CN114341362B - Preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivative thereof, and levopraziquantel - Google Patents
Preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivative thereof, and levopraziquantel Download PDFInfo
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- CN114341362B CN114341362B CN202080007474.2A CN202080007474A CN114341362B CN 114341362 B CN114341362 B CN 114341362B CN 202080007474 A CN202080007474 A CN 202080007474A CN 114341362 B CN114341362 B CN 114341362B
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- OXFGRWIKQDSSLY-SECBINFHSA-N (1r)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Chemical compound C1=CC=C2[C@H](C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-SECBINFHSA-N 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title abstract description 27
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- -1 compound ester Chemical class 0.000 claims abstract description 14
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- 238000004519 manufacturing process Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229960002957 praziquantel Drugs 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- OCPCZCANFUBIEX-LLVKDONJSA-N (1r)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1C[NH2+][C@@H](C([O-])=O)C2=C1C=C(OC)C(OC)=C2 OCPCZCANFUBIEX-LLVKDONJSA-N 0.000 claims description 3
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- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 3
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ARDNMIBEYQMEAN-UHFFFAOYSA-N tert-butyl n-formylcarbamate Chemical compound CC(C)(C)OC(=O)NC=O ARDNMIBEYQMEAN-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
Classifications
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
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- C12M1/00—Apparatus for enzymology or microbiology
- C12M1/02—Apparatus for enzymology or microbiology with agitation means; with heat exchange means
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- C12M1/00—Apparatus for enzymology or microbiology
- C12M1/36—Apparatus for enzymology or microbiology including condition or time responsive control, e.g. automatically controlled fermentors
- C12M1/38—Temperature-responsive control
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/16—Particles; Beads; Granular material; Encapsulation
- C12M25/20—Fluidized bed
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- C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
- C12M27/02—Stirrer or mobile mixing elements
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- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
- C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
- C12M41/22—Heat exchange systems, e.g. heat jackets or outer envelopes in contact with the bioreactor walls
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
Abstract
The invention discloses a preparation method of a compound shown in a formula (I) and levopraziquantel, which takes a racemate of a compound ester shown in the formula (I) as a substrate, and reacts under the catalysis of immobilized lipase to generate the compound shown in the formula (I), wherein a special circulating fluidized bed reactor is adopted, the special circulating fluidized bed reactor comprises an external circulation system and a reaction column, the immobilized lipase is arranged in the reaction column, the substrate is prepared into substrate mother liquor, the substrate mother liquor circulates and circulates for a plurality of times between the external circulation system and the reaction column, the reaction is carried out in the reaction column, and the substrate mother liquor is circulated once between the external circulation system and the reaction column; the preparation of the levopraziquantel comprises the preparation steps of the formula (I); the preparation method of the formula (I) can obviously improve the utilization rate of the enzyme and reduce the use ratio of the enzyme/substrate, and has the advantages of mild reaction conditions, strong stereoselectivity, high reaction efficiency, relatively simple process and industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of biochemical engineering, and particularly relates to a preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and a derivative thereof, and levopraziquantel.
Background
In nature, tetrahydroisoquinoline alkaloids are widely distributed in plants, such as Lauraceae, magnoliaceae, papaveraceae, ranunculaceae, menispermaceae, aristolochiaceae, etc. In 1974, canadian scientists Kluepfel et al first isolated tetrahydroisoquinoline Naphthyridinomycin (NDM) from Streptomyces vitis (Streptomyces lusitanusAYB-1206) from a soil source. With the intensive research of phytochemicals, more tetrahydroisoquinoline compounds are separated and obtained. To date, 60 members of this family have been reported.
In order to enrich the structural diversity of tetrahydroisoquinolines, students have used a number of classical chemical synthetic methods to modify and engineer them, such as the Pictect-Spengler method, the Pomoanz-fischer method, the Bischler-Napieralski method and the biomimetic synthesis method. The family of compounds, because of their unique chemical structure, exhibit a diversity of biological activities, and are one of the hot spots for long-term research by chemists and biologists. Along with the deep research, more and more action targets of the compounds are found, and important biological activity effects are exerted on the aspects of antibiosis, anti-tumor, antivirus, anti-inflammatory, anticoagulation, bronchiectasis, central nervous system influence and the like, so that the compounds have great clinical medical value.
1,2,3, 4-Tetrahydroisoquinoline (THIQ) exists as a special heterocyclic backbone in many natural alkaloids. Many clinical drugs have THIQ as a core skeleton, and they have various effective therapeutic activities. Over the last decade, the core framework for many potent anticancer antibiotics has been found to be the THIQ alkaloid. Among them, the most well known ones belong to the genus Trabectedin (Ecteinascidin 743,) Is a development of (a). The medicine has high antitumor activity, and is approved by European Committee and Food and Drug Administration (FDA) in 2007 and 2015, respectively, for treating soft tissue sarcoma. Many reports have studied the mechanism of action of Ecteinascidin743 in detail. In addition, (R) -1-methyl-6, 7-dihydroxy-1, 2,3, 4-tetrahydroisoquinoline]And 1-methyl-1, 2,3, 4-tetrahydroisoquinoline is also an effective module for the synthesis of therapeutic agents for Parkinson's disease.
Carboxylic acid derivatives of THIQ are important compounds, and the carboxyl substitution position is 1 position or 3 position. As cyclic alpha-amino acids with limited conformations, they can replace the original protein amino acids and play an important role in the design of novel artificial peptides. Among them, 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid (1-TIC) has been widely used for drug development and medical research. Sulfonamide hydroxamates synthesized using 1-TIC are effective in inhibiting Matrix Metalloproteinases (MMPs). 1-TIC is also useful for the synthesis of receptor antagonists for gonadotropin releasing hormone (GnRH). On the other hand, partial derivatives of 1-TIC occur naturally, for example (-) -salsola-1-carboxylic acid found and identified in the human brain. These natural alkaloids have a wide range of therapeutic effects, for example, 1-TIC derivatives containing 6, 7-dimethoxy or 6, 7-methylenedioxy, and can be used to synthesize β -amyloid precursor protein cleaving enzyme inhibitors for the treatment of alzheimer's disease.
Wherein (R) -1-TIC is a potential building block for a modified peptide or other pharmacologically active compound. (R) -1-TIC, as a conformational analogue of phenylglycine, is the structural basis for the synthesis of many bioactive peptides, such as antibacterial peptides (AMPs) for innate immune protection. When it is used as a structural analogue substitute for phenylalanine, it can be used for synthesizing a Nicotyl transferase inhibitor, and is a new means for treating cancers.
At present, no report on the synthesis of (R) -1-TIC is found.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel method for preparing (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivatives thereof. The method can obviously improve the utilization rate of the enzyme and reduce the use ratio of the enzyme/the substrate, has the characteristics of mild reaction condition, strong stereoselectivity, high reaction efficiency, relatively simple process and the like, and has industrial application prospect.
The invention also provides a preparation method of the levo praziquantel, which comprises the preparation method of the (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and the derivatives thereof.
In order to achieve the above purpose, the invention adopts a technical scheme as follows:
a process for preparing a compound of formula (I),
in the formula (I), R 1 、R 2 Independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group, the method comprising: the raceme of the compound ester of the formula (I) is taken as a substrate to react under the catalysis of immobilized lipase to generate the compound of the formula (I), and is characterized in that:
the method is carried out by adopting a special circulating fluidized bed reactor, the special circulating fluidized bed reactor comprises an external circulation system and a reaction column, and the immobilized lipase is arranged in the reaction column, wherein the substrate is prepared into a substrate mother liquor, so that the substrate mother liquor circulates for a plurality of times between the external circulation system and the reaction column, the reaction is carried out in the reaction column, and the substrate mother liquor is carried out once per cycle between the external circulation system and the reaction column.
According to some preferred aspects of the invention, the method further comprises: and after the reaction of the first batch of substrates is completed, taking out the first batch of reaction mixed liquor after the reaction, adding the second batch of substrates to continue the reaction, taking out the second batch of reaction mixed liquor after the reaction, adding the third batch of substrates to continue the reaction, taking out the third batch of reaction mixed liquor after the reaction, adding the fourth batch of substrates to continue the reaction, and the like, so as to prepare the n batches of reaction mixed liquor.
According to the invention, n is 5 or more; preferably n is 10 or more; more preferably, n is 15 or more; further preferably, n is 20 or more.
According to some specific aspects of the invention, n is 10-40, preferably 15-35, further preferably 20-30.
According to some preferred and specific aspects of the invention, the substrate mother liquor flows through the reaction column from bottom to top, which may be advantageous to maintain the immobilized lipase in a fluidized state.
According to some preferred aspects of the present invention, the reaction column comprises a reaction tube which extends in the up-down direction and is hollow, a jacket which is wrapped outside the reaction tube and can be used for maintaining the reaction temperature in the reaction tube, and optionally a piston which is telescopic and is used for controlling the liquid volume in the reaction tube, and the reaction tube is communicated with the external circulation system.
According to some preferred aspects of the present invention, the upper and lower ends of the reaction tube are respectively provided with a filter membrane for preventing the immobilized lipase from flowing out of the reaction column.
According to some preferred aspects of the invention, the external circulation system comprises a substrate vessel for containing the substrate mother liquor, and a temperature control device for controlling the temperature of the substrate vessel, and optionally a stirring device for stirring the substrate mother liquor, the substrate vessel being in communication with the reaction column.
According to a specific aspect of the invention, the temperature control device is a constant temperature water bath, the substrate container is arranged in the constant temperature water bath, the stirring device is a magnetic stirrer, and the stirring of the substrate mother liquor inside can be realized by placing a magnet in the substrate container.
According to a specific aspect of the invention, the dedicated circulating fluidized bed reactor further comprises a drive mechanism for driving the circulation of the substrate mother liquor between the external circulation system and the reaction column, the drive mechanism including, but not limited to, a peristaltic pump.
According to some preferred aspects of the invention, the concentration of the racemate of the compound of formula (I) or the racemate of the salt of the compound of formula (I) in the substrate mother liquor is in the range of 5 to 11g/L, more preferably 9.5 to 10.5g/L.
According to some preferred aspects of the invention, the immobilized lipase is present in the substrate mother liquor at a concentration of 3.0-3.5g/L, more preferably 3.15-3.45g/L.
According to some preferred aspects of the invention, the flow rate of the substrate mother liquor in the circulating fluidized bed reactor is 0.40-0.45m/s, more preferably 0.41-0.43m/s.
According to some preferred aspects of the invention, the temperature of the reaction is controlled to be 25-35 ℃, more preferably 28-33 ℃, still more preferably 29-32 ℃.
According to some preferred aspects of the invention, the reaction is controlled to be carried out at a predetermined pH value, the predetermined pH value being 7.8-8.2.
According to some preferred aspects of the invention, the immobilized lipase is a combination of one or more selected from the group consisting of lipase QLlip-9 from Tonic medicine Co., ltd. Su, novozyme 435 from Tonic medicine Co., ltd. Su, immo 8285 from Bolet Co., ltd., immo plus from Bolet Co., ltd., D5544 from Bolet Co., ltd., and SZ-PLE-100 (CAL-B) -IMMO from Shanghai) Co., ltd.
According to a specific and preferred aspect of the present invention, the immobilized lipase comprises at least lipase QLlip-9 of Tonic Biomedicine Co., ltd.
According to some specific aspects of the invention, in formula (I), R 1 、R 2 Independently selected from hydrogen, methyl, ethyl, isopropyl, methoxy or ethoxy.
According to some specific and preferred aspects of the invention, the compound ester of formula (I) is a carboxylic acid ester. According to a particular aspect of the invention, the compound ester of formula (I) is (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid ester or (R) -6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid ester.
According to some preferred and specific aspects of the present invention, the compound of formula (I) is (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid or (R) -6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid.
According to some specific and preferred aspects of the invention, the substrate solution comprises the substrate, and a pH buffer and/or a pH adjuster.
According to a specific and preferred aspect of the present invention, the pH buffer is phosphate, which can be formulated as a phosphate buffer solution by dissolving it in water.
According to some preferred aspects of the invention, the pH adjuster is preferably aqueous ammonia, an alkali metal hydroxide or an aqueous solution thereof.
According to a specific and preferred aspect of the present invention, the pH adjustor is 20wt% to 35wt% ammonia water.
The invention also provides another technical scheme: a preparation method of levopraziquantel comprises the following steps: comprising the above-mentioned process for preparing a compound represented by the formula (I), wherein R 1 、R 2 Are each hydrogen, and are represented by the formula (I) (R) 1 、R 2 Are all hydrogen) The levo praziquantel is prepared by the following route as raw materials:
(a) Preparation of Compound 1 (R is an amino protecting group)
The R group can be specifically t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, p-methoxybenzyl or benzyl, etc.;
(b) Preparation of Compound 5 (i.e., levopraziquantel) from Compound 1
According to a specific and preferred aspect of the present invention, in step (1), compound 1 and chloroformate (e.g., methyl chloroformate, ethyl chloroformate, isobutyl chloroformate) are reacted in the presence of pyridine in a solvent, and after the reaction, the precipitate is removed by filtration, and ammonia gas is introduced into the reaction solution to react to produce compound 2. The solvent may be tetrahydrofuran. Further, step (1) may be implemented as follows: adding the compound 1 into tetrahydrofuran, cooling to 0-5 ℃, adding pyridine, dropwise adding chloroformate (such as methyl chloroformate, ethyl chloroformate and isobutyl chloroformate), filtering the separated precipitate, continuously stirring the filtrate for 1-1.5 hours, introducing ammonia gas, stirring at room temperature overnight, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating, and pulping the residue with petroleum ether to obtain the compound 2.
According to the present invention, in step (1), compound 1 may also be reacted with ammonia in the presence of N, N' -Carbonyldiimidazole (CDI) to give compound 2. According to a specific aspect, compound 1 and N, N' -carbonyldiimidazole are reacted in a solvent to provide a carbonylimidazole intermediate, and then the carbonylimidazole intermediate is reacted with ammonia to provide compound 2. Further, step (1) may be implemented as follows: dissolving the compound 1 into a solvent, adding N, N' -carbonyl diimidazole, stirring for more than 5min at room temperature, cooling to below 10 ℃, and dropwise adding ammonia water for reaction. Wherein, the stirring time at room temperature is preferably 10-30min, and the temperature of the reaction system is preferably controlled to be 0-5 ℃ when ammonia water is added dropwise. The solvent is preferably tetrahydrofuran. Preferably, after the crude product is obtained, it is purified by chromatography on a silica gel column, eluting with: methanol: dichloromethane = 0:100-5:95. preferably, the eluent is in the form of dichloromethane: the volume ratio of the methanol is 15-25: 1.
Preferably, in step (2), compound 2 is reduced using a sodium borohydride/trifluoro boric acid/diethyl ether system.
According to a specific aspect, step (2) is implemented as follows: adding the compound 2 into tetrahydrofuran, adding sodium borohydride in batches under the protection of argon at room temperature, heating and refluxing, dropwise adding boron trifluoride diethyl ether, continuously stirring the generated suspension for 1.5-3 hours, detecting the disappearance of the compound 2 by TLC when the gas release is not obvious, ending the reaction, pouring the reaction liquid into HCl ice water, adjusting the pH value to 8.5-9.5, extracting with chloroform for three times, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, and removing the solvent to obtain a crude product of the compound 3, and directly using the crude product for the next reaction.
According to yet another specific aspect, step (2) is embodied as follows: dissolving the compound 2 into a solvent, adding sodium borohydride under the protection of nitrogen and ice bath, dropwise adding boron trifluoride diethyl etherate, keeping the temperature below 10 ℃, stirring and reacting at the temperature of 20-25 ℃ after the addition, wherein the solvent is preferably tetrahydrofuran, and the stirring and reacting time is preferably 30-42h. Preferably, the temperature is reduced to 0-5 ℃ after the reaction is finished, and water is added dropwise to quench the reaction. Preferably, after the crude product is obtained, dichloromethane: the volume ratio of methanol is 19: the mixed solvent with the composition 1 is subjected to column passing.
Further, step (3) is implemented as follows: adding the compound 3 into acetonitrile, adding pyridine and hydrochloric acid, cooling to 0-5 ℃, slowly dropwise adding a solution of cyclohexyl formyl chloride dissolved in chloroform, and stirring at room temperature for reaction after the dropwise addition is finished.
Further, step (4) is implemented as follows: adding the dichloromethane solution of the compound 4 into the dichloromethane solution of chloroacetyl chloride, then adding one or more selected from sodium hydroxide, potassium tert-butoxide and organic amine, stirring for 20-40 minutes, adding benzyl triethyl ammonium chloride, and heating and refluxing to react until the reaction is completed. Wherein, the sodium hydroxide, potassium tert-butoxide or organic amine can be added in the original form, or can be prepared into an aqueous solution, and the latter is preferable. According to a particular aspect, it is preferred to add 30% to 50% by weight of aqueous sodium hydroxide.
The invention also provides another technical scheme: a levo-praziquantel product prepared by the method and process route described above.
The invention also provides another technical scheme: a pharmaceutical composition for preventing and/or treating parasitic diseases, comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient at least comprises the levopraziquantel product.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the invention innovatively enables the racemate of the compound ester of the formula (I) to react and split into the compound of the formula (I) in a specific circulating fluidized bed reactor under the catalysis of immobilized lipase, and not only can have high conversion rate (more than 99 percent) but also can produce enantiomeric excess (e.e. p ) The value (up to 96%), and the utilization rate of the immobilized lipase can be obviously improved (the repeated utilization rate can reach 20 times or even 30 times or more without manual separation), and meanwhile, the enzyme/substrate use ratio is obviously reduced, so that the enzyme use cost is greatly saved (the cost can be reduced by 30 times or even 35 times or more), and the method is favorable for industrialized application.
Drawings
FIG. 1 is a schematic diagram of a dedicated circulating fluidized bed reactor employed in the present invention; wherein, 1, a constant temperature water bath; 2. a magnetic stirrer; 3. a peristaltic pump; 4. a reaction column;
FIG. 2 shows the conversion and e.e of each batch of reaction solution measured in example 1. p A value;
FIG. 3 shows specific enzyme activities of the immobilized enzyme QLlip-9 after 20 batches of recycling and the unused novel immobilized enzyme QLlip-9 in example 1;
FIG. 4 shows the conversion and e.e of the 5 batches of reaction mixture measured in example 5. p Values.
Detailed Description
The above-described aspects are further described below in conjunction with specific embodiments; it should be understood that these embodiments are provided to illustrate the basic principles, main features and advantages of the present invention, and that the present invention is not limited by the scope of the following embodiments; the implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
In the examples which follow, all starting materials are commercially available or prepared by methods conventional in the art, unless otherwise specified. In the following, (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid is abbreviated as (R) -1-TIC; the racemic substrate 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid ester (abbreviated as (+ -) -1) is purchased from Suzhou Tongli biological medicine Co., ltd, and QLlip-9 is purchased from Suzhou Tongli biological medicine Co., ltd. The target product (R) -1-TIC was detected and analyzed by a high performance liquid chromatograph Fuli FL2200, and a chiral analytical column of CHIRALPAK ZWIX (-) (0.40 cm. Phi. Times.15 cm. Times.3 μm) was used; HPLC detection conditions: the mobile phase is methanol: acetonitrile=6:4 (containing 50mM formic acid and 25mM diethylamine); the flow rate was 0.4 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the The detection wavelength is 220nm; the column temperature was 30 ℃.
Example 1 preparation and isolation of (R) -1-TIC
Preparation of (R) -1-TIC:
preparing a substrate mother solution: 10g/L of (+ -) -1 substrate mother liquor was prepared with 0.1M aqueous ammonium acetate buffer (pH=8.0) and the initial pH of the solution was adjusted to 8.0 with 30% ammonia.
0.9g QLlip-9 was weighed.
As shown in fig. 1, this example provides a special circulating fluidized bed reactor, which comprises an external circulation system, a reaction column 4 and a peristaltic pump 3;
wherein the external circulation system comprises a substrate container for containing substrate mother liquor, a temperature control device for controlling the temperature of the substrate container and a stirring device for stirring the substrate mother liquor, and the substrate container is communicated with the reaction column; specifically, the temperature control device is a constant temperature water bath 1, the stirring device is a magnetic stirrer 2, and stirring of internal substrate mother liquor can be realized by placing a magnet in a substrate container;
the reaction column 4 comprises a hollow reaction tube extending along the up-down direction, a jacket (which can be used for keeping the reaction temperature in the reaction tube) coated outside the reaction tube, and a telescopic piston for controlling the volume of liquid in the reaction tube, wherein the reaction tube is communicated with an external circulation system; specifically, in the embodiment, the inner diameter of the reaction tube is 10mm, the height is 30cm, and the upper end and the lower end of the reaction tube are respectively provided with a filter membrane for preventing QLlip-9 from flowing out of the reaction column;
the peristaltic pump 3 is used for driving the substrate mother liquor to circulate between an external circulation system (in this example, a substrate container) and a reaction column 4 (in this example, a reaction tube);
further, 270mL of substrate mother liquor is weighed and added into a substrate container (continuously stirred under the action of a magnetic stirrer 2), the temperature is kept at 30 ℃, QLlip-9 (0.9 g, the concentration of which is about 3.33g/L relative to the substrate mother liquor) is added into a reaction tube, a peristaltic pump 3 is started, the substrate mother liquor in the substrate container is introduced into the reaction tube from bottom to top, the flow rate of the substrate mother liquor flowing through the reaction tube is controlled to be 0.42m/s, and then the substrate mother liquor flows out of the top of the reaction tube and returns to the substrate container, and the reaction is circulated, wherein once reaction (reaction principle: (+ -) -1 reacts under the catalysis of QLlip-9 to generate a compound (R) -1-TIC) of formula (I) is carried out every cycle, the reaction is carried out for 12h, and after the reaction is finished, a reaction mixture after the reaction is taken out from the substrate container, the reaction mixture is recorded as a first batch of reaction mixture;
and then adding a second batch of substrates into the substrate container to continue the reaction, taking out the reacted second batch of reaction mixed solution after the second batch of substrates are reacted, then adding a third batch of substrates to continue the reaction, taking out the reacted third batch of reaction mixed solution after the third batch of substrates are reacted, then adding a fourth batch of substrates to continue the reaction, and the like, so as to prepare 20 batches of reaction mixed solution.
Treatment of each batch of reaction mixture:
and respectively adding a certain amount of 1M hydrochloric acid solution into each batch of reaction mixed solution, uniformly mixing to obtain a sample solution, and then transferring all the sample solution containing 0.5mL of reaction solution into a 25mL volumetric flask, and fixing the volume and diluting by using a mobile phase. After shaking up, a certain amount of diluent is taken, filtered by a microporous organic filter membrane and injected, and the content of two configurations of 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid is detected by high performance liquid chromatography, wherein the detection results are shown in figure 2, and the conversion rate is about or equal to 99% (the conversion rate= [ (the concentration of initial racemic substrate (g/L) -the concentration of residual substrate (g/L))/the concentration of initial racemic substrate (g/L)]×100%),e.e. p About 95.9% [ e.e. p = (R acid product amount-S acid product amount)/(R acid product amount + S acid product amount) ×100%]The preparation method provided by the invention can greatly improve the utilization rate of the enzyme and obviously reduce the use cost of the enzyme.
Isolation and purification of (R) -1-TIC:
after the reaction is finished, the first batch of reaction mixture is filtered while the reaction mixture is hot, and a clear reaction solution is obtained. The reaction solution is concentrated by rotary evaporation at 60 ℃, a large amount of crystals are separated out, and then the filtration is carried out fully, and a product filter cake is obtained by separation. And (3) drying the filter cake at 50 ℃ to finally obtain the dried (R) -1-TIC crystal, wherein the separation yield is about 80%, and the purity is more than 99%.
And meanwhile, the immobilized enzyme QLlip-9 which is recycled in 20 batches is recovered, and the dried recovered enzyme is obtained through vacuum freezing treatment, so that the water content is calculated to be about 72%. As shown in FIG. 3, comparing the difference of the specific enzyme activities of the recovered enzyme and the new enzyme which is not subjected to catalytic reaction, the relative specific enzyme activity of the new enzyme is 100%, and the result shows that the relative specific enzyme activity of QLlip-9 which is subjected to repeated use of 20 batches and vacuum freeze drying treatment can still be kept to be 98.86%, thus proving that the enzyme has excellent operation stability, the repeated use times can reach more than 20 times, and the use cost of the enzyme is obviously reduced.
Example 2 preparation and isolation of (R) -1-TIC
The preparation of (R) -1-TIC is substantially the same as in example 1, except that: weighing 90mL of substrate mother solution, and adding into a reaction tubeThe content of two configurations of 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid is detected by high performance liquid chromatography after 0.3g QLlip-9 is treated with the reaction mixture, and the conversion is about 99% or more (conversion= [ (initial racemic substrate concentration (g/L) -residual substrate concentration (g/L))/initial racemic substrate concentration (g/L)]×100%),e.e. p About 94.3% [ e.e. p = (R acid product amount-S acid product amount)/(R acid product amount + S acid product amount) ×100%]。
The separation and purification method of (R) -1-TIC is the same as that of example 1, and the dried (R) -1-TIC crystal is obtained after treatment, and the purity is more than 99%.
Example 3 preparation and isolation of (R) -1-TIC
The preparation of (R) -1-TIC is substantially the same as in example 1, except that: 180mL of substrate mother liquor is weighed, 0.6g of QLlip-9 is added into a reaction tube, the content of two configurations of 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid is detected by high performance liquid chromatography after the reaction mixed liquor is treated, and the conversion rate is more than or equal to 99 percent (the conversion rate= [ (the concentration of initial racemization substrate (g/L) -the residual substrate concentration (g/L))/the concentration of initial racemization substrate (g/L)]×100%),e.e. p About 95.2% [ e.e. p = (R acid product amount-S acid product amount)/(R acid product amount + S acid product amount) ×100%]。
The separation and purification method of (R) -1-TIC is the same as that of example 1, and the dried (R) -1-TIC crystal is obtained after treatment, and the purity is more than 99%.
Example 4 preparation and isolation of (R) -1-TIC
The preparation of (R) -1-TIC is substantially the same as in example 1, except that: 360mL of substrate mother liquor is weighed, 1.2g of QLlip-9 is added into a reaction tube, the content of two configurations of 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid is detected by high performance liquid chromatography after the reaction mixed liquor is treated, and the conversion rate is more than or equal to 99 percent (the conversion rate= [ (the concentration of initial racemization substrate (g/L) -the residual substrate concentration (g/L))/the concentration of initial racemization substrate (g/L)]×100%),e.e. p About 96.0% [ e.e. p = (R acid product amount-S acid product amount)/(R acid product amount + S acid product amount) ×100%]。
The separation and purification method of (R) -1-TIC is the same as that of example 1, and the dried (R) -1-TIC crystal is obtained after treatment, and the purity is more than 99%.
EXAMPLE 5 preparation and isolation of (R) -1-TIC
The preparation of (R) -1-TIC is substantially the same as in example 1, except that: weighing 4L of substrate mother liquor, adding 13.4g of QLlip-9 into a reaction tube, and detecting the contents of two configurations of 1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid by utilizing high performance liquid chromatography in the reaction process, wherein the contents are as follows:
in this example, 5 batches of the reaction mixture were repeated, and the conversion and e.e. of the reaction mixture obtained in 5 batches were found by referring to FIG. 4. p Substantially identical, not only a better conversion and e.e. was obtained. p The value shows that the catalytic level of QLlip-9 is still stable after repeated use, and the use cost of the enzyme is obviously reduced.
EXAMPLE 6 preparation of Levopraziquantel
The route for the preparation of levopraziquantel from (R) -1-TIC is as follows:
(a) Preparation of Compound 1 (R is an amino protecting group Boc)
50g (0.283 mol) of 1- (R) -tetrahydroisoquinoline carboxylic acid is added to 150 ml of tetrahydrofuran, cooled to 0-5 ℃, a solution of 120.2 g (1.13 mol) of sodium carbonate dissolved in 450 ml of water is added dropwise, and then Boc dissolved in 50ml of tetrahydrofuran is added 2 O (73.9 g, 0.399 mol) was added dropwise to the reaction mixture, and stirred overnight. After the reaction, ethyl acetate is used for extraction, the extracted organic layers are combined, saturated saline is used for washing, anhydrous sodium sulfate is used for drying, filtration, vacuum concentration is carried out for removing the solvent, and the residue is pulped by petroleum ether, so that the Boc-formic acid white solid is obtained as the compound 1.
(b) Preparation of Compound 5 (i.e., levopraziquantel) from Compound 1, wherein R is the same in formulas 1 to 3 and represents an amino protecting group Boc
50g (180 mmol) of Compound 1 are added to 200 ml of tetrahydrofuran, cooled to 0℃and 28.4g (360 mmol) of pyridine are added, 23.4g (216 mmol) of methyl chloroformate are added dropwise, the precipitated precipitate is filtered off, the filtrate is stirred for further 1 hour, ammonia gas is introduced and stirring is continued overnight. 10 ml of water and ethyl acetate are added for extraction three times, 30ml of anhydrous sodium sulfate is used for each time, the mixture is dried, filtered and concentrated, and the residue is pulped by petroleum ether to obtain a white solid Boc-formamide which is the compound 2.
The nuclear magnetic data of compound 2 are: 1 H NMR(CDCl 3 ,400MHz,δppm):1.75(s,1H,CH 3 ),2.78-2.86(m,2H,CH 2 CH 2 N),3.58-3.76(m,2H,CH 2 CH 2 N),5.3(d,1H,CHCONH 2 ),6.17-6.42(d,1H,CHC ONH 2 ),6.61-6.86(s,1H,CHCONH 2 ),7.18-7.25(m,4H,ArH)。
35g (126.7 mmol) of Compound 2 are added to 350ml of tetrahydrofuran, 27g (633.5 mmol) of sodium borohydride are added in portions at room temperature under argon protection, heated under reflux, 70ml (633.5 mmol) of boron trifluoride diethyl ether are added dropwise, the resulting suspension is stirred for 2 hours, and TLC detects the disappearance of the starting amide when the gas release is not evident.
The reaction solution was poured into 0.1M HCl ice water, pH was adjusted to 9 with 1N sodium hydroxide, and extracted three times with 50ml of chloroform. Washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and removing the solvent to obtain 22g of the crude compound 3.
22g of the crude product of compound 3 (83.86 mmol) was added to 230 ml of acetonitrile, pyridine (125 ml, 125 mmol) was added, 2N hydrochloric acid (62.2 ml, 125 mmol) was cooled to 0-5℃and a solution of 19.7g (135 mmol) of cyclohexylformyl chloride dissolved in 71 ml of chloroform was slowly added dropwise, the mixture was stirred at room temperature for reaction overnight, the solvent was removed by concentration under reduced pressure, and 23.1g of the residue was obtained.
The residue (23.1 g) was dissolved in 200 ml of ethyl acetate saturated with hydrogen chloride, stirred at room temperature overnight, the solvent was removed by rotary evaporation, the residue was recrystallized from methanol, and a white solid was separated out, and dried in vacuo to give cyclohexanecarboxamide hydrochloride as a white solid, which was compound 4.
Cyclohexanamide hydrochloride as a white solid (22 g,71.23mmol, compound 4) was dissolved in 90mL of dichloromethane and chloroacetyl chloride (8.29 g,71.23 mmol) dissolved in 30mL of dichloromethane was added followed by 50% NaOH solution (25.32 mL). After stirring for 30 minutes, benzyltriethylammonium chloride (TEBAC, 1.64g,7.12 mmol) was added and heated under reflux for 2 hours. After the reaction was completed, 125mL of water was added, and extracted with dichloromethane. The combined organic phases were washed twice with 5% hydrochloric acid solution, then with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography with PE/ea=20:1 to 5:1 as eluent, the peak of the target product was collected, concentrated, and the obtained concentrate was dissolved in ethyl acetate, heated to dissolve, slowly cooled to precipitate crystals, filtered, and dried to give a white solid of levopraziquantel (compound 5) with a purity of 99.16% and 100% ee.
The data of the levpraziquantel crystal form nuclear magnetism are as follows: 1 HNMR(300MHz,DMSO-d6):δ1.26-1.30(m,3H),1.46-1.63(m,3H),1.72-1.88(m,5H),2.43-2.56(m,1H),2.77-2.87(m,2H),2.90-3.25(m,2H),3.84-4.10(m,1H),4.35-4.49(m,1H),4.79-4.87(m,2H),5.15-5.18(d,1H),7.17-7.19(d,2H),7.24-7.28(d,2H)。
the above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (14)
1. A process for preparing a compound of formula (I),
formula (I)Wherein R is 1 、R 2 Independently selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group, the method comprising: the raceme of the compound ester of the formula (I) is taken as a substrate to react under the catalysis of immobilized lipase to generate the compound of the formula (I), and is characterized in that:
the method is carried out by adopting a special circulating fluidized bed reactor, wherein the special circulating fluidized bed reactor comprises an external circulation system and a reaction column, the immobilized lipase is arranged in the reaction column, wherein the substrate is prepared into a substrate mother liquor, the substrate mother liquor circulates and circulates for a plurality of times between the external circulation system and the reaction column, the reaction is carried out in the reaction column, and the substrate mother liquor is carried out once every time the substrate mother liquor circulates between the external circulation system and the reaction column;
the substrate mother liquor flows through the reaction column from bottom to top;
the reaction column comprises a hollow reaction tube extending along the up-down direction, a jacket coating the outside of the reaction tube, and optionally a piston which is telescopic and used for controlling the volume of liquid in the reaction tube, wherein the reaction tube is communicated with the external circulation system; filtering membranes for preventing the immobilized lipase from flowing out of the reaction column are respectively arranged at the upper end and the lower end of the reaction tube;
the external circulation system comprises a substrate container for containing the substrate mother liquor, a temperature control device for controlling the temperature of the substrate container, and optionally a stirring device for stirring the substrate mother liquor, wherein the substrate container is communicated with the reaction tube;
the flow rate of the substrate mother liquor in the circulating fluidized bed reactor is 0.40-0.45m/s;
controlling the temperature of the reaction to be 25-35 ℃;
controlling the reaction to be carried out at a preset pH value, wherein the preset pH value is 7.8-8.2;
the concentration of the immobilized lipase in the substrate mother solution is 3.0-3.5g/L;
the concentration of the racemate of the compound ester of the formula (I) in the substrate mother liquor is 9.5-10.5g/L;
the immobilized lipase is lipase QLlip-9 of Suzhou Hold biological medicine Co., ltd;
the method further comprises the steps of: and after the reaction of the first batch of substrates is completed, taking out the first batch of reaction mixed liquor after the reaction, adding the second batch of substrates to continue the reaction, after the reaction of the second batch of substrates is completed, taking out the second batch of reaction mixed liquor after the reaction, adding the third batch of substrates to continue the reaction, after the reaction of the third batch of substrates is completed, taking out the third batch of reaction mixed liquor after the reaction, adding the fourth batch of substrates to continue the reaction, and the like, so as to prepare n batches of reaction mixed liquor, wherein n is more than or equal to 5.
2. The method for producing a compound represented by the formula (I) according to claim 1, wherein n is 10 or more.
3. The method for producing a compound represented by the formula (I) according to claim 2, wherein n is 20 or more.
4. The process for preparing a compound of formula (I) according to claim 1, wherein n is 10 to 40.
5. The method for producing a compound represented by the formula (I) according to claim 4, wherein n is 15 to 35.
6. The method for producing a compound represented by the formula (I) according to claim 5, wherein n is 20 to 30.
7. The method for preparing a compound represented by formula (I) according to claim 1, wherein the concentration of the immobilized lipase in the substrate mother liquor is 3.15 to 3.45g/L.
8. The method for preparing a compound represented by formula (I) according to claim 1, wherein the flow rate of the substrate mother liquor in the circulating fluidized bed reactor is 0.41 to 0.43m/s.
9. The method for preparing a compound represented by formula (I) according to claim 1, wherein the temperature of the reaction is controlled to 28-33 ℃.
10. The method for preparing a compound represented by formula (I) according to claim 9, wherein the temperature of the reaction is controlled to be 29-32 ℃.
11. The process for preparing a compound of the formula (I) according to claim 1, wherein R in the formula (I) 1 、R 2 Independently selected from hydrogen, methyl, ethyl, isopropyl, methoxy or ethoxy, wherein the compound ester of formula (I) is a carboxylate.
12. The method for preparing the compound shown in the formula (I) according to claim 11, wherein the compound shown in the formula (I) is (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid or (R) -6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylic acid.
13. The method of preparing a compound of formula (I) according to claim 1, wherein the substrate mother liquor comprises the substrate and a pH buffer and/or pH adjuster.
14. A process for preparing levo-praziquantel, which comprises the process for preparing a compound of the formula (I) as claimed in any one of claims 1 to 13, wherein the levo-praziquantel is prepared by using a compound of the formula (I) as a starting material, wherein R in the formula (I) 1 、R 2 All are hydrogen, and the process for preparing the levopraziquantel is as follows:
r is an amino protecting group.
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