CN104356197A - Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib - Google Patents

Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib Download PDF

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CN104356197A
CN104356197A CN201410532609.3A CN201410532609A CN104356197A CN 104356197 A CN104356197 A CN 104356197A CN 201410532609 A CN201410532609 A CN 201410532609A CN 104356197 A CN104356197 A CN 104356197A
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formula
compound
base
preparation
carbon
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CN104356197B (en
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姚全兴
李靖
纳特·芬妮
翠茜·伯尔
吴进
喻威
艾威
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Chongqing xingtaihao Pharmaceutical Co.,Ltd.
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Chongqing Taihao Pharmaceutical Co Ltd
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    • 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

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Abstract

The invention provides a carfilzomib intermediate with a structure shown as the formula (XIII). The preparation process of the intermediate is simple, only amino acid condensation and deprotection reactions are related, and the reaction condition is mild and controllable. The intermediate is taken as a raw material to prepare carfilzomib, only an epoxidation reaction is needed, the epoxidation reaction condition has higher selectivity, yield and purity of carfilzomib are improved, the yield of the prepared carfilzomib is higher than 35%, the purity is higher than 99%, and an economical and environment-friendly synthetic process is provided for preparation of carfilzomib.

Description

A kind of Ka Feizuo meter intermediate and preparation method thereof, and the preparation method of a kind of Ka Feizuo meter
Technical field
The present invention relates to medical compounds technical field, particularly relate to a kind of Ka Feizuo meter intermediate and preparation method thereof, and the preparation method of a kind of Ka Feizuo meter.
Background technology
Ka Feizuo meter (Carfilzomib); chemical name is (2S)-N-((S)-1-((S)-4-methyl isophthalic acid-((R)-2-methyl oxirane-2-base)-1-oxo-pentane-2-base formamyl)-2-styroyl)-2-((S)-2-(2-morpholine acetamido)-4-phenylbutanamides base)-4-methylpentanamide; commodity are called Kyprolis; molecular formula is C40H57N5O7, has structure shown in formula (I):
In the last thirty years, world's cancer morbidity with average annual 3% ~ 5% speed increase, cancer has become the mankind's first cause of the death.How effectively prevention and therapy cancer is the emphasis problem of medical research always.Wherein, multiple myeloma is the Clonal disease of a kind of plasma cell dyscrasias, and sickness rate increases year by year, has occupied the second of neoplastic hematologic disorder, and along with the raising for the treatment of level, although complete remission rate is higher, survival rate is still lower, and one of the main reasons is recurrence.
On July 20th, 2012, FDA (FDA) have approved the listing of ONYXPHARMSINC Products Ka Feizuo meter (carfilzomib) freeze-dried powder injection, Carfilzomib accepted at least 2 kinds of medicines before can be used for treatment, comprised the multiple myeloma patients of Velcade and immunomodulator treatment.Carfilzomib's is granted, is the multiple myeloma patients of those recurrences after current therapy treatment, provides a kind of therapeutic choice.
In the clinical trial of Carfilzomib medicine, have 266 patients and receive test, researchist represents, patient, after the treatment accepting this medicine, wherein has neoplastic conditions in the patient body of 23% to improve.In clinical trial, the modal bad phenomenon of patient is tired, blood cell number and thrombocyte less, short of breath, diarrhoea and fever, serious words then can the symptom of heart failure.Claim according to Onyx drugmaker, compared with current leukemia medicine, the advantage of Carfilzomib is to reduce nervous lesion.Carfilzomib is played a role by a kind of albumen composition in optionally T suppression cell, thus makes cancer cell more easily dead.The II phase clinical research data display that Onyx drugmaker announces, to the unfruitful patient of other treatment, has 24% to have certain curative effect at least after taking Carfilzomib.
Carfilzomib is by one of consulting firm of U.S. Fiercebiotech terminal cancer medicine being chosen as 10 kinds of most potentiality.Analyst claims, and by 2016, the annual sales amount of carfilzomib will reach 6.84 hundred million dollars.
At present, the synthetic method report about Ka Feizuo meter is less.In patent US20050245435; Ka Feizuo meter synthesis step is as follows: N-Boc leucine and phenylalanine benzyl ester condensation reaction; then under trifluoroacetic acid effect, deprotection obtains its trifluoroacetate; afterwards at N; two peptamines are generated with amino acid condensation under the catalysis of N-diisopropylethylamine, 1-hydroxy benzo triazole; react with chloroacetyl chloride, sodium iodide, morpholine after gained two peptamine deprotection; pass into hydrogen again; under the catalysis of palladium carbon, reduction obtains compound, gained compound and side chain condensation and get Ka Feizuo meter crude product.The final Synthesis Card Fei Zuo meter of this method energy, but still there are some problems when being applied to scale operation, as adopted sodium iodide chlorine substitution reaction yield not high, not only consuming more starting raw material, and causing the yield of the finished product lower; And reaction type is more in this synthetic method, reaction conditions complexity is various, and poor controllability is not suitable for large-scale commercial production.
Therefore, study the synthetic method of Ka Feizuo meter, the synthesis for Ka Feizuo meter provides different possibilities, and the Ka Feizuo meter synthetic method that research and development are applicable to suitability for industrialized production has great importance.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of Ka Feizuo meter intermediate and preparation method thereof, and the preparation method of a kind of Ka Feizuo meter, has higher yield.
The invention provides a kind of Ka Feizuo meter intermediate, there is structure shown in formula (XIII):
Present invention also offers a kind of preparation method of Ka Feizuo meter intermediate, comprising:
Under the effect of condensing agent and organic bases, compound shown in formula (XI), with compound formula (XII) Suo Shi, or carry out condensation reaction with the salt of compound formula (XII) Suo Shi, obtain compound shown in formula (XIII);
Preferably, shown in compound shown in described formula (XI), formula (XII), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 10).
Preferably, described condensing agent is selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, described organic bases is selected from triethylamine, DIPEA, pyridine, morpholine and or N-methylmorpholine in any one or a few.
Preferably, compound shown in described formula (XI) is prepared in accordance with the following methods:
A) under the effect of condensing agent and organic bases, compound generation condensation reaction shown in compound and formula (III) shown in formula (II), obtain compound shown in formula (IV), then through deaminizating protection, generate compound shown in formula V;
Wherein, R is carboxyl-protecting group;
B) under the effect of condensing agent and organic bases, shown in formula (V), shown in compound and formula (VI), compound or its salt carries out condensation reaction, obtain compound shown in formula (VII), again through decarboxylation protection, compound shown in production (VIII);
C) under the effect of condensing agent and organic bases, shown in formula (VIII), shown in compound and formula (IX), compound carries out condensation reaction, obtain compound shown in formula (X), then through decarboxylation protection, compound shown in production (XI);
Wherein, R 1for carboxyl-protecting group.
Preferably, described R, R 1independently be selected from the first group, or the hydrochloride of the first group, vitriol, acetate, Citrate trianion, nitrate, benzene sulfonate or tosilate; Described first group is C 1~ C 5alkyl.
Preferably, described first group is methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.
Preferably, described step a) in, shown in compound shown in described formula (II), formula (III), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 18); Shown in described formula (V), shown in compound, formula (VI), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20); Described step c) in, shown in described formula (VIII), shown in compound, formula (IX), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20).
Preferably, described step a), b) with step c) in, described condensing agent is independently selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, described organic bases be independently selected from triethylamine, DIPEA, pyridine, morpholine and N-methylmorpholine any one or a few.
Present invention also offers the preparation method of a kind of Ka Feizuo meter, comprising:
Under the effect of oxygenant, the compound shown in formula (XIII) is carried out epoxidation reaction, obtains the Ka Feizuo meter shown in formula (I) structure;
Preferably, described oxygenant is ammonium persulfate-sodium bisulfate.
Preferably, the temperature of described epoxidation reaction is-15 DEG C ~ 0 DEG C; The time of described epoxidation reaction is 5 ~ 15h.
Preferably, after preparing Ka Feizuo meter, also comprise and column chromatography and/or recrystallization purifying are carried out to described Ka Feizuo meter.
Compared with prior art, the invention provides a kind of Ka Feizuo meter intermediate, there is structure shown in formula (XIII); The preparation process of described intermediate is simple, and only relate to the condensation between amino acid, deprotection reaction, reaction conditions gentleness is controlled.With described intermediate for Ka Feizuo meter prepared by raw material, only carry out epoxidation reaction, and the epoxidation reaction condition adopted has higher selectivity, improve yield and the purity of Ka Feizuo meter, the Ka Feizuo meter yield of preparation is more than 35%, purity is more than 99%, and the preparation for Ka Feizuo meter provides the synthesis technique of an economy, environmental protection.
Accompanying drawing explanation
The HPLC spectrogram of the compound that Fig. 1 provides for the embodiment of the present invention 2;
Fig. 2 is the HPLC collection of illustrative plates of the compound that the embodiment of the present invention 10 prepares;
Fig. 3 is the HPLC spectrogram of compound prepared by the embodiment of the present invention 16;
Fig. 4 is the HPLC spectrogram of the compound that the embodiment of the present invention 21 prepares;
Fig. 5 is the HPLC spectrogram of the Ka Feizuo meter that the embodiment of the present invention 26 prepares.
Embodiment
The invention provides a kind of Ka Feizuo meter intermediate, there is structure shown in formula (XIII);
The preparation process of described intermediate is simple, and only relate to the condensation between amino acid, deprotection reaction, reaction conditions gentleness is controlled.With described intermediate for Ka Feizuo meter prepared by raw material, only carry out epoxidation reaction, and the epoxidation reaction condition adopted has higher selectivity, improve yield and the purity of Ka Feizuo meter, the Ka Feizuo meter yield of preparation is more than 35%, purity is more than 99%, and the preparation for Ka Feizuo meter provides the synthesis technique of an economy, environmental protection.
A kind of Ka Feizuo meter intermediate provided by the invention, has structure shown in formula (XIII).
Present invention also offers a kind of preparation method of above-mentioned Ka Feizuo meter intermediate, comprising:
Under the effect of condensing agent and organic bases, by compound formula (XI) Suo Shi, with compound formula (XII) Suo Shi, or carry out condensation reaction with the salt of compound formula (XII) Suo Shi, obtain compound shown in formula (XIII);
In the present invention, shown in described formula (XI), shown in compound, formula (XII), the mol ratio of compound, organic bases and condensing agent is preferably 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 10), are more preferably 1:(1.1 ~ 2.): (3 ~ 10): (1.5 ~ 5).
The temperature of described condensation reaction is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The time of described condensation reaction is preferably 1 ~ 24h, is more preferably 4 ~ 10h.
In the present invention, described condensing agent can cause compound shown in compound and formula (XII) shown in formula (XI) for any, or shown in formula (XI), shown in compound and formula (XII), the salt of compound carries out the reagent of condensation reaction, and the present invention is preferably dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, is more preferably dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, most preferred is phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl.
Described organic bases can be any can compound shown in catalysis type (XI) and compound formula (XII) shown, or shown in compound and formula (XII), the salt of compound carries out the reagent of condensation reaction shown in formula (XI), the present invention is preferably triethylamine, N, N-diisopropylethylamine, pyridine, morpholine and or N-methylmorpholine in any one or a few, be more preferably triethylamine, DIPEA, N-methylmorpholine; Most preferably be DIPEA.
In the present invention, shown in described formula (XI), compound is preferably prepared in accordance with the following methods:
A) under condensing agent and organic bases effect, compound generation condensation reaction shown in compound and formula (III) shown in formula (II), obtain compound shown in formula (IV), then through deaminizating protection, generate compound shown in formula V;
Wherein, R is carboxyl-protecting group;
B) under the effect of condensing agent and organic bases, compound or its salt generation condensation reaction shown in compound and formula (VI) shown in formula (V), obtain compound shown in formula (VII), again through decarboxylation protection, compound shown in production (VIII);
C) under the effect of condensing agent and organic bases, compound generation condensation reaction shown in compound and formula (IX) shown in formula (VIII), obtain compound shown in formula (X), then through decarboxylation protection, compound shown in production (XI);
Wherein, R 1for carboxyl-protecting group.
First; under the effect of condensing agent and organic bases, compound generation condensation reaction shown in compound and formula (III) shown in formula (II), obtains compound shown in formula (IV); again through deaminizating protection, generate compound shown in formula V.
Wherein, in formula (III), formula (IV), formula (V), R is carboxy protective group, and can realize decarboxylation protection under normal temperature and pressure conditions, the present invention is preferably the first group, the hydrochloride of the first group, vitriol, acetate, Citrate trianion, nitrate, benzene sulfonate or tosilate; Described first group is C 1~ C 5alkyl.Preferred, described first group is methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.Most preferred embodiment the most of the present invention, described R can be, but be not limited to, methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, the hydrochloride of methyl, the hydrochloride of ethyl, the hydrochloride of sec.-propyl, the hydrochloride of normal-butyl, the hydrochloride of isobutyl-, the hydrochloride of the tertiary butyl, the acetate of methyl, the acetate of ethyl, the acetate of sec.-propyl, the acetate of normal-butyl, the acetate of isobutyl-, the acetate of the tertiary butyl, the Citrate trianion of methyl, the Citrate trianion of ethyl, the Citrate trianion of sec.-propyl, the Citrate trianion of normal-butyl, the Citrate trianion of isobutyl-, the Citrate trianion of the tertiary butyl, the nitrate of methyl, the nitrate of ethyl, the nitrate of sec.-propyl, the nitrate of normal-butyl, the nitrate of isobutyl-, the nitrate of the tertiary butyl, the benzene sulfonate of methyl, the benzene sulfonate of ethyl, the benzene sulfonate of sec.-propyl, the benzene sulfonate of normal-butyl, the benzene sulfonate of isobutyl-, the benzene sulfonate of the tertiary butyl, the tosilate of methyl, the tosilate of ethyl, the tosilate of sec.-propyl, the tosilate of normal-butyl, the tosilate of isobutyl-or the tosilate of the tertiary butyl.
The present invention is preferred, described step a) in, shown in formula (II), shown in compound, formula (III), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5) (1.1 ~ 20): (1.1 ~ 18), are more preferably 1:(1.2 ~ 1.5): (3 ~ 10): (1.1 ~ 5).
The temperature of described condensation reaction is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The time of described condensation reaction is preferably 1 ~ 24h, is more preferably 2 ~ 8h.In the present invention, described condensation reaction can be carried out under atmosphere of inert gases or normality, and wherein, described atmosphere of inert gases is preferably nitrogen or argon gas; Described normality is the non-isolated air condition of normal pressure and temperature.
The temperature of described deaminizating protection is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The reaction times of described deaminizating protection is preferably 0.5 ~ 12h, is more preferably 1 ~ 5h.
Described deaminizating protection is preferably carried out under sour environment, preferably, carries out under hydrochloric acid, sulfuric acid or trifluoroacetic acid existent condition.
After preparing compound shown in formula (V); under the effect of condensing agent and organic bases; by compound or its salt generation condensation reaction shown in itself and formula (VI); obtain compound shown in formula (VII); again through decarboxylation protection, compound shown in formula (VIII) can be prepared.
In compound shown in formula (VI), the scope of described R is identical with the scope of above-mentioned R, does not repeat them here.
Step of the present invention a) in, shown in compound shown in described formula (V), formula (VI), the mol ratio of compound, organic bases and condensing agent is preferably 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20); Be more preferably 1:(1.05 ~ 2.0): (3 ~ 10): (1.5 ~ 5).
The temperature of described condensation reaction is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The time of described condensation reaction is preferably 1 ~ 24h, is more preferably 2 ~ 5h.In the present invention, described condensation reaction can be carried out under atmosphere of inert gases or normality, and wherein, described atmosphere of inert gases is preferably nitrogen or argon gas; Described normality is the non-isolated air condition of normal pressure and temperature.
The temperature of described decarboxylation protection is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The reaction times of described decarboxylation protection is preferably 1 ~ 24h, is more preferably 2 ~ 10h.
The catalyzer of described decarboxylation protection is preferably lithium hydroxide.
The solvent of described decarboxylation protection is preferably the aqueous solution of methyl alcohol or methyl alcohol.
The present invention adopts lithium hydroxide, can realize the decarboxylation protection of compound, avoid and use expensive, inflammable palladium-carbon catalyst under normal temperature and pressure.
After preparing compound shown in formula (VIII); under the effect of condensing agent and organic bases; by compound generation condensation reaction shown in itself and formula (IX); obtain compound shown in formula (X); again through decarboxylation protection, compound shown in formula (XI) can be obtained.
Wherein, in formula (IX), formula (X), R 1for carboxy protective group, and can realize decarboxylation protection under normal temperature and pressure conditions, the present invention is preferably the first group, the hydrochloride of the first group, vitriol, acetate, Citrate trianion, nitrate, benzene sulfonate or tosilate; Described first group is C 1~ C 5alkyl.Preferred, described first group is methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.Most preferred embodiment the most of the present invention, described R can be, but be not limited to, methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, the hydrochloride of methyl, the hydrochloride of ethyl, the hydrochloride of sec.-propyl, the hydrochloride of normal-butyl, the hydrochloride of isobutyl-, the hydrochloride of the tertiary butyl, the acetate of methyl, the acetate of ethyl, the acetate of sec.-propyl, the acetate of normal-butyl, the acetate of isobutyl-, the acetate of the tertiary butyl, the Citrate trianion of methyl, the Citrate trianion of ethyl, the Citrate trianion of sec.-propyl, the Citrate trianion of normal-butyl, the Citrate trianion of isobutyl-, the Citrate trianion of the tertiary butyl, the nitrate of methyl, the nitrate of ethyl, the nitrate of sec.-propyl, the nitrate of normal-butyl, the nitrate of isobutyl-, the nitrate of the tertiary butyl, the benzene sulfonate of methyl, the benzene sulfonate of ethyl, the benzene sulfonate of sec.-propyl, the benzene sulfonate of normal-butyl, the benzene sulfonate of isobutyl-, the benzene sulfonate of the tertiary butyl, the tosilate of methyl, the tosilate of ethyl, the tosilate of sec.-propyl, the tosilate of normal-butyl, the tosilate of isobutyl-or the tosilate of the tertiary butyl.
Step c of the present invention) in, compound, organic bases and condensing agent shown in compound shown in described formula (VIII), formula (IX) mole be preferably 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20), are more preferably 1:(1.2 ~ 2.0): (3 ~ 10): (1.5 ~ 5).
The temperature of described condensation reaction is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The time of described condensation reaction is preferably 1 ~ 24h, is more preferably 2 ~ 5h.In the present invention, described condensation reaction can be carried out under atmosphere of inert gases or normality, and wherein, described atmosphere of inert gases is preferably nitrogen or argon gas; Described normality is the non-isolated air condition of normal pressure and temperature.
The temperature of described decarboxylation protection is preferably-20 DEG C ~ 60 DEG C, is more preferably-5 DEG C ~ 30 DEG C; The reaction times of described decarboxylation protection is preferably 1 ~ 24h, is more preferably 2 ~ 10h.
The catalyzer of described decarboxylation protection is preferably lithium hydroxide.
The solvent of described decarboxylation protection is preferably the aqueous solution of methyl alcohol or methyl alcohol.
The present invention is preferred, and described step a), step b) and step c) in, described condensing agent can be any reagent causing described condensation reaction, and the present invention is preferably dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl.
Described organic bases can for any can the reagent of condensation reaction described in catalysis, the present invention be preferably in triethylamine, DIPEA, pyridine, morpholine and N-methylmorpholine any one or a few.
In the present invention, compound shown in described formula (XII), can prepare according to method well known to those skilled in the art, preferably prepares in accordance with the following methods:
First, under condensing agent phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl (PyBOP) existent condition, compound L-Boc-leucine formula (1) Suo Shi and N, O-dimethyl hydroxylamine hydrochloride are reacted, generates such as formula compound (2) Suo Shi; The solvent of described reaction is preferably methylene dichloride.
Then compound formula (2) Suo Shi and grignard reagent pseudoallyl magnesium bromide are reacted, obtain such as formula compound (3) Suo Shi; The solvent of described reaction is preferably THF, and described reaction is preferably carried out under the condition of nitrogen protection.
Then remove amino protecting group in acid condition, can obtain such as formula compound or its salt (XII) Suo Shi.
After preparing described Ka Feizuo meter intermediate, under the effect of oxygenant, carried out epoxidation reaction, the Ka Feizuo meter shown in formula (I) structure can be obtained.
In the present invention, described oxygenant is preferably ammonium persulfate-sodium bisulfate (Oxone).
The temperature of described epoxidation reaction is preferably-15 DEG C ~ 0 DEG C, is more preferably-10 DEG C ~-5 DEG C; The time of described epoxidation reaction is preferably 5 ~ 15h, is more preferably 8 ~ 10h.
The present invention is preferred, after preparing Ka Feizuo meter, also comprises and carries out column chromatography and/or recrystallization purifying to described Ka Feizuo meter.
The method of the present invention to described column chromatography and recrystallization there is no particular determination, can be the method for column chromatography well known in the art and recrystallization.The present invention is preferred, and the solvent of described column chromatography is the mixing solutions of ethyl acetate and normal hexane.The solvent of described recrystallization is ethanol/water, or ethyl acetate/methyl tertiary butyl ether, or acetone/normal hexane.
The invention provides a kind of Ka Feizuo meter intermediate, there is structure shown in formula (XIII); The preparation process of described intermediate is simple, and only relate to the condensation between amino acid, deprotection reaction, reaction conditions gentleness is controlled.With described intermediate for Ka Feizuo meter prepared by raw material, only carry out epoxidation reaction, and the epoxidation reaction condition adopted has higher selectivity, improve yield and the purity of Ka Feizuo meter, the Ka Feizuo meter yield of preparation is more than 35%, purity is more than 99%, and the preparation for Ka Feizuo meter provides the synthesis technique of an economy, environmental protection.
In order to further illustrate the present invention, below in conjunction with embodiment to Ka Feizuo meter intermediate provided by the invention and preparation method thereof, and the preparation method of Ka Feizuo meter is described in detail.
In the preparation method of the Ka Feizuo meter provided in the present invention, raw materials used or reagent all can be buied by market.
In Ka Feizuo metric system Preparation Method provided by the invention, raw material Chinese and English title corresponding relation used is as shown in table 1:
Raw materials used Chinese and English title correspondence table in table 1 preparation method provided by the invention
The preparation of compound shown in embodiment 1 formula (XII)
Structure N-Boc-L-leucine 23.1g (0.10mol) formula (1) Suo Shi is added in 1000mL there-necked flask, adds 400mL methylene dichloride, stirring and dissolving; Solution is under agitation cooled to-10 DEG C, add PyBOP 78.1g (0.15mol) wherein, slowly N is dripped again, methylene dichloride (100mL) solution of O-dimethyl hydroxylamine hydrochloride 10.7g (0.11mol) in mixed solution.By the solution that obtains at room temperature, stirring reaction 10h, then thin up reaction solution, and with dichloromethane extraction twice, merge organic phase, use saturated common salt water washing, anhydrous magnesium sulfate drying, cross and filter anhydrous magnesium sulfate.Evaporated under reduced pressure solvent, obtains the compound of 23.6g such as formula structure (2) Suo Shi.
Under nitrogen protection, structural compounds 13.7g (0.05mol) formula (2) Suo Shi is added in 1000mL there-necked flask, adds 400mL anhydrous tetrahydro furan, stirring and dissolving; Solution is under agitation cooled to-10 DEG C, slowly drips 10.8mL (0.07mol) pseudoallyl magnesium bromide.The mixing solutions obtained under nitrogen protection, about 0 DEG C, stirring reaction 5h.After reaction terminates, add 200mL saturated ammonium chloride solution, termination reaction, then use dichloromethane extraction twice, merge organic phase, wash with water, anhydrous magnesium sulfate drying, filter, evaporated under reduced pressure solvent, obtains 9.7g such as formula structural compounds (3) Suo Shi.Then add trifluoroacetic acid wherein: the mixing solutions 100mL of methylene dichloride=3:1, react about 2h in 30 DEG C, after reaction terminates, evaporated under reduced pressure solvent, obtains the trifluoroacetate of structural compounds shown in 9.5g formula (XII).
The preparation of compound shown in embodiment 2 formula (V-a)
Under nitrogen protection; N-Boc-L-hyperphenylalaninemia 27.9g (0.10mol) and L-Leu methyl esters trifluoroacetate 26.0g (0.105mol) are added in 1000mL there-necked flask; add 500mL tetrahydrofuran (THF); add DIEA 51.7g (0.4mol) more wherein, mixture is under agitation cooled to 0 DEG C.HOBT 14.9g (0.11mol) is added in this mixture.Under reactant is placed in nitrogen, stirring reaction 2h, underpressure distillation, be dissolved in by residuum in 300mL methylene dichloride, and wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound 36.5g shown in formula (IV), add trifluoroacetic acid wherein again: the mixing solutions 120mL of methylene dichloride=4:1,15 DEG C of stirring reaction 7h, after concentrated, namely obtain off-white color solid 29.3g.
HPLC detection is carried out to the compound formula prepared (V-a) Suo Shi, chromatographic column used is agilentSB-C18, specification is 5 μm × 4.6mm × 150mm, column temperature is 25 DEG C, sample size is 10 μ L, flow velocity is 1.2mL/min, and using 0.1% trifluoroacetic acid-water (A) and acetonitrile (B) as eluent gradient wash-out, solvent is as follows:
Detect under 210nm wavelength, detected result as shown in Figure 1, the HPLC spectrogram of the compound that Fig. 1 provides for the embodiment of the present invention 2.As shown in Figure 1, the present invention prepares the compound of structure shown in formula (V-a), and purity is 96.5%, yield 69.7%.
The preparation of compound shown in embodiment 3 formula (V-b)
Under argon shield; N-Boc-L-hyperphenylalaninemia 27.9g (0.10mol) and L-Leu carbethoxy hydrochloride 39.2g (0.2mol) is added in 1000mL there-necked flask; add 600mL acetonitrile; add pyridine 158.2g (2.0mol) more wherein, mixture is under agitation cooled to-5 DEG C.HBTU 113.8g (0.3mol) is added in this mixture, under reactant is placed in argon gas, stirring reaction 18h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula (IV) compound 37.2g, joined in HCl-ethyl acetate (about 1.5mol/L) solution, after 20 DEG C of reaction 10h, be concentrated into dry, after purifying, obtain off-white color solid 26.6g.
According to the method for embodiment 2, carry out HPLC detection to product, result shows, this type of white solid is the compound of structure shown in formula (V-b), and purity is 97.4%, yield 74.6%.
The preparation of compound shown in embodiment 4 formula (V-b)
N-Boc-L-hyperphenylalaninemia 28.1g (0.10mol) and L-Leu carbethoxy hydrochloride 25.5g (0.13mol) is added in 2000mL there-necked flask, add 1000mL 1, 4-dioxane, add triethylamine 50.6g (0.50mol) more wherein, stir at mixture being 10 DEG C, TBTU 64.2g (0.2mol) is added in this mixture, under reactant is placed in nitrogen, stirring reaction 14h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula (IV) compound 29.8g, joined in HCl-ethyl acetate (about 3.0mol/L) solution, after-5 ~ 0 DEG C of reaction 3h, be concentrated into dry, off-white color solid 20.8g is obtained after purifying.
According to the detection method of embodiment 2, carry out HPLC detection to product, result shows, this type of white solid is the compound of structure shown in formula (V-b), purity 96.8%, yield 58.2%.
The preparation of compound shown in embodiment 5 formula (V-c)
N-Boc-L-hyperphenylalaninemia 28.0g (0.10mol) and L-Leu isopropyl ester 38.1g (0.22mol) is added in 2000mL there-necked flask, add 1000mL1, 4-dioxane, add triethylamine 50.6g (0.50mol) more wherein, mixture is stirred at 10 DEG C, TBTU64.2g (0.2mol) is added in this mixture, under reactant is placed in nitrogen, stirring reaction 14h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, and use saturated sodium bicarbonate successively, water and salt water washing, organic layer evaporated under reduced pressure obtains formula IV compound 31.8g, joined in HCl-ethyl acetate (about 3.0mol/L) solution, after-5 DEG C of reaction 1h, be concentrated into and dryly add 200mL methylene dichloride, PH=8 ~ 9 are adjusted with saturated sodium bicarbonate solution, use 100mL dichloromethane extraction twice water layer respectively, merge organic phase saturated sodium-chloride and wash 1 time, be concentrated into dry off-white color solid 20.9g.
Carry out HPLC detection according to the method for embodiment 2 to product, result shows, this type of white solid is the compound of structure shown in formula (V-c), purity 97.6%, yield 62.5%.
The preparation of compound shown in embodiment 6 formula (V-d)
N-Boc-L-hyperphenylalaninemia 27.8g (0.10mol) and L-Leu tert-butyl ester 57.8g (0.25mol) is added in 1000mL there-necked flask, add 500mLNMP, add DIEA14.2g (0.11mol) more wherein, mixture is stirred at 30 DEG C.The mixture that CDI:DMAP mol ratio is 1:2 is added, altogether 271.1g (2mol) in this mixture.Under reactant is placed in nitrogen, stirring reaction 5h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula IV compound 35.2g, add trifluoroacetic acid wherein: the mixing solutions 120mL of methylene dichloride=4:1, 30 DEG C of stirring reaction 0.5h, concentrating under reduced pressure, then add 150mL methylene dichloride to dissolve, pH to 8 ~ 9 are regulated with saturated sodium bicarbonate solution, be separated organic layer, aqueous phase 70mL dichloromethane extraction 2 times, merge organic phase, use saturated common salt water washing, after concentrated, obtain off-white color solid 24.7g.Carry out HPLC detection according to the detection method of embodiment 2 to product, this type of white solid is the compound of structure shown in formula (V-d), purity 98.3%, yield 70.9%.
The preparation of compound shown in embodiment 7 formula (V-e)
N-Boc-L-hyperphenylalaninemia 27.9g (0.10mol) and L-Leu isobutyl ester 28.1g (0.15mol) is added in 2000mL there-necked flask, add 1500mLNMP, add pyridine 87.0g (1.1mol) more wherein, mixture is under agitation cooled to-20 DEG C.TBTU417.4g (1.3mol) is added in this mixture.Under reactant is placed in nitrogen, stirring reaction 24h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula IV compound 35.9g, add trifluoroacetic acid wherein: the mixing solutions 120mL of methylene dichloride=4:1 ,-20 DEG C of stirring reaction 5h, after concentrated, namely obtain off-white color solid 32.4g.According to the detection method of embodiment 2, carry out HPLC detection to product, result shows, this type of white solid is the compound of structure shown in formula (V-e), purity 95.7%, yield 70.0%.
The preparation of compound shown in embodiment 8 formula (V-f)
N-Boc-L-hyperphenylalaninemia 28.0g (0.10mol) and the positive butyl ester 19.7g (0.105mol) of L-Leu are added in 1000mL there-necked flask, add 500mLNMP, add morpholine 87.1g (1mol) more wherein, mixture is stirred at 60 DEG C.CDI 24.3g (0.15mol) is added in this mixture.Under reactant is placed in nitrogen, stirring reaction 1h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula IV compound 31.4g, joined in HCl-ethyl acetate (about 1.7mol/L) solution, after 10 DEG C of reaction 5h, be concentrated into dry, add 200mL methylene dichloride, PH=8 ~ 9 are adjusted with saturated sodium bicarbonate solution, use 100mL dichloromethane extraction twice water layer respectively, merge organic phase saturated sodium-chloride to wash, namely off-white color solid 22.1g is obtained after concentrating under reduced pressure.Carry out HPLC detection according to the detection method of embodiment 2 to product, result shows, this type of white solid is the compound of structure shown in formula (V-f), purity 96.9%, yield 63.4%.
The preparation of compound shown in embodiment 9 formula (V-g)
N-Boc-L-hyperphenylalaninemia 27.9g (0.10mol) and L-Leu n-pentyl ester acetate 52.3g (0.2mol) are added in 1000mL there-necked flask, add 500mLNMP, add N-methylmorpholine 30.3g (0.3mol) more wherein, mixture is stirred at 25 DEG C.DMAP61.1g (0.5mol) is added in this mixture.Under reactant is placed in nitrogen, stirring reaction 5h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains formula IV compound 33.8g, add trifluoroacetic acid wherein: the mixing solutions 120mL of methylene dichloride=4:1,10 DEG C of stirring reaction 6h, after concentrated, namely obtain off-white color solid 35.1g.Carry out HPLC detection according to the detection method of embodiment 2 to product, result shows, this type of white solid is the compound of structure shown in formula (V-g), purity 97.2%, yield 73.8%.
The preparation of compound shown in embodiment 10 formula (VIII)
Under nitrogen protection; the compound 42.0g (0.10mol) embodiment 2 prepared and morpholine-4-base-acetic acid 15.3g (0.105mol) adds in 1000mL there-necked flask; add 500mL acetonitrile; add DIEA51.7g (0.4mol) more wherein, mixture is under agitation cooled to 0 DEG C.In this mixture, add HOBT 14.9g (0.11mol) in five minutes, then point to add PyBOP 57.3g (0.11mol) altogether for three times.Under reactant is placed in nitrogen, stirring reaction 8h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 150mL, and organic layer evaporated under reduced pressure obtains compound 27.1g shown in formula (VII).Be dissolved in methyl alcohol: in the mixing solutions of water=3:1 (volume ratio), be cooled to 0 DEG C, add lithium hydroxide 12.1g (0.5mol) and react 12h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, with 100mL dichloromethane extraction twice, after organic phase evaporate to dryness, namely obtain white solid 26.2g.
HPLC detection is carried out to product, chromatographic column used is agilent SB-C18, specification is 5 μm × 4.6mm × 150mm, column temperature is 25 DEG C, sample size is 10 μ l, flow velocity is 1.2mL/min, and using 0.1% trifluoroacetic acid-water (A) and acetonitrile (B) as eluent gradient wash-out, solvent is as follows:
Detect under 210nm wavelength, as shown in Figure 2, Fig. 2 is the HPLC collection of illustrative plates of the compound that the embodiment of the present invention 10 prepares to acquired results.As shown in Figure 2, this white solid is the compound of structure shown in formula (VIII), purity 97.1%, yield 62.5%.
The preparation of compound shown in embodiment 11 formula (VIII)
Under argon shield; the compound 35.7g (0.10mol) embodiment 3 prepared and morpholine-4-base-acetic acid 36.3g (0.25mol) adds in 2000mL there-necked flask; add 1200mL tetrahydrofuran (THF); add pyridine 158.2g (2.0mol) more wherein, mixture is under agitation cooled to-20 DEG C.HATU 380.2g (1.0mol) is added in this mixture, under reactant is placed in nitrogen, stirring reaction 24h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound 27.8g shown in formula (VII), be dissolved in methyl alcohol: in the mixing solutions of water=9:1, be cooled to 0 DEG C, add lithium hydroxide 24.2g (1.0mol) and react 8h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, with 100mL dichloromethane extraction twice, namely white solid 24.5g is obtained after organic phase evaporate to dryness.Carry out HPLC detection according to the detection method of embodiment 11 to product, result shows, this white solid is the compound of structure shown in formula (VIII), purity 97.3%, yield 58.4%.
The preparation of compound shown in embodiment 12 formula (VIII)
The compound 33.5g (0.10mol) embodiment 5 prepared and morpholine-4-base-acetic acid 33.4g (0.23mol) adds in 2000mL there-necked flask, add 600mLDMF, add triethylamine 50.6g (0.50mol) more wherein, stir at mixture being 20 DEG C, TBTU 64.2g (0.2mol) is added in this mixture, under reactant is placed in nitrogen, stirring reaction 24h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound 28.6g shown in formula (VII), be dissolved in methyl alcohol: in the mixing solutions of water=5:1, be cooled to 0 DEG C, add lithium hydroxide 19.4g (0.8mol) and react 8h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, use 100mL dichloromethane extraction twice respectively, namely white solid 29.8g is obtained after organic phase evaporate to dryness.Adopt the detection method of embodiment 11 to carry out HPLC detection to product, result shows, this white solid is the compound of structure shown in formula (VIII), purity 97.3%, yield 71.1%.
The preparation of compound shown in embodiment 13 formula (VIII)
The compound 34.8g (0.10mol) embodiment 6 prepared and morpholine-4-base-acetic acid 17.4g (0.12mol) adds in 2000mL there-necked flask, add 600mLDMF, add triethylamine 50.6g (0.50mol) more wherein, stir at mixture being 20 DEG C, TBTU 64.2g (0.2mol) is added in this mixture, under reactant is placed in nitrogen, stirring reaction 24h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and salt water washing, organic layer evaporated under reduced pressure obtains compound 32.4g shown in formula (VII), after being dissolved in methyl alcohol, add lithium hydroxide 19.4g (0.8mol) at-5 DEG C and react 8h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, use 100mL dichloromethane extraction twice respectively, namely white solid 26.4g is obtained after organic phase evaporate to dryness.Adopt the detection method of embodiment 11 to carry out HPLC detection to product, result shows, this white solid is the compound of structure shown in formula (VIII), purity 96.7%, yield 63.0%.
The preparation of compound shown in embodiment 14 formula (VIII)
The compound 34.9g (0.10mol) embodiment 8 prepared and morpholine-4-base-acetic acid 36.3g (0.25mol) adds in 2000mL there-necked flask, add 1200mL solvent DMA, add N-methylmorpholine 9.6g (0.11mol) more wherein, mixture is under agitation cooled to-5 DEG C, EDCI 345.1g (1.8mol) is added in this mixture, under reactant is placed in normality, stirring reaction 2h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound 37.2g shown in formula (VII), be dissolved in methyl alcohol: in the mixing solutions of water=6:1, at 60 DEG C, add lithium hydroxide 14.6g (0.6mol) react 1h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, with 100mL dichloromethane extraction twice, namely white solid 32.1g is obtained after organic phase evaporate to dryness.Adopt the detection method of embodiment 11 to carry out HPLC detection to product, result shows, this white solid is the compound of structure shown in formula (VIII), purity 96.8%, yield 76.4%.
The preparation of compound shown in embodiment 15 formula (VIII)
The compound 47.6g (0.10mol) embodiment 9 prepared and morpholine-4-base-acetic acid 21.7g (0.15mol) adds in 2000mL there-necked flask, add 1200mL solvent DMA, add triethylamine 101.2g (1mol) more wherein, mixture is stirred at 30 DEG C, HOBT14.9g (0.11mol) is added in this mixture, under reactant is placed in normality, stirring reaction 8h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound 34.2g shown in formula (VII), be dissolved in methyl alcohol: in the mixing solutions of water=6:1, be cooled to-5 DEG C, add lithium hydroxide 24.3g (1mol) and react 2h, by 200mL saturated ammonium chloride termination reaction, with about 1N salt acid for adjusting pH value to 3, with 100mL dichloromethane extraction twice, namely white solid 28.1g is obtained after organic phase evaporate to dryness.Adopt the detection method of embodiment 11 to carry out HPLC detection to product, result shows, this white solid is the compound of structure shown in formula (VIII), purity 97.3%, yield 67.0%.
The preparation of compound shown in embodiment 16 formula (XI)
Under nitrogen protection; structural compounds 41.9g (0.10mol) formula (VIII) Suo Shi and 22.6g (0.105mol) L-Phe methyl ester hydrochloride are added in 1000mL there-necked flask; add 500mL acetonitrile; add 51.7g (0.4mol) DIEA more wherein, mixture is under agitation cooled to 0 DEG C.In this mixture, add 17.6g (0.13mol) HOBT, then divided in five minutes and add PyBOP 57.3g (0.11mol) altogether for three times.Under reactant is placed in nitrogen, stirring reaction 8h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, wash twice respectively with saturated sodium bicarbonate, water and saturated aqueous common salt successively, each consumption is 200mL, organic layer evaporated under reduced pressure obtains 38.4g formula (X) compound, be dissolved in methyl alcohol: in the mixing solutions of water=3:1 (volume ratio), be cooled to 0 DEG C, add 12.1g (0.5mol) lithium hydroxide reaction 12h, by 200mL saturated ammonium chloride termination reaction, with 150mL dichloromethane extraction twice, after evaporate to dryness, namely obtain 35.3g white solid.
HPLC detection is carried out to described white solid, chromatographic column used is agilent SB-C18, specification is 5 μm × 4.6mm × 150mm, column temperature is 25 DEG C, sample size is 10 μ l, flow velocity is 1.2mL/min, and using 0.1% trifluoroacetic acid-water (A) and acetonitrile (B) as eluent gradient wash-out, solvent is as follows:
Detect under 210nm wavelength, result is the HPLC spectrogram of compound prepared by the embodiment of the present invention 16 see Fig. 3, Fig. 3.As shown in Figure 3, described white solid is structural compounds shown in formula (XI), and its purity is 97.2%, and yield is 62.3%.
The preparation of compound shown in embodiment 17 formula (XI)
Structural compounds 41.9g (0.10mol) formula (VIII) Suo Shi and 76.8g (0.25mol) L-Phe ethyl ester trifluoroacetate are added in 2000mL there-necked flask, add 1000mLDMF, add 50.6g (0.50mol) triethylamine more wherein, stir at mixture being 20 DEG C, 321g (1.0mol) TBTU is added in this mixture, under reactant is placed in nitrogen, stirring reaction 24h, underpressure distillation, residuum is dissolved in 300mL methylene dichloride, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound shown in 44.1g formula (X), be dissolved in methyl alcohol: in the mixing solutions of water=5:1, be cooled to 0 DEG C, add 19.4g (0.8mol) lithium hydroxide reaction 8h, by 200mL saturated ammonium chloride termination reaction, use 100mL dichloromethane extraction twice respectively, namely 39.0g white solid is obtained after evaporate to dryness.Detect through HPLC, this white solid is the compound of structure shown in formula (XI), purity 97.6%, yield 68.9%.
The preparation of compound shown in embodiment 18 formula (XI)
Structural compounds 41.9g (0.10mol) formula (VIII) Suo Shi and 50.0g (0.15mol) L-Phe n-pentyl ester vitriol are added in 2000mL there-necked flask, add 1200mL solvent DMA, add 116.4g (0.9mol) N more wherein, N-diisopropylethylamine, mixture is stirred at 25 DEG C, 189.6g (0.5mol) HBTU is added in this mixture, under reactant is placed in normality, stirring reaction 6h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound shown in 43.9g formula (X), be dissolved in methyl alcohol: in the mixing solutions of water=6:1, 12.2g (0.5mol) lithium hydroxide reaction 7h is added at 30 DEG C, by 200mL saturated ammonium chloride termination reaction, with 150mL dichloromethane extraction twice, namely white solid 37.2g is obtained after evaporate to dryness, detect through HPLC, this white solid is the compound of structure shown in formula (XI), purity 97.7%, yield 65.7%.
The preparation of compound shown in embodiment 19 formula (XI)
Under nitrogen protection, structural compounds 41.9g (0.10mol) formula (VIII) Suo Shi and the positive butyl ester Citrate trianion of 49.6g (0.12mol) L-Phe are added in 2000mL there-necked flask, add 1200mL solvent DMSO, add 174.2g (2.0mol) morpholine more wherein, mixture is stirred at 60 DEG C, the mixture that DCC:DIC is 1:1 is added in this mixture, 18.3g (0.11mol) altogether, under reactant is placed in argon gas, stirring reaction 1h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound shown in 39.8g formula (X), be dissolved in methyl alcohol: in the mixing solutions of water=4:1, be cooled to-20 DEG C, add 14.6g (0.6mol) lithium hydroxide reaction 24h, by 200mL saturated ammonium chloride termination reaction, with 120mL dichloromethane extraction twice, namely white solid 34.1g is obtained after evaporate to dryness, detect through HPLC, this white solid is the compound of structure shown in formula (XI), purity 96.5%, yield 60.1%.
The preparation of compound shown in embodiment 20 formula (XI)
Structural compounds 41.9g (0.10mol) formula (VIII) Suo Shi and 51.8g (0.25mol) L-Phe isopropyl ester are added in 2000mL there-necked flask, add 1000mL solvent DMA, add 9.6g (0.11mol) N-methylmorpholine more wherein, mixture is under agitation cooled to-5 DEG C, 345.1g (1.8mol) EDCI is added in this mixture, under reactant is placed in normality, stirring reaction 2h, underpressure distillation, residuum is dissolved in 300mL ethyl acetate, use saturated sodium bicarbonate successively, water and saturated aqueous common salt wash twice respectively, each consumption is 150mL, organic layer evaporated under reduced pressure obtains compound shown in 48.9g formula (X), be dissolved in methyl alcohol: in the mixing solutions of water=6:1, 14.6g (0.6mol) lithium hydroxide reaction 1h is added at 60 DEG C, by 300mL saturated ammonium chloride termination reaction, with 150mL dichloromethane extraction twice, namely white solid 43.3g is obtained after evaporate to dryness, detect through HPLC, this white solid is the compound of structure shown in formula (XI), purity 96.8%, yield 76.4%.
The preparation of compound shown in embodiment 21 formula (XIII)
Under nitrogen protection; shown in the formula (XII) prepare compound 28.3g (0.05mol) formula (XI) Suo Shi and embodiment 1, the trifluoroacetate 14.8g (0.055mol) of compound adds in 2000mL there-necked flask; add 800mLDMF; add DIEA129.2g (1.0mol) more wherein; HOBT43.4g (0.32mol), is under agitation cooled to 0 DEG C by mixture.Divide and add PyBOP 93.3g (0.18mol) altogether for three times.Under reactant is placed in nitrogen, 0 ~ 5 DEG C of stirring reaction 20h, reactant saturated sodium-chloride dilutes, be extracted with ethyl acetate, organic layer washes twice respectively with water and saturated aqueous common salt successively, and each consumption is 150mL, through anhydrous magnesium sulfate drying, organic layer evaporated under reduced pressure, obtains white solid 21.6g after purifying.
Carry out HPLC detection to described white solid, result is the HPLC spectrogram of the compound that the embodiment of the present invention 21 prepares see Fig. 4, Fig. 4, as shown in Figure 4, described white solid has structure shown in formula (XIII), and its purity is 96.9%, and yield is 61.3%.
The preparation of compound shown in embodiment 22 formula (XIII)
Under argon shield; shown in the formula (XII) prepare compound 28.3g (0.05mol) formula (XI) Suo Shi and embodiment 1, the trifluoroacetate 32.3g (0.12mol) of compound adds in 2000mL there-necked flask; add 1000mL tetrahydrofuran (THF); add triethylamine 50.6g (0.5mol) more wherein; HATU30.4g (0.08mol), is under agitation cooled to less than 10 DEG C points and adds PyBOP 41.4g (0.08mol) altogether for three times by mixture.Under reactant is placed in argon gas, 10 ~ 15 DEG C of stirring reaction 10h, reactant saturated sodium-chloride dilutes, with dichloromethane extraction, organic layer washes twice respectively with water and saturated aqueous common salt successively, and each consumption is 150mL, through anhydrous magnesium sulfate drying, organic layer evaporated under reduced pressure, obtain white solid 22.9g after purifying, detect through HPLC, this white solid is the compound of structure shown in formula (XIII), purity 97.0%, yield 65.1%.
The preparation of compound shown in embodiment 23 formula (XIII)
The trifluoroacetate 18.8g (0.07mol) of compound shown in compound 28.3g (0.05mol) formula (XI) Suo Shi and the formula (XII) prepared according to embodiment 1 is added in 2000mL there-necked flask, add 800mL glycol dimethyl ether, add triethylamine 45.5g (0.45mol) more wherein, HOBT 41.3g (0.15mol), is under agitation cooled to-10 DEG C by mixture.Divide and add PyBOP 51.7g (0.1mol) altogether for three times.By reaction mixture at-10 ~ 0 DEG C of stirring reaction 8h, reactant saturated sodium-chloride dilutes, and with dichloromethane extraction, organic layer washes twice respectively with water and saturated aqueous common salt successively, each consumption is 150mL, through anhydrous magnesium sulfate drying, organic layer evaporated under reduced pressure, obtains white solid 23.7g after purifying, detect through HPLC, this white solid is the compound of structure shown in formula (XIII), purity 97.5%, yield 67.5%.
The preparation of compound shown in embodiment 24 formula (XIII)
The trifluoroacetate 26.9g (0.1mol) of compound shown in compound 28.3g (0.05mol) formula (XI) Suo Shi and the formula (XII) prepared according to embodiment 1 is added in 2000mL there-necked flask, add the mixed solvent that 800mLDMSO:DMF is 1:2, add triethylamine wherein again: DIEA is the mixture of 1:2,89.8g (0.75mol) altogether, TNTU:HBPyu is the mixture 0.055mol altogether of 2:1, wherein TNTU6.8g, HBPyu 15.8g, mixture is under agitation cooled to-20 DEG C, stirring reaction 1h.Then by reaction mixture at 20 ~ 60 DEG C of stirring reaction 15h, reactant saturated sodium-chloride dilutes, and with dichloromethane extraction, organic layer washes twice respectively with water and saturated aqueous common salt successively, each consumption is 150mL, through anhydrous magnesium sulfate drying, organic layer evaporated under reduced pressure, obtains white solid 18.5g after purifying, detect through HPLC, this white solid is the compound of structure shown in formula (XIII), purity 96.9%, yield 52.7%.
The preparation of compound shown in embodiment 25 formula (XIII)
Under nitrogen protection; the trifluoroacetate 16.1g (0.06mol) of compound shown in compound 28.3g (0.05mol) formula (XI) Suo Shi and the formula (XII) prepared according to embodiment 1 is added in 2000mL there-necked flask; add 700mL tetrahydrofuran (THF): acetonitrile is the mixed solvent of 1:1; mixture is under agitation cooled to 0 DEG C; add triethylamine wherein again: DIEA: pyridine is the mixture of 1:1:1; 0.055mol altogether; wherein triethylamine 1.8g; pyridine 1.4g; DIEA2.4g, then add HAPyu172.9g (0.4mol).Under reaction mixture is placed in nitrogen protection, 50 DEG C of stirring reaction 4h, reactant saturated sodium-chloride dilutes; with dichloromethane extraction; organic layer washes twice respectively with water and saturated aqueous common salt successively, and each consumption is 150mL, through anhydrous magnesium sulfate drying; organic layer evaporated under reduced pressure; obtain white solid 19.2g after purifying, detect through HPLC, this white solid is the compound of structure shown in formula (XIII); purity 97.2%, yield 54.5%.
The preparation of embodiment 26 Ka Feizuo meter
16.0g (0.19mol) sodium bicarbonate is added in there-necked flask, adds water 70mL, under stirring, be cooled to-10 DEG C, add 100mL trifluoroacetone; Under vigorous stirring, add 12.3g (0.04mol) Oxone (ammonium persulfate-sodium bisulfate) in batches, then the dichloromethane solution of structural compounds 17.6g (0.025mol) formula (XIII) Suo Shi is added in reaction mixture.8h is about at-10 DEG C of stirring reactions, with TLC (thin-layer chromatography) monitoring reaction, until raw material point disappears, stopped reaction.Cross and filter excessive salt, in filtrate, add 100mL water, be separated organic phase, aqueous phase 50mL dichloromethane extraction twice, merge organic phase, anhydrous magnesium sulfate drying, after concentrated, obtain Ka Feizuo meter crude product.Ka Feizuo meter crude product silica gel column chromatography separating purification, eluent is ethyl acetate: normal hexane=2:1.The a small amount of dissolve with ethanol of the solid chemical compound obtained after separation, joins crystallization in 0 DEG C of water, suction filtration fast under stirring, obtain compound as white solid 7.2g after oven dry.
With HPLC, product is detected, chromatographic column used is agilent SB-C18, specification is 5 μm × 4.6mm × 150mm, column temperature is 25 DEG C, sample size is 10 μ l, flow velocity is 1.2mL/min, and using 0.1% trifluoroacetic acid-water (A) and acetonitrile (B) as eluent gradient wash-out, solvent is as follows:
Detect under 210nm wavelength, as shown in Figure 5, Fig. 5 is the HPLC spectrogram of the Ka Feizuo meter that the embodiment of the present invention 26 prepares to detected result, and this white solid is Ka Feizuo meter as shown in Figure 5, purity 99.7%, yield 40.2%.
Gained white solid is carried out magnetic resonance detection, and gained hydrogen nuclear magnetic resonance modal data is: 1h-NMR (400MHz, DMSO) δ 8.25-8.15 (m, 1H), 8.07 (t, J=7.3Hz, 1H), 7.90 (m, 2H), 7.28 (t, J=7.4Hz, 2H), 7.18 (m, 7H), 7.10 (m, 1H), 4.62-4.51 (m, 1H), 4.44-4.34 (m, 1H), 4.33-4.20 (m, 1H), 3.61 (m, 4H), 3.14 (dd, J=15.1, 5.2Hz, 1H), 3.03-2.74 (m, 5H), 2.45 (m, 4H), 2.01-1.76 (m, 2H), 1.70-1.48 (m, 2H), 1.40 (m, 9H), 0.84 (m, 12H), 8.07 (t, J=7.3Hz, 1H).To survey data consistent with Ka Feizuo meter standard substance hydrogen modal data, therefore the present invention has prepared Ka Feizuo meter.
The preparation of embodiment 27 Ka Feizuo meter
13.4g (0.16mol) sodium bicarbonate is added in there-necked flask, adds water 100mL, under stirring, be cooled to-5 DEG C, add 120mL trifluoroacetone; Under vigorous stirring, add 18.4g (0.06mol) Oxone (ammonium persulfate-sodium bisulfate) in batches, then the dichloromethane solution of structural compounds 17.6g (0.025mol) formula (XIII) Suo Shi is added in reaction mixture.6h is about at 0 DEG C of stirring reaction, with TLC (thin-layer chromatography) monitoring reaction, until raw material point disappears, stopped reaction.Cross and filter excessive salt, in filtrate, add 100mL water, be separated organic phase, aqueous phase 70mL dichloromethane extraction twice, merge organic phase, anhydrous magnesium sulfate drying, after concentrated, obtain Ka Feizuo meter crude product.Ka Feizuo meter crude product silica gel column chromatography separating purification, eluent is ethyl acetate: normal hexane=2:1.The solid chemical compound ethyl acetate obtained after separation and methyl tertiary butyl ether are refined and are namely obtained Ka Feizuo meter 8.2g, yield 45.6%.Detect through HPLC, its purity is 99.8%.
The preparation of embodiment 28 Ka Feizuo meter
20.1g (0.24mol) sodium bicarbonate is added in there-necked flask, adds 150mL water, under stirring, be cooled to-15 DEG C, add 110mL trifluoroacetone; Under vigorous stirring, add 15.4g (0.05mol) Oxone (ammonium persulfate-sodium bisulfate) in batches, then the acetonitrile solution of structural compounds 17.6g (0.025mol) formula (XIII) Suo Shi is added in reaction mixture.13h is about at-5 DEG C of stirring reactions, with TLC (thin-layer chromatography) monitoring reaction, until raw material point disappears, stopped reaction.Cross and filter excessive salt, in filtrate, add 120mL water, be separated organic phase, aqueous phase 50mL dichloromethane extraction twice, merge organic phase, anhydrous magnesium sulfate drying, after concentrated, obtain Ka Feizuo meter crude product.Ka Feizuo meter crude product silica gel column chromatography separating purification, eluent is ethyl acetate: normal hexane=2:1.The solid chemical compound acetone obtained after separation and normal hexane are refined and are namely obtained Ka Feizuo meter 6.4g, yield 35.8%.Detect through HPLC, its purity is 99.6%.
The preparation of embodiment 29 Ka Feizuo meter
17.6g (0.21mol) sodium bicarbonate is added in there-necked flask, adds 130mL water, under stirring, be cooled to-15 DEG C, add 120mL trifluoroacetone; Under vigorous stirring, add 12.3g (0.04mol) Oxone (ammonium persulfate-sodium bisulfate) in batches, then the acetonitrile solution of compound 17.6g (0.025mol) formula (XIII) Suo Shi is added in reaction mixture.10h is about at-10 DEG C of stirring reactions, with TLC (thin-layer chromatography) monitoring reaction, until raw material point disappears, stopped reaction.Cross and filter excessive salt, in filtrate, add 120mL water, be separated organic phase, aqueous phase 50mL extraction into ethyl acetate twice, merge organic phase, anhydrous magnesium sulfate drying, after concentrated, obtain Ka Feizuo meter crude product.Ka Feizuo meter crude product silica gel column chromatography separating purification, eluent is ethyl acetate: normal hexane=2:1.The a small amount of dissolve with ethanol of the solid chemical compound obtained after separation, joins crystallization in 0 DEG C of water fast under stirring, filter, and dries and namely obtains Ka Feizuo meter 6.9g, yield 38.4%.Detect through HPLC, purity is 99.8%.
From above-described embodiment, the present invention has prepared the intermediate shown in formula (XIII), and with it for raw material, preparation Ka Feizuo meter, has higher yield and purity.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.

Claims (13)

1. Yi Zhong Ka Feizuo meter intermediate, has structure shown in formula (XIII):
2. the preparation method of Yi Zhong Ka Feizuo meter intermediate, comprising:
Under the effect of condensing agent and organic bases, compound shown in formula (XI), with compound formula (XII) Suo Shi, or carry out condensation reaction with the salt of compound formula (XII) Suo Shi, obtain compound shown in formula (XIII);
3. preparation method according to claim 2, it is characterized in that, shown in described formula (XI), shown in compound, formula (XII), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 10).
4. preparation method according to claim 2, is characterized in that, described condensing agent is selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, described organic bases is selected from triethylamine, DIPEA, pyridine, morpholine and or N-methylmorpholine in any one or a few.
5. preparation method according to claim 2, is characterized in that, shown in described formula (XI), compound is prepared in accordance with the following methods:
A) under the effect of condensing agent and organic bases, compound generation condensation reaction shown in compound and formula (III) shown in formula (II), obtain compound shown in formula (IV), then through deaminizating protection, generate compound shown in formula V;
Wherein, R is carboxyl-protecting group;
B) under the effect of condensing agent and organic bases, shown in formula (V), shown in compound and formula (VI), compound or its salt carries out condensation reaction, obtain compound shown in formula (VII), again through decarboxylation protection, compound shown in production (VIII);
C) under the effect of condensing agent and organic bases, shown in formula (VIII), shown in compound and formula (IX), compound carries out condensation reaction, obtain compound shown in formula (X), then through decarboxylation protection, compound shown in production (XI);
Wherein, R 1for carboxyl-protecting group.
6. preparation method according to claim 5, is characterized in that, described R, R 1independently be selected from the first group, or the hydrochloride of the first group, vitriol, acetate, Citrate trianion, nitrate, benzene sulfonate or tosilate; Described first group is C 1~ C 5alkyl.
7. preparation method according to claim 6, is characterized in that, described first group is methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.
8. preparation method according to claim 5, it is characterized in that, described step a) in, shown in compound shown in described formula (II), formula (III), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 18); Shown in described formula (V), shown in compound, formula (VI), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20); Described step c) in, shown in described formula (VIII), shown in compound, formula (IX), the mol ratio of compound, organic bases and condensing agent is 1:(1.05 ~ 2.5): (1.1 ~ 20): (1.1 ~ 20).
9. preparation method according to claim 5, is characterized in that, described step a), b) with step c) in, described condensing agent is independently selected from dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 4-N, N-lutidine, 1-hydroxy benzo triazole, O-(7-azepine benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(5-Chloro-Benzotriazole-1-base)-two (dimethylin) carbon hexafluorophosphate, O-(benzotriazole-1-base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-succimide base)-two (dimethylin) carbon a tetrafluoro borate, O-(N-endo-5-norcamphene-2,3-bis-carbon imide)-two (dimethylin) carbon a tetrafluoro borate, O-(7-azepine benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate, any one or a few in O-(benzotriazole-1-base)-two (Pyrrolidine base) carbon hexafluorophosphate and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, described organic bases be independently selected from triethylamine, DIPEA, pyridine, morpholine and N-methylmorpholine any one or a few.
10. the preparation method of Yi Zhong Ka Feizuo meter, comprising:
Under the effect of oxygenant, the compound shown in formula (XIII) is carried out epoxidation reaction, obtains the Ka Feizuo meter shown in formula (I) structure;
11. preparation methods according to claim 10, is characterized in that, described oxygenant is ammonium persulfate-sodium bisulfate.
12. preparation methods according to claim 10, is characterized in that, the temperature of described epoxidation reaction is-15 DEG C ~ 0 DEG C; The time of described epoxidation reaction is 5 ~ 15h.
13. preparation methods according to claim 10, is characterized in that, after preparing Ka Feizuo meter, also comprise and carry out column chromatography and/or recrystallization purifying to described Ka Feizuo meter.
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CN105518019A (en) * 2013-09-06 2016-04-20 桑多斯股份公司 Synthesis of peptide epoxy ketones
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US10364269B2 (en) 2015-05-21 2019-07-30 Laurus Labs Limited Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof
US10800809B2 (en) 2015-05-21 2020-10-13 Laurus Labs Limited Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof
CN105440106A (en) * 2015-12-17 2016-03-30 昆明贵研药业有限公司 Preparation method of carfilzomib
CN107417767A (en) * 2016-08-18 2017-12-01 杭州市西溪医院 Dipeptide compound, its preparation method and the application of piperidines or piperazine structure
CN107417767B (en) * 2016-08-18 2021-09-03 杭州市西溪医院 Dipeptide compound constructed by piperidine or piperazine, preparation method and application thereof
CN108484728A (en) * 2018-03-23 2018-09-04 哈尔滨师范大学 A kind of road Deng Su straight chains derivative, its preparation method and purposes
CN108929371A (en) * 2018-08-02 2018-12-04 哈尔滨师范大学 A kind of Phakellistatin13 straight chain derivative, its preparation method and purposes
CN110759967A (en) * 2019-09-05 2020-02-07 雅本化学股份有限公司 Preparation method of carfilzomib
CN113024637A (en) * 2021-03-10 2021-06-25 江西师范大学 Method for preparing carfilzomib by using water-soluble alkynylamide as condensing agent
CN116023347A (en) * 2022-10-09 2023-04-28 无锡紫杉药业股份有限公司 Method for preparing carfilzomib side chain isomer

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