CN108689984A - A kind of biological synthesis method and its intermediate of ticagrelor intermediate - Google Patents

A kind of biological synthesis method and its intermediate of ticagrelor intermediate Download PDF

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CN108689984A
CN108689984A CN201810409842.0A CN201810409842A CN108689984A CN 108689984 A CN108689984 A CN 108689984A CN 201810409842 A CN201810409842 A CN 201810409842A CN 108689984 A CN108689984 A CN 108689984A
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compound
reaction
anhydrous
ticagrelor
biological
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CN201810409842.0A
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CN108689984B (en
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黄燕鸽
华鹏
游庆红
张世忠
徐海青
许莹
袁君
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淮阴工学院
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02Oxygen as only ring hetero atoms
    • C12P17/04Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Abstract

The invention discloses a kind of biological synthesis method and its intermediate of ticagrelor intermediate, which is first made compound (3) by the oxidized reaction of compound (2);Compound (4) is obtained by the reaction through vicinal diols protection in the compound (3);Compound (5) is made through addition reaction with ethylene oxide in the compound (4);Ticagrelor midbody compound (1) is made through biological transformation in the compound (5), and reaction equation is as follows:

Description

A kind of biological synthesis method and its intermediate of ticagrelor intermediate

Technical field

The invention belongs to technical field of medicine synthesis, and in particular to a kind of biological synthesis method of ticagrelor intermediate and Wherein mesosome.

Background technology

Ticagrelor (common name:Ticagrelor, trade name BRILINTA), entitled (1S, 2S, 3R, the 5S) -3- of chemistry [7-[(1R, 2S) -2- (3,4- difluorophenyls) cyclopropane An Jis ]- 5- (propane sulfydryl) -3H-[1,2,3]San Danzuo [4,5-d] Bi Ding-3-Ji ]- 5- (2- hydroxyl ethanes oxygen) pentamethylene -1,2- glycol.The molecular weight of ticagrelor:522.57;CAS registration numbers: 274693-27-5;Structural formula is as follows:

Ticagrelor is researched and developed by AstraZeneca AB.A kind of platelet aggregation inhibitor of the FDA approvals of in September, 2015, Ticagrelor is approved for the Antiplatelet therapy of ACS patient in the U.S..

Existing patented technology document:WO 2008018822A1 and WO 2008018823A1 etc. in the prior art, for closing Often more complicated at the synthesis technology of the intermediate of ticagrelor, cost is higher, but also there are product yield is low and quality The defect of difference, can not be suitble to industrialized production.

Invention content

Goal of the invention:In view of the problems of the existing technology, the present invention provides a kind of biology conjunction of ticagrelor intermediate At method, this method has many advantages, such as synthetic yield height, good product purity.

The present invention also provides a kind of ticagrelor midbody compound (1), the ticagrelor midbody compound (1) be for Ge Ruiluo provides new raw material.

Technical solution:To achieve the goals above, a kind of biosynthesis side of ticagrelor intermediate as described herein First compound (3) is made in the oxidized reaction of compound (2) by method;The compound (3) protects being obtained by the reaction through vicinal diols Close object (4);Compound (5) is made through addition reaction with ethylene oxide in the compound (4);The compound (5) turns through biology Ticagrelor midbody compound (1) is made in the effect of changing, and reaction equation is as follows:

Wherein, the solvent of the oxidation reaction of compound (3) is made selected from no water beetle in the oxidized reaction of the compound (2) Alcohol, absolute ethyl alcohol, anhydrous tertiary butanol, anhydrous isopropyl alcohol, anhydrous sec-butyl alcohol, anhydrous THF, anhydrous ether, dry toluene, anhydrous two One or more of toluene, anhydrous methylene chloride, anhydrous 2- methyltetrahydrofurans and anhydrous TBME, the oxidation reaction it is anti- It is 20 DEG C~60 DEG C to answer temperature.

Wherein, the solvent that compound (4) is obtained by the reaction through vicinal diols protection for the compound (3) is anhydrous propanone, nothing It is water tetrahydrofuran, anhydrous ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous The reaction temperature of one or more of 2- methyltetrahydrofurans, the protection reaction is 20 DEG C~60 DEG C.

Wherein, the solvent that the addition reaction of compound (5) is made with ethylene oxide through addition reaction for the compound (4) is Anhydrous tetrahydro furan, anhydrous ether, anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, nothing One or more of water 2- methyltetrahydrofurans;The temperature of reaction is 0 DEG C~30 DEG C;The reagent of reaction is selected from copper chloride, chlorine Change cuprous, copper bromide, cuprous bromide, zinc chloride, alchlor, ferric trichloride, trifluoromethayl sulfonic acid ytterbium, titanium tetrachloride and chlorination One or more of silver.

Wherein, the biology conversion of ticagrelor midbody compound (1) is made through biological transformation for the compound (5) Enzyme is its initial body or the orthomutation body of the biology converting Enzyme;The amino acid sequence of the biology converting Enzyme is SEQ ID Shown in NO.1;

SEQ ID NO.1:MAFSADTSEI VYTHDTGLDY ITYSDYELDP ANPLAGGAAW IEGAFVPPSE ARISIFDQGY LHSDVTYTVF HVWNGNAFRL DDHIERLFSN AESMRIIPPL TQDEVKEIAL ELVAKTELRE AFVSVSITRG YSSTPGERDI TKHRPQVYMY AVPYQWIVPF DRIRDGVHAM VAQSVRRTPR SSIDPQVKNF QWGDLIRAVQ ETHDRGFEAP LLLDGDGLLA EGSGFNVVVI KDGVVRSPGR AALPGITRKT VLEIAESLGH EAILADITLA ELLDADEVLG CTTAGGVWPF VSVDGNPISD GVPGPVTQSI IRRYWELNVE SSSLLTPVQY;

The orthomutation body is T68V, N76L, the one or several kinds in L213E and V302M.Wherein T68V is mother The T that body is 68 becomes V, other are equivalent.

Wherein, the reaction dissolvent of ticagrelor midbody compound (1) is made through biological transformation for the compound (5) Selected from water/dimethyl sub-maple, water/methanol, water/ethyl alcohol, water/isopropanol, water/acetone, water/dimethyl sub-maple/first alcohol and water/bis- One or several kinds in methyl Asia maple/acetone.

Further, the reaction of ticagrelor midbody compound (1) is made through biological transformation for the compound (5) In further include ammonia source, one or several kinds of the ammonia source in isopropylamine, triethylamine, propylamine, ethamine and butylamine are a concentration of 0.2-1M。

Compound in the reaction of ticagrelor midbody compound (1) is made through biological transformation in the compound (5) (5) mass concentration is 2-200g/L, and reaction temperature is 22-45 DEG C, and reaction pH is 7.5-8.5.

Preferably, the reaction temperature is 22-25 DEG C, reaction pH is 8.0.

Compound in the reaction of ticagrelor midbody compound (1) is made through biological transformation in the compound (5) (5) and the mass concentration ratio of biological converting Enzyme is 1:1~70:1.

The synthesized ticagrelor midbody compound of the biological synthesis method of ticagrelor intermediate of the present invention (1), structural formula is:

Advantageous effect:Compared with prior art, the invention has the advantages that:It is auspicious for lattice that the present invention provides a kind of synthesis The biological method of Lip river intermediate, this method have synthetic yield height, good product purity, raw material is cheap and easy to get and is suitable for industry The advantages that metaplasia is produced, while synthesized ticagrelor intermediate provides new intermediate feed for ticagrelor preparation.

Specific implementation mode

The invention will be further described with reference to embodiments.

The method of the detection purity of ticagrelor intermediate HPLC of the present invention:

Test apparatus:1100 high performance liquid chromatographs of Agilent (DAD detectors).

Chromatographic condition:With OB-H (4.6 × 250mm, 5 μm) for chromatographic column, flow velocity:0.5ml/min.

Mobile phase A:Isopropanol;Mobile phase B:Normal heptane

According to the form below carries out linear gradient elution:

Time (minute) Mobile phase A (%) Mobile phase B (%) 0 1 99 30 5 95 50 25 75 60 45 55

Ultraviolet detection wavelength:210nm.

Embodiment 1

The preparation of compound (3)

Under the conditions of 30 DEG C, 980g (10mol) compound (2) is added into 50L reaction kettles in 20L anhydrous tertiary butanols, N-methylmorpholine N- oxides (NMO) 2.6kg (22mol) is added, OsO is eventually adding4127g (0.5mol) TLC monitoring is anti- After answering (about 15 hours), niter cake 1.8kg is added, stirs 30 minutes, room temperature is down to after solvent evaporated, with quality point The aqueous sulfuric acid of number 50% adjusts pH to 1 or so, filtering, and filter cake 10L water washings dry to obtain compound (3) 1.21kg (9.2mol), yield 92%, HPLC detect purity:97.3%.

1H NMR(400 MHz,DMSO-d6)δ4.35(m,1H),4.18–4.10(m,1H),3.86(m,1H),2.33(dd, J=19.0,7.0Hz, 1H), 1.96 (dd, J=19.0,7.0Hz, 1H)

ESI+[M+H]+=133.

The preparation of compound (4)

Under the conditions of 25 DEG C, 1.19kg (9.0mol) compound (3) is added into 50L reaction kettles in 18L anhydrous propanones, first 2,2-dimethoxypropane 1.03kg (9.9mol) is added, adds p-methyl benzenesulfonic acid 78g (0.45mol), TLC monitoring reaction knots After beam (about 5 hours), 15L dichloromethane extraction (2 times) is added, merges organic phase, is concentrated under reduced pressure to give compound (4) crude product It is directly used in the next step.

The preparation of compound (5)

Under the conditions of 25 DEG C, above compound (4) crude product (9.0mol) is added into 50L reaction kettles in the anhydrous tetrahydrochysenes of 18L In furans, trifluoromethayl sulfonic acid ytterbium hydrate 6.1kg (9.9mol) is first added, is slow added into ethylene oxide 416g (9.45mol), TLC are monitored after reaction (about 4 hours), and 5% aqueous ammonium chloride solution 15L of mass fraction is added, heats up, point Liquid, water phase are extracted with 10L dichloromethane, are merged organic phase, compound (5) crude product are concentrated under reduced pressure to obtain, crude product is through ethyl acetate/stone Oily ether recrystallizes to obtain highly finished product 1.72kg (7.95mol), and yield is 88.3% (2 step), and HPLC detects purity:98.7%.

1H NMR(400MHz,DMSO-d6) δ 4.95 (t, J=7.0Hz, 1H), 4.66 (d, J=6.9Hz, 1H), 4.38 (m, 1H), 3.52 (m, 1H), 3.46-3.34 (m, 2H), 3.01 (m, 1H), 2.33 (dd, J=19.0,7.0Hz, 1H), 1.97 (dd, J =19.0,7.0Hz, 1H), 1.22 (s, 3H), 1.17 (s, 3H)

ESI+[M+H]+=217.

The preparation of compound (1)

Under the conditions of 25 DEG C, reaction dissolvent is added into reaction kettle, ammonia source is then added, with salt acid for adjusting pH to 8.0, then Be added PLP (phosphopyridoxal pyridoxal phosphate) and biology converting Enzyme (amino acid of T68V, N76L, L213E, V302M, 4 positions together by Substitution), it is slowly stirred to whole dissolvings, compound (5) is then added and reacts afterwards 16 hours, uses salt acid for adjusting pH after reaction To 2.0, isopropyl acetate extraction is added, leaves water phase, adjusts pH to 12.0 with sodium hydrate aqueous solution, isopropyl acetate is added Extraction, by isopropyl acetate through compound (1) is concentrated under reduced pressure to obtain.Wherein reaction dissolvent is water and Dimethyl Asian Maple, the two volume ratio It is 1:1.Ammonia source is isopropylamine and triethylamine, and the molar ratio of a concentration of 0.5M, the two are 1:1.What wherein compound (5) was added is first A concentration of 100g/L of prothyl amount.The mass concentration ratio of compound (5) and biological converting Enzyme (T68V, N76L, L213E, V302M) is 35:1, PLP is 0.1 times of equivalent of compound (5), and mass concentration is in 10g/L.

Gained intermediate is detected by preceding method, the mass yield of compound 1 is that 97%, HPLC detects purity: 99.92%.

1H NMR(400MHz,DMSO-d6) δ 4.04 (t, J=7.0Hz, 1H), 3.75 (q, J=7.0Hz, 1H), 3.63- 3.44(m,2H),3.43–3.16(m,2H),3.14–2.88(m,3H),1.89(m,2H),1.78(br,2H),1.34(s,3H), 1.33–1.24(s,3H).

ESI+[M+H]+=218.

Embodiment 2

According to the biological synthesis method of embodiment 1, the difference is that:Reaction dissolvent replaces with nothing in prepared by compound 3 Water-ethanol, temperature are 20 DEG C.Compound (3), yield 91.5%, HPLC detect purity:97%.

Reaction dissolvent replaces with anhydrous tetrahydro furan in prepared by compound 4, and temperature is 20 DEG C.

Reaction dissolvent replaces with anhydrous ether in the preparation of compound 5, and reaction reagent replaces with copper chloride, the temperature of reaction It it is 0 DEG C, compound (5) crude product, yield is 87.5% (2 step), and HPLC detects purity:97.8%.

Reaction dissolvent replaces with water and methanol in the preparation of compound 1, and the two volume ratio is 1:1.Ammonia source replaces with ethamine, A concentration of 0.2M, pH are adjusted to 7.5.The mass concentration of compound (5) is 2g/L.Compound (5) and biological converting Enzyme biology conversion The mass concentration ratio of enzyme (amino acid of T68V, 1 position are substituted together) is 1:1, reaction temperature is 22 DEG C, and reaction pH is 7.5.Compound (1) mass yield is that 96%, HPLC detects purity:99.8%.

Embodiment 3

According to the biological synthesis method of embodiment 1, the difference is that:Reaction dissolvent replaces with nothing in prepared by compound 3 Water isopropanol, anhydrous sec-butyl alcohol, volume ratio 1:1, temperature is 60 DEG C.Compound (3), yield 92.5%, HPLC detections are pure Degree:97.8%.

Reaction dissolvent replaces with anhydrous methylene chloride, dry toluene, volume ratio 1 in prepared by compound 4:1, temperature 60 ℃。

Reaction dissolvent replaces with anhydrous methyl tertbutyl ether, anhydrous methylene chloride, volume ratio 1 in the preparation of compound 5: 1, reaction reagent replaces with stannous chloride and copper bromide, molar ratio 1:1, the temperature of reaction is 30 DEG C, compound (5) crude product, Yield is 89% (2 step), and HPLC detects purity:99%.

Reaction dissolvent replaces with water and ethyl alcohol in the preparation of compound 1, and the two volume ratio is 1:1.Ammonia source replaces with three second The molar ratio of amine, propylamine, a concentration of 1M, the two is 1:1, pH is adjusted to 8.5.The mass concentration of compound (5) is 200g/L.Chemical combination Object (5) and the mass concentration ratio of biological converting Enzyme (amino acid of T68V, N76L, L213E, 3 positions is substituted together) are 70: 1, reaction temperature is 45 DEG C, and reaction pH is 8.5.Compound (1) mass yield is that 97%, HPLC detects purity:99.98%.

Embodiment 4

According to the biological synthesis method of embodiment 1, the difference is that:Reaction dissolvent replaces with nothing in prepared by compound 3 Water methanol, temperature are 40 DEG C.Compound (3), yield 92.4%, HPLC detect purity:98%.

Reaction dissolvent replaces with anhydrous methyl tertbutyl ether in prepared by compound 4, and temperature is 40 DEG C.

Reaction dissolvent replaces with anhydrous methyl tertbutyl ether in the preparation of compound 5, and reaction reagent replaces with ferric trichloride, The temperature of reaction is 15 DEG C, compound (5) crude product, and yield is 89.2% (2 step), and HPLC detects purity:99.3%.

Reaction dissolvent replaces with water and acetone in the preparation of compound 1, and the two volume ratio is 1:1.Ammonia source replaces with propylamine, A concentration of 0.6M.The mass concentration of compound (5) is 100g/L.Compound (5) and biological converting Enzyme (L213E, V302M, 2 The amino acid of position is substituted together) mass concentration ratio be 35:1, reaction temperature is 35 DEG C, and reaction pH is 8.0.Compound (1) mass yield is that 96.6%, HPLC detects purity:99.95%.

Sequence table

<110>Huaiyingong College

<120>A kind of biological synthesis method and its intermediate of ticagrelor intermediate

<160> 1

<170> SIPOSequenceListing 1.0

<210> 1

<211> 330

<212> PRT

<213>Artificial sequence (Artificial Sequence)

<400> 1

Met Ala Phe Ser Ala Asp Thr Ser Glu Ile Val Tyr Thr His Asp Thr

1 5 10 15

Gly Leu Asp Tyr Ile Thr Tyr Ser Asp Tyr Glu Leu Asp Pro Ala Asn

20 25 30

Pro Leu Ala Gly Gly Ala Ala Trp Ile Glu Gly Ala Phe Val Pro Pro

35 40 45

Ser Glu Ala Arg Ile Ser Ile Phe Asp Gln Gly Tyr Leu His Ser Asp

50 55 60

Val Thr Tyr Thr Val Phe His Val Trp Asn Gly Asn Ala Phe Arg Leu

65 70 75 80

Asp Asp His Ile Glu Arg Leu Phe Ser Asn Ala Glu Ser Met Arg Ile

85 90 95

Ile Pro Pro Leu Thr Gln Asp Glu Val Lys Glu Ile Ala Leu Glu Leu

100 105 110

Val Ala Lys Thr Glu Leu Arg Glu Ala Phe Val Ser Val Ser Ile Thr

115 120 125

Arg Gly Tyr Ser Ser Thr Pro Gly Glu Arg Asp Ile Thr Lys His Arg

130 135 140

Pro Gln Val Tyr Met Tyr Ala Val Pro Tyr Gln Trp Ile Val Pro Phe

145 150 155 160

Asp Arg Ile Arg Asp Gly Val His Ala Met Val Ala Gln Ser Val Arg

165 170 175

Arg Thr Pro Arg Ser Ser Ile Asp Pro Gln Val Lys Asn Phe Gln Trp

180 185 190

Gly Asp Leu Ile Arg Ala Val Gln Glu Thr His Asp Arg Gly Phe Glu

195 200 205

Ala Pro Leu Leu Leu Asp Gly Asp Gly Leu Leu Ala Glu Gly Ser Gly

210 215 220

Phe Asn Val Val Val Ile Lys Asp Gly Val Val Arg Ser Pro Gly Arg

225 230 235 240

Ala Ala Leu Pro Gly Ile Thr Arg Lys Thr Val Leu Glu Ile Ala Glu

245 250 255

Ser Leu Gly His Glu Ala Ile Leu Ala Asp Ile Thr Leu Ala Glu Leu

260 265 270

Leu Asp Ala Asp Glu Val Leu Gly Cys Thr Thr Ala Gly Gly Val Trp

275 280 285

Pro Phe Val Ser Val Asp Gly Asn Pro Ile Ser Asp Gly Val Pro Gly

290 295 300

Pro Val Thr Gln Ser Ile Ile Arg Arg Tyr Trp Glu Leu Asn Val Glu

305 310 315 320

Ser Ser Ser Leu Leu Thr Pro Val Gln Tyr

325 330

Claims (10)

1. a kind of biological synthesis method of ticagrelor intermediate, which is characterized in that first the oxidized reaction of compound (2) is made Compound (3);Compound (4) is obtained by the reaction through vicinal diols protection in the compound (3);The compound (4) and epoxy second Compound (5) is made through addition reaction in alkane;Ticagrelor midbody compound is made through biological transformation in the compound (5) (1), reaction equation is as follows:
2. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound (2) solvent of the oxidation reaction of compound (3) is made selected from absolute methanol, absolute ethyl alcohol, anhydrous tertiary butanol, nothing in oxidized reaction Water isopropanol, anhydrous sec-butyl alcohol, anhydrous THF, anhydrous ether, dry toluene, anhydrous dimethyl benzene, anhydrous methylene chloride, anhydrous 2- The reaction temperature of one or more of methyltetrahydrofuran and anhydrous TBME, the oxidation reaction is 20 DEG C~60 DEG C.
3. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound (3) solvent that compound (4) is obtained by the reaction through vicinal diols protection is anhydrous propanone, anhydrous tetrahydro furan, anhydrous ether, anhydrous Methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, one kind in anhydrous 2- methyltetrahydrofurans or Several, the reaction temperature of the protection reaction is 20 DEG C~60 DEG C.
4. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound (4) with ethylene oxide be made through addition reaction compound (5) addition reaction solvent be anhydrous tetrahydro furan, anhydrous ether, One in anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans Kind is several;The temperature of reaction is 0 DEG C~30 DEG C;The reagent of reaction be selected from copper chloride, stannous chloride, copper bromide, cuprous bromide, Zinc chloride, alchlor, ferric trichloride, trifluoromethayl sulfonic acid ytterbium, one or more of titanium tetrachloride and silver chlorate.
5. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound (5) the biological converting Enzyme that ticagrelor midbody compound (1) is made through biological transformation is its initial body or the biology The orthomutation body of converting Enzyme;The amino acid sequence of the biology converting Enzyme is shown in SEQ ID NO.1;The orthomutation body For T68V, N76L, the one or several kinds in L213E and V302M.
6. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the feature exists In the reaction dissolvent that ticagrelor midbody compound (1) is made through biological transformation for the compound (5) is selected from water/bis- Methyl Asia maple, water/methanol, water/ethyl alcohol, water/isopropanol, water/acetone, water/dimethyl sub-maple/first alcohol and water/dimethyl sub-maple/ One or several kinds in acetone.
7. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the feature exists In, it further includes ammonia source that the compound (5), which is made through biological transformation in the reaction of ticagrelor midbody compound (1), One or several kinds of the ammonia source in isopropylamine, triethylamine, propylamine, ethamine and butylamine, a concentration of 0.2-1M.
8. the biological synthesis method of the ticagrelor intermediate according to claim 1-7, which is characterized in that the compound (5) mass concentration that compound (5) in the reaction of ticagrelor midbody compound (1) is made through biological transformation is 2- 200g/L, reaction temperature are 22-45 DEG C, and reaction pH is 7.5-8.5.
9. the biological synthesis method of ticagrelor intermediate according to claim 5, which is characterized in that the compound (5) matter of compound (5) and biological converting Enzyme in the reaction of ticagrelor midbody compound (1) is made through biological transformation It is 1 to measure concentration ratio:1~70:1.
10. among a kind of synthesized ticagrelor of the biological synthesis method of ticagrelor intermediate as described in claim 1 Body compound (1), structural formula are:
CN201810409842.0A 2018-05-02 2018-05-02 A kind of biological synthesis method and its intermediate of ticagrelor intermediate CN108689984B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092263A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds
CN103539773A (en) * 2013-09-25 2014-01-29 开原亨泰制药股份有限公司 Method for preparing ticagrelor key intermediate
CN105073983A (en) * 2013-02-28 2015-11-18 默沙东公司 Immobilized transaminases and process for making and using immobilized transaminase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092263A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds
CN105073983A (en) * 2013-02-28 2015-11-18 默沙东公司 Immobilized transaminases and process for making and using immobilized transaminase
CN103539773A (en) * 2013-09-25 2014-01-29 开原亨泰制药股份有限公司 Method for preparing ticagrelor key intermediate

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