CN108689984B - 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 PDFInfo
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Abstract
The invention discloses the biological synthesis method and its intermediate of a kind of ticagrelor intermediate, which is first made compound (3) through oxidation reaction for compound (2)；The compound (3) obtains compound (4) through vicinal diols protection reaction；Compound (5) are made through addition reaction in the compound (4) and ethylene oxide；Ticagrelor midbody compound (1) is made through biological transformation in the compound (5), and reaction equation is as follows:
Description
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 technique
Ticagrelor (common name: Ticagrelor, trade name BRILINTA), entitled (1S, 2S, 3R, the 5S) -3- of chemistry
[7- [(1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl alkylamino] -5- (propane sulfydryl) -3H- [1,2,3] triazole [4,5-d]
Pyridin-3-yl] -5- (2- hydroxyl ethane oxygen) pentamethylene -1,2- glycol.The molecular weight of ticagrelor: 522.57；CAS registration number:
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 of in September, 2015 approval,
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
It is often more complicated at the synthesis technology of the intermediate of ticagrelor, higher cost, but also there are product yield is low and quality
The defect of difference, can not be suitble to industrialized production.
Summary of the invention
Goal of the invention: in view of the problems of the existing technology, the biology that the present invention provides a kind of ticagrelor intermediate closes
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) are made through oxidation reaction in compound (2) by method；The compound (3) protects reactionization through vicinal diols
It closes object (4)；Compound (5) are made through addition reaction in the compound (4) and ethylene oxide；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 compound (2) through oxidation reaction be made compound (3) oxidation reaction solvent selected from no water beetle
Alcohol, dehydrated 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- methyltetrahydrofuran and anhydrous TBME, the oxidation reaction it is anti-
Answering temperature is 20 DEG C~60 DEG C.
Wherein, the solvent that the compound (3) obtains compound (4) through vicinal diols protection reaction 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- methyltetrahydrofuran, the protection reaction is 20 DEG C~60 DEG C.
Wherein, the solvent for the addition reaction that compound (5) is made through addition reaction in the compound (4) and ethylene oxide 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- methyltetrahydrofuran；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 that ticagrelor midbody compound (1) is made through biological transformation in the compound (5) is converted
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, one of L213E and V302M or several.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 of methyl Asia maple/acetone is several.
Further, the reaction of ticagrelor midbody compound (1) is made through biological transformation for the compound (5)
In further include ammonia source, the ammonia source is selected from one of isopropylamine, triethylamine, propylamine, ethamine and butylamine or several, and concentration is
0.2-1M。
Compound in the reaction of ticagrelor midbody compound (1) is made through biological transformation for 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 for 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 are as follows:
The utility model has the advantages that compared with prior art, the present invention has the advantage that the present invention provides a kind of synthesis to replace lattice auspicious
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 produces, while synthesized ticagrelor intermediate provides new intermediate feed for ticagrelor preparation.
Specific embodiment
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 chromatograph of Agilent (DAD detector).
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) are added into 50L reaction kettle in 20L anhydrous tertiary butanol,
N-methylmorpholine N- oxide (NMO) 2.6kg (22mol) is added, OsO is eventually adding4127g (0.5mol) TLC monitoring is anti-
After answering (about 15 hours), sodium bisulfate 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 washing dries to obtain compound (3) 1.21kg
(9.2mol), yield 92%, HPLC detection 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) are added into 50L reaction kettle in 18L anhydrous propanone, first
It is added 2,2-dimethoxypropane 1.03kg (9.9mol), adds p-methyl benzenesulfonic acid 78g (0.45mol), TLC monitoring reaction knot
After beam (about 5 hours), 15L methylene chloride 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 kettle in the anhydrous tetrahydro of 18L
In furans, trifluoromethayl sulfonic acid ytterbium hydrate 6.1kg (9.9mol) first is 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 methylene chloride, 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), HPLC detection 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
Replace), it is slowly stirred to whole dissolutions, compound (5) is then added and react afterwards 16 hours, use 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, is concentrated under reduced pressure to obtain compound (1) for isopropyl acetate.Wherein reaction dissolvent is water and Dimethyl Asian Maple, the two volume ratio
For 1:1.Ammonia source is isopropylamine and triethylamine, and concentration 0.5M, the molar ratio of the two is 1:1.What wherein compound (5) was added is first
Beginning mass concentration is 100g/L.Compound (5) and the mass concentration ratio of biological converting Enzyme (T68V, N76L, L213E, V302M) are
35:1, PLP are 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 the preparation of compound 3
Water-ethanol, temperature are 20 DEG C.Compound (3), yield 91.5%, HPLC detection purity: 97%.
Reaction dissolvent replaces with anhydrous tetrahydro furan in the preparation of 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 is 0 DEG C, compound (5) crude product, yield is 87.5% (2 step), HPLC detection 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,
Concentration is 0.2M, and pH is 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, and reaction temperature is 22 DEG C, and reaction pH is
7.5.Compound (1) mass yield is 96%, HPLC detection purity: 99.8%.
Embodiment 3
According to the biological synthesis method of embodiment 1, the difference is that: reaction dissolvent replaces with nothing in the preparation of compound 3
Water isopropanol, anhydrous sec-butyl alcohol, volume ratio 1:1, temperature are 60 DEG C.Compound (3), yield 92.5%, HPLC detection are pure
Degree: 97.8%.
Reaction dissolvent replaces with anhydrous methylene chloride, dry toluene, volume ratio 1:1, temperature 60 in the preparation of compound 4
℃。
Reaction dissolvent replaces with anhydrous methyl tertbutyl ether, anhydrous methylene chloride in the preparation of compound 5, volume ratio 1:
1, reaction reagent replaces with stannous chloride and copper bromide, molar ratio 1:1, and the temperature of reaction is 30 DEG C, compound (5) crude product,
Yield is 89% (2 step), HPLC detection 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, concentration 1M, the two is 1:1, and 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 97%, HPLC detection purity: 99.98%.
Embodiment 4
According to the biological synthesis method of embodiment 1, the difference is that: reaction dissolvent replaces with nothing in the preparation of compound 3
Water methanol, temperature are 40 DEG C.Compound (3), yield 92.4%, HPLC detection purity: 98%.
Reaction dissolvent replaces with anhydrous methyl tertbutyl ether in the preparation of 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), HPLC detection 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,
Concentration is 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 be 35 DEG C, reaction pH be 8.0.Compound
(1) mass yield is 96.6%, HPLC detection 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 (9)
1. a kind of biological synthesis method of ticagrelor intermediate, which is characterized in that first compound (2) is made through oxidation reaction
Compound (3)；The compound (3) obtains compound (4) through vicinal diols protection reaction；The compound (4) and epoxy second
Compound (5) are 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 that the oxidation reaction of compound (3) is made through oxidation reaction is selected from anhydrous methanol, dehydrated alcohol, anhydrous tertiary butanol, nothing
Water isopropanol, anhydrous sec-butyl alcohol, anhydrous THF, anhydrous ether, dry toluene, anhydrous dimethyl benzene, anhydrous methylene chloride, anhydrous 2-
One or more of methyltetrahydrofuran and anhydrous TBME, the reaction temperature of the oxidation reaction are 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 for obtaining compound (4) through vicinal diols protection reaction be anhydrous propanone, it is anhydrous tetrahydro furan, anhydrous ether, anhydrous
One of methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofuran 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) and ethylene oxide through addition reaction be made compound (5) addition reaction solvent be anhydrous tetrahydro furan, anhydrous ether,
Anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, one in anhydrous 2- methyltetrahydrofuran
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, one of L213E and V302M or several.
6. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound
(5) through biological transformation be made ticagrelor midbody compound (1) reaction dissolvent be selected from water/dimethyl sulfoxide, water/
One in methanol, water/ethyl alcohol, water/isopropanol, water/acetone, water/dimethyl sulfoxide/first alcohol and water/dimethyl sulfoxide/acetone
Kind is several.
7. the biological synthesis method of ticagrelor intermediate according to claim 1, which is characterized in that the compound
(5) being made through biological transformation in the reaction of ticagrelor midbody compound (1) further includes ammonia source, and the ammonia source is selected from different
One of propylamine, triethylamine, propylamine, ethamine and butylamine are several, concentration 0.2-1M.
8. the biological synthesis method of -7 any ticagrelor intermediates according to claim 1, which is characterized in that describedization
Closing the mass concentration that compound (5) in the reaction of ticagrelor midbody compound (1) is made through biological transformation in object (5) 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
Amount concentration ratio is 1:1~70:1.
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