichlorotrityl chloride takes polystyrene with a resin substitution degree of 0.2-1mmol/g and a low crosslinking degree of 1% -2% as a carrier.
The preparation process as described above, the protecting group Z 1 Or Z 2 Each independently an amino protecting group, a hydroxyl protecting group, or a carboxyl protecting group.
The preparation process as described above, the protecting group Z 1 May be an otbu group.
The preparation method as described above, the protecting group Z 2 Can be Fmoc group, alloc group, dde group, MMT group.
The preparation method as described above, wherein the glutamic acid derivative is Fmoc-Glu (otbu) -OH, the lysine (Lys) derivative is H-Lys (Fmoc) -otbu, the naphthylalanine (Nal) derivative is Fmoc-2-Nal-OH, and/or the 4-aminomethyl-cyclohexylcarboxylic acid derivative is Fmoc-trans-4-Amc-OH.
The preparation method as described above, wherein the step (2) is carried out by adding an appropriate amount of Fmoc-Glu (otbu) -O-resin to a reaction tube, removing Fmoc protecting groups with a piperidine solution, and then adding CDI and DIEA to the resin to obtain ureido-modified H-Glu (otbu) -O-resin intermediate.
The preparation method as described above, said step (3) being a preparation method in which after H-Lys (Fmoc) -otbu is dissolved, it is added to ureido-modified H-Glu (otbu) -O-resin intermediate resin, followed by addition of DIEA, to obtain the compound of formula 4.
The preparation method in the step (5) comprises the following steps of adding TFA cutting solution TFA: water: thioanisole: tips =85.5-95%:2-5%:2-5%:1.5-2.5%.
More specifically, the present application provides the following preparation methods:
1. preparation of resin carrier: selecting queen resin as a solid phase carrier, selecting polystyrene with a substitution degree of 0.2-1mmol/g and a low crosslinking degree (1% -2%) as a resin material as a carrier, taking Fmoc-Glu (otbu) -OH as a first bonded amino acid, swelling the queen resin, adding the Fmoc-Glu (otbu) -OH, HOBT and DIC into the resin carrier, carrying out nitrogen bubbling stirring reaction, adding DMAP, continuing reaction, carrying out suction filtration, and adding acetic anhydride and pyridine to carry out resin end capping. And (3) continuing nitrogen bubbling reaction, performing suction filtration, adding DMF (dimethyl formamide) for washing, and shrinking the resin by using methanol to obtain the target resin, namely Fmoc-Glu (otbu) -O-wang resin.
Optionally, dichlorotrityl chloride resin is used as a solid phase carrier, polystyrene with a substitution degree of 0.2-1mmol/g and a low crosslinking degree (1% -2%) is used as a resin material as a carrier, the first bonded amino acid is Fmoc-Glu (otbu) -OH, after swelling with dichlorotrityl chloride resin, fmoc-Glu (otbu) -OH and DIEA are uniformly mixed and then added into the resin carrier, nitrogen is bubbled, stirring is carried out, suction filtration is carried out, after DMF is washed clean, methanol and DIEA are added for carrying out resin end capping. And (3) continuing nitrogen bubbling reaction, performing suction filtration, adding DMF (dimethyl formamide) for washing, shrinking the resin by using methanol, and performing vacuum drying to obtain the target resin, namely Fmoc-Glu (otbu) -O-2-CTC resin.
2. Preparation of ureido modules
The method comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using piperidine solution, then adding CDI and DIEA into the resin, sealing the reaction container, carrying out nitrogen bubbling reaction for 2-3H, and washing the resin by using DMF to obtain a ureido-modified H-Glu (otbu) -O-wang resin intermediate.
The method 2 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using piperidine solution, then adding triphosgene and DIEA into the resin, sealing the reaction vessel, carrying out nitrogen bubbling reaction, and washing the resin by using DMF to obtain an isocyanate modified H-Glu (otbu) -O-wang resin intermediate.
The method 3 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using piperidine solution, then adding p-nitrophenyl chloroformate and DIEA into the resin, sealing the reaction container, reacting under the protection of nitrogen, and then washing the resin by using DMF to obtain a carbamido modified H-Glu (otbu) -O-wang resin intermediate.
The method 4 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using piperidine solution, then adding phenyl chloroformate and DIEA into the resin, sealing the reaction container, reacting under the protection of nitrogen, and then washing the resin by using DMF to obtain a ureido modified H-Glu (otbu) -O-wang resin intermediate.
3. Preparation of Module K
The method comprises the following steps:
dissolving H-Lys (Fmoc) -otbu with DMF, adding into ureido modified H-Glu (otbu) -O-wang resin intermediate, adding DIEA, carrying out nitrogen bubbling reaction at room temperature, and washing the resin with DMF to obtain the resin of PSMA parent compound.
The method 2 comprises the following steps:
dissolving H-Lys (Alloc) -otbu in DMF, adding the solution into ureido modified H-Glu (otbu) -O-wang resin intermediate, adding DIEA, carrying out nitrogen bubbling reaction at room temperature, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
The method 3 comprises the following steps:
dissolving H-Lys (Dde) -otbu with DMF, adding into ureido-modified H-Glu (otbu) -O-wang resin intermediate, adding DIEA, carrying out nitrogen bubbling reaction at room temperature, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
The method 4 comprises the following steps:
dissolving H-Lys (MMT) -otbu with DMF, adding the solution into ureido-modified H-Glu (otbu) -O-wang resin intermediate, adding DIEA, carrying out nitrogen bubbling reaction at room temperature, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
4. Modification of the PSMA precursor
After Fmoc of resin of a PSMA parent compound is removed, fmoc-2-Nal-OH and Fmoc-trans-4-Amc-OH are sequentially coupled to obtain PSMA-617Linker resin.
5. Cleavage and purification of PSMA precursors
After the resin is drained, TFA cutting fluid (TFA (85.5-95%): water (2-5%): thioanisole (2-5%): tips (1.5-2.5%)) is added, after reaction, the resin is filtered, and after the filtrate is lyophilized, the final product is obtained after preparative high performance liquid phase purification.
The wang resin in the above chemical formula represents a resin, and may be any resin suitable for solid phase synthesis, and may be a Wang resin or a dichlorotrityl chloride resin.
The present invention starts with the starting material to obtain the PSMA parent compound in 20-37% yield.
The invention abandons the traditional liquid phase organic synthesis method and uses the solid phase organic synthesis method to construct the parent compound. The advantages of simple purification, self-contained 'pseudo-dilution' effect and quick and efficient reaction of the solid-phase organic synthesis intermediate are fully utilized, so that the construction of the compound becomes simple and convenient.
In the construction process of the key intermediate module urea, the invention abandons the harsh conditions of triphosgene, anhydrous solvent and the like, selects cheap and easily obtained raw materials such as DSC, CDI and the like, has no influence even if the feeding proportion is higher and selects industrial solvent, and greatly simplifies the construction process of the key module.
In the process of cracking the PSMA parent substance, the invention adopts a two-step cracking mode, firstly, the parent substance is cracked from resin by weak acid, and then, concentrated acid is used for cracking. The condition that a large amount of TFA is used in one-step cracking is avoided, the amount of waste liquid is reduced, and the post-treatment is simpler.
The terminology convention:
"alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C as used herein 1 -C 6 Alkyl represents an alkyl group having 1 to about 6 carbon atoms. When C is used in combination with another group herein 0 -C n When alkyl, with (phenyl) C 0 -C 4 Alkyl is an example, a group specified, in which case the phenyl group is via a single covalent bond (C) 0 ) Directly bonded or bonded by having a specified number of carbon atoms (in this case, 1 to about4 carbon atoms) are linked. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
"alkenyl" or "alkenyl" refers to straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. Alkenyl groups described herein typically have 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, such as: c 2 -C 8 、C 2 -C 6 And C 2 -C 4 An alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.
"alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
The term "heterocycle" means a 5-to 8-membered saturated ring, partially unsaturated ring, or aromatic ring containing 1 to about 4 heteroatoms selected from N, O, and S with the remaining ring atoms being carbon, or a 7-to 11-membered saturated, partially unsaturated, or aromatic heterocyclic system and a 10-to 15-membered tricyclic ring system containing at least 1 heteroatom in a polycyclic ring system selected from N, O, and S and containing up to about 4 heteroatoms independently selected from N, O, and S in each ring in the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on carbon or nitrogen atoms, so long as the resulting compounds are stable. The nitrogen atoms in the heterocycle may optionally be quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not more than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridazinyl (pyridizinyl), pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl (benz [ b ] thiophenyl), isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7, 8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.
"aryl" or "heteroaryl" means a stable 5-or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S, and the remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably the total number of S and O atoms in the heteroaryl group is not more than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. The nitrogen atoms in the heterocycle may optionally be quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 5-to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S, thereby forming, for example, a [1,3] dioxazolo [4,5-c ] pyridyl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.
Drawings
FIG. 1: schematic diagram of PSMA synthetic route.
FIG. 2 is a schematic diagram: mass spectrum of PSMA-617 Linker.
FIG. 3: PSMA-617 Linker.
FIG. 4: mass spectrum of PSMA-SH.
FIG. 5: analytical liquid phase diagram of PSMA-SH.
FIG. 6: PSMA-617DOTA mass spectrum.
FIG. 7 is a schematic view of: PSMA-617DOTA analysis of liquid phase diagram.
Detailed Description
The present invention will be further described with reference to the following examples.
EXAMPLE one preparation of resin Carrier
1. Queen resin as solid phase carrier
Selecting a queen resin as a solid phase carrier, selecting a resin material as a carrier, wherein the resin material is polystyrene with a substitution degree of 0.2-1mmol/g and a low crosslinking degree (1% -2%), the first bonded amino acid is Fmoc-Glu (otbu) -OH, swelling the queen resin with 2 times of volume of DCM, washing the queen resin with DMF, uniformly mixing 2eq of Fmoc-Glu (otbu) -OH, 2eq of HOBT and 2eq of DIC in a glass beaker, adding the mixture into the resin carrier, carrying out nitrogen bubbling stirring reaction for 30min, adding 1eq of DMAP, carrying out stirring reaction for 10h at room temperature, carrying out suction filtration, washing the DMF, and adding 2eq of acetic anhydride and 2eq of pyridine to carry out resin end capping. And (3) continuously carrying out nitrogen bubbling reaction for 4h, carrying out suction filtration, adding DMF (dimethyl formamide) to wash the resin, shrinking the resin by methanol, and carrying out vacuum drying to obtain the target resin, namely Fmoc-Glu (otbu) -O-wang resin. The degree of substitution of the resin was measured by ultraviolet spectrophotometry to be 0.7mmol/g.
2. Dichloro trityl chloride resin as solid phase carrier
Dichlorotrityl chloride resin is used as a solid phase carrier, a resin material is polystyrene with substitution degree of 0.2-1mmol/g and low crosslinking degree (1% -2%) as a carrier, the first bonded amino acid is Fmoc-Glu (otbu) -OH, dichlorotrityl chloride resin is swelled with DCM with 2 times volume, DMF is washed clean, 2eq of Fmoc-Glu (otbu) -OH and 6eq of DIEA are uniformly mixed in a glass beaker and then added into the resin carrier, nitrogen is bubbled, stirred and reacted for 4h, suction filtration is carried out, DMF is washed clean, and 4eq of methanol and 6eq of DIEA are added for resin end capping. And (3) continuing nitrogen bubbling reaction for 30min, performing suction filtration, adding DMF (dimethyl formamide) to wash, shrinking the resin by using methanol, and performing vacuum drying to obtain the target resin, namely Fmoc-Glu (otbu) -O-2-CTC resin.
The degree of resin substitution was measured by ultraviolet spectrophotometry to be 0.5mmol/g.
EXAMPLE two preparation of ureido Module
The method comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using 20% piperidine solution, washing the resin, adding 2eq of CDI and 3eq of DIEA into the resin, sealing the reaction container, controlling the reaction temperature to be 25-30 ℃, carrying out nitrogen bubbling reaction for 2-3H, and washing the resin by using DMF to obtain a ureido-modified H-Glu (otbu) -O-wang resin intermediate.
The method 2 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using 20% piperidine solution, washing the resin, then adding 3eq of triphosgene and 3eq of DIEA into the resin, sealing the reaction container, controlling the reaction temperature to be 25-30 ℃ under the protection of nitrogen, carrying out nitrogen bubbling reaction for 2-3H, and washing the resin by using DMF to obtain an isocyanate modified H-Glu (otbu) -O-wang resin intermediate.
The method 3 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, removing Fmoc protecting groups by using a 20% piperidine solution, washing the resin, then adding 4eq of p-nitrophenyl chloroformate and 3eq of DIEA into the resin, sealing the reaction container, reacting for 5 hours under the condition of nitrogen protection, and then washing the resin by using DMF to obtain an intermediate of ureido-modified H-Glu (otbu) -O-wang resin.
The method 4 comprises the following steps:
adding a proper amount of Fmoc-Glu (otbu) -O-wang resin into a reaction tube, washing the resin clean after removing Fmoc protecting groups by using a 20% piperidine solution, then adding 3eq of phenyl chloroformate and 6eq of DIEA into the resin, sealing the reaction container, reacting for 5 hours under the nitrogen protection condition, and then washing the resin by using DMF to obtain a carbamido modified H-Glu (otbu) -O-wang resin intermediate.
EXAMPLE III preparation of Module K
The method comprises the following steps:
selecting commercial H-Lys (Fmoc) -otbu as an amino acid for constructing a K module, dissolving the H-Lys (Fmoc) -otbu with DMF, adding the dissolved H-Lys (Fmoc) -otbu into ureido modified H-Glu (otbu) -O-wang resin intermediate, adding 3eq of DIEA, carrying out nitrogen bubbling reaction at room temperature for 10 hours, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
The method 2 comprises the following steps:
dissolving H-Lys (Alloc) -otbu with DMF, adding the solution into ureido modified H-Glu (otbu) -O-wang resin intermediate, adding 3eq DIEA, carrying out nitrogen bubbling reaction at room temperature for 10H, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
The method 3 comprises the following steps:
dissolving H-Lys (Dde) -otbu with DMF, adding into ureido modified H-Glu (otbu) -O-wang resin intermediate, adding 3eq DIEA, carrying out nitrogen bubbling reaction at room temperature for 10H, and washing the resin with DMF to obtain the resin of the PSMA parent compound.
The method 4 comprises the following steps:
dissolving H-Lys (MMT) -otbu with DMF, adding the solution into an intermediate resin of ureido-modified H-Glu (otbu) -O-wang resin, adding 3eq of DIEA, carrying out nitrogen bubbling reaction at room temperature for 10 hours, and washing the resin with DMF to obtain the resin of a PSMA parent compound.
Example four modification of the PSMA precursor
After Fmoc of the resin of the PSMA parent compound is removed, fmoc-2-Nal-OH and Fmoc-trans-4-Amc-OH are coupled in sequence to obtain PSMA-617Linker resin.
EXAMPLE V cleavage and purification of PSMA precursor
After the resin is drained, TFA cutting fluid (TFA (85.5-95%): water (2-5%): thioanisole (2-5%): tips (1.5-2.5%)) is added, the resin is filtered after stirring and reacting for 2h at room temperature, the filtrates are combined and dried by nitrogen, a proper amount of glacial ethyl ether is added for precipitation, the precipitate is washed by a proper amount of glacial ethyl ether and then dissolved by a proper amount of acetonitrile and water, and then the precipitate is lyophilized. And (4) after the freeze-dried powder is purified by a preparative high-performance liquid phase, freeze-drying to obtain a final product.
The present invention starts with the starting material to obtain the PSMA parent compound in 20-37% yield.
The foregoing description is a general description of the invention. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation, as form changes and equivalents may be employed. Various changes or modifications may be effected therein by one skilled in the art and equivalents may be made thereto without departing from the scope of the invention as defined in the claims appended hereto.
Claims (10)
1. A process for preparing a compound of formula 1:
the method is characterized in that glutamic acid or derivatives thereof are used as starting materials and are prepared by a solid-phase synthesis method;
the method comprises the following steps:
(1) Preparation of resin Carrier
Glutamic acid or derivatives thereof are used as initial raw materials, resin is used as a solid phase carrier, and the compound shown in the formula 2 is prepared;
(2) Preparation of ureido moieties
After the compound shown in the formula 2 is subjected to deamination protection, a compound shown in a formula 3 is prepared;
(3) Preparation of Module K
Reacting the compound of formula 3 with lysine (lys) or a derivative thereof to prepare a compound of formula 4;
(4) Modification of the PSMA precursor
Sequentially coupling a compound of formula 4 with naphthylalanine (Nal) or a derivative thereof, and 4-aminomethyl-cyclohexylcarboxylic acid or a derivative thereof to obtain a compound of formula 5;
(5) Cleavage and purification of PSMA precursors
Cracking and purifying the compound shown in the formula 5 to obtain a compound shown in the formula 1;
wherein the groups Z1 and Z2 each independently represent a protecting group;
R 1 and R 2 Each of which is independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkenyl, substituted or unsubstituted C1-C8 alkynyl, substituted or unsubstituted C1-C8 alkyl-keto, substituted or unsubstituted C1-C8 alkyl-amino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl;
or R 1 And R 2 Together with the N atom to which they are attached form a substituted or unsubstituted 3-10 membered heterocyclic ring or 3-10 membered heteroaryl group;
the substituent can be H, OH, NH 2 Halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxy, C1-C8 alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl;
2. the method according to claim 1, wherein the resin is a royal resin or a dichlorotrityl chloride resin.
3. The method according to claim 1, wherein the queen resin or dichlorotrityl chloride is a polystyrene having a degree of substitution of the resin of 0.2 to 1mmol/g and a low degree of crosslinking of 1% to 2% as a carrier.
4. The process according to claim 1 to 3, wherein the protecting group Z 1 Or Z 2 Each independently is an amino groupA protecting group, a hydroxyl protecting group or a carboxyl protecting group.
5. The process according to any one of claims 1 to 3, wherein the protecting group Z is 1 May be an otbu group.
6. The process according to any one of claims 1 to 3, wherein the protecting group Z is 2 Can be Fmoc group, alloc group, dde group, MMT group.
7. The method of claim 1, wherein the glutamic acid derivative is Fmoc-Glu (otbu) -OH, the lysine (Lys) derivative is H-Lys (Fmoc) -otbu, the naphthylalanine (Nal) derivative is Fmoc-2-Nal-OH, and/or the 4-aminomethyl-cyclohexylcarboxylic acid derivative is Fmoc-trans-4-Amc-OH.
8. The preparation method as set forth in claim 1, wherein the step (2) is carried out by adding an appropriate amount of Fmoc-Glu (otbu) -O-resin to the reaction tube, removing the Fmoc protecting group with piperidine solution, and then adding CDI and DIEA to the resin to obtain ureido-modified H-Glu (otbu) -O-resin intermediate.
9. The preparation method as set forth in claim 1, wherein the step (3) is carried out by dissolving H-Lys (Fmoc) -otbu, adding it to ureido-modified H-Glu (otbu) -O-resin intermediate resin, and then adding DIEA to obtain the compound of formula 4.
10. The preparation method of claim 1, wherein the step (5) is carried out by adding TFA cutting solution TFA: water: thioether ether: tips =85.5-95%:2-5%:2-5%:1.5-2.5%.
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