CN105348241B - A kind of synthetic method of the husky intermediate of sulfuric acid Walla handkerchief - Google Patents
A kind of synthetic method of the husky intermediate of sulfuric acid Walla handkerchief Download PDFInfo
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- CN105348241B CN105348241B CN201510916334.8A CN201510916334A CN105348241B CN 105348241 B CN105348241 B CN 105348241B CN 201510916334 A CN201510916334 A CN 201510916334A CN 105348241 B CN105348241 B CN 105348241B
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- sodium borohydride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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Abstract
The present invention is a kind of synthetic method of the husky intermediate of sulfuric acid Walla handkerchief, using compound II as initiation material, is reacted with sodium borohydride, then is acted on iodine, hydrolyzes to obtain intermediate III b；Then flowed back through manganese dioxide in dichloromethane, obtain intermediate compound I.Compound II is by sodium borohydride and iodine, under the conditions of the reaction temperature of the present invention, carboxylic acid is optionally directly reduced to alcohol, and ester does not influence the lactone in structure, the confession preparation technology that the present invention is carried, the features such as stablizing with high-selectivity reduction, easily controllable reaction condition, safe operation, intermediate, be adapted to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical intermediate preparing technical field, more particularly to a kind of anticoagulant sulfuric acid Walla handkerchief is husky
(vorapaxar) intermediate and preparation method thereof.
Background technology
May 8 in 2014, Mo Shadong anticoagulant sulfuric acid Walla handkerchief husky (vorapaxar) obtained FDA approvals, for by the heart
The patient of popular name for breaking-out or leg arteries have the patient of blocking, to reduce further heart attack, apoplexy, cardiovascular death
With the risk for needing to perform the operation.Vorapaxar is a kind of proteinase activated receptors 1 (PAR-1) of pioneering (first-in-class)
Antagonist, is a kind of anti-platelet agent, it is intended to reduces platelet aggregation tendency, suppresses the formation of blood clotting grumeleuse, there is wide
The market demand and social value.
Handkerchief husky structural formula in sulfuric acid Walla is as follows：
The route of existing literature report is as follows, and initiation material contains 7 hand-type centers it can be seen from structure, by two
After fragments molecules docking, drug molecule sulfuric acid Walla handkerchief sand is obtained, the difficult point of this process route is the husky intermediate of sulfuric acid Walla handkerchief
Compound I (the dihydro naphtho-s [2,3-c] of (1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9- formoxyl -1- methyl -3- oxos ten
Furans -6- bases) urethanes preparation on.
The synthetic route of Vorapaxar techniques
Patent of invention WO2006/076564 is reacted using intermediate II, and carboxylic acid first changes into the derivative acyl of carboxylic acid
Chlorine.Then it is reduced into aldehyde with dry Pd/C again.The method has a disadvantage that：A, dry Pd/C are highly combustible, particularly in dry season
Section, factory is influenceed very big when amplifying in the presence of very big danger, and by the property in season.In b, literature procedures, in firstly generating
Mesosome acyl chlorides IIIa, the highly unstable property of this intermediate is very sensitive to water, this by the anhydrous requirement of reaction dissolvent very
It is high.Because the water of a molecule will consume the acyl chlorides of two molecules, acid anhydrides is generated, the yield of reaction will be had a strong impact on.Intermediate
Post-processing operation in will as far as possible avoid aqueous vapor, add the operation difficulty of post processing.Its route is as follows：
The present inventor once attempted first to change into intermediate II its carboxylic acid derivates chloride compounds ((1R, 3aR, 4aR,
6R, 8aR, 9S, 9aR) ten dihydro-naphtho [2,3-c] furans -6- bases of -9- (chloroformyl) -1- methyl -3- oxos) carbamic acid
Ethyl ester, is then reduced into aldehyde with three (tert-butyl alcohol) lithium aluminium hydrides.But experimental result is unsatisfactory, product purity is poor,
Accessory substance is more, is that the ester group position of intermediate can be also reduced into alcohol by three (tert-butyl alcohol) lithium aluminium hydrides the reason for possible, with knot
Lactone in structure is incompatible.The present inventor attempt intermediate II being first reduced into its alcoholic compound ((1R, 3aR, 4aR, 6R, 8aR,
9S, 9aS) ten dihydro-naphtho [2,3-c] furans -6- bases of -9- (methylol) -1- methyl -3- oxos) urethanes IIb, so
Reselection is oxidized to aldehyde afterwards.Attempt using reducing agent lithium aluminium hydride reduction, borine and ruthenium agent etc., experimental result is equally undesirable,
Accessory substance is more, product purification difficult, is that these catalyst can be by the lactone in midbody compound structure also the reason for possible
Original reduces lactone and urethanes together.
In addition, the carboxyl functional group of intermediate II to be directly reduced into aldehyde I reaction, also without actual operation.It is first
Choosing is, it is necessary to reduce the activity of reducing agent, and typically from diisobutyl aluminium hydride (DIBAL-H) as reducing agent, this reducing agent is real
Room is tested using more, its price is higher, is rarely used in industrial production, industrially also without more cheap substitute；Secondly, react very
Hardly possible control reaction is only docked to aldehyde, without continuing to be reduced into alcohol, even if adding the reducing agent of equivalent.Finally, diisobutyl hydrogen
The lactone in structure can be reduced by changing aluminium.
Due to starting material compound II special construction, no matter by direct-reduction or conventional indirect reduction, all
Object I can not effectively be converted it into.The method of the only document report of amplification production can be adapted to, and condition is harsh, in
Mesosome is unstable.The focus that we innovate, which there is provided, a kind of has that high-selectivity reduction, reaction condition be easily controllable, behaviour
Make the husky intermediate compound I of sulfuric acid Walla handkerchief that safety, intermediate are stable, product purity is preferable, be adapted to industrialized production, i.e., ((1R,
3aR, 4aR, 6R, 8aR, 9S, 9aS) ten dihydro naphtho- [2,3-c] furans -6- bases of -9- formoxyl -1- methyl -3- oxos) ammonia
Base Ethyl formate, preparation technology.
The content of the invention
A kind of synthetic method of the husky intermediate compound I of sulfuric acid Walla handkerchief, i.e. ((1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS) -9- first
Dihydro naphtho- [2, the 3-c] furans -6- bases of acyl group -1- methyl -3- oxos ten) urethanes synthetic method, Ke Yitong
Following technical scheme is crossed to realize：
The synthetic route of the husky intermediate compound I of sulfuric acid Walla handkerchief is as follows：
Comprise the following steps：
(1) initiation material II reacts with sodium borohydride in polar organic solvent, then is acted on iodine, hydrolyzes to obtain intermediate
IIIb；
(2) intermediate III b and activated manganese dioxide flow back in dichloromethane, obtain intermediate compound I.
Further,
In step (1), compound II is tetrahydrofuran with the solvent that sodium borohydride reacts.
In step (1), compound II is -5~5 DEG C with the temperature that sodium borohydride reacts.
In step (1), the molar ratio of sodium borohydride and compound II and iodine is (2.6~3.5)：(1.5~2.5)：
1。
In a kind of scheme, sodium borohydride is added in anhydrous tetrahydro furan, then by the anhydrous tetrahydro furan of raw material II
Solution is added drop-wise in reaction system, and process temperature control is at -2~0 DEG C, stirring to bubble-free generation.The tetrahydrofuran solution of iodine is delayed
Slow is added drop-wise in reaction system, is reacted, and the molar ratio of sodium borohydride and compound II and iodine is 2.69：2：1.
The present invention reacts using compound II as initiation material with sodium borohydride, then is acted on iodine, hydrolyzes to obtain intermediate
IIIb；Then flowed back through manganese dioxide in dichloromethane, obtain intermediate compound I.Compound II is by sodium borohydride and iodine, in this hair
Under the conditions of bright reaction temperature, carboxylic acid is optionally directly reduced to alcohol, and ester does not influence the lactone in structure, the present invention
The confession preparation technology carried is stable, suitable industrial with high-selectivity reduction, easily controllable reaction condition, safe operation, intermediate
The features such as metaplasia is produced.
Specific embodiment
For ease of understanding, the present invention will be described in detail by specific embodiment below.Need to particularly point out
, specific embodiment is merely to explanation, it is clear that one of ordinary skill in the art can be according to illustrating, in the present invention herein
In the range of various amendments are made to the present invention.
Embodiment 1：
The THF of sodium borohydride (300mg, 7.93mmol) and 15mL is added in 100mL there-necked flask.By raw material II
(2.00g, 5.89mmol) is dissolved in 15mL THF, is added drop-wise to by constant pressure funnel in reaction system, and process temperature control is -2
~0 DEG C, during will produce a large amount of bubbles, stir about 0.5h is generated until bubble-free.By 13mL containing iodine (0.75g,
THF solution 2.95mmol) is transferred in constant pressure funnel.It is slowly dropped in reaction system.Drop continues to stir 1h after finishing.
Post processing, by 0.8mL at 0 DEG C, 1mol/L HCl are slowly dropped in the reaction system of stirring, are added after appropriate water, second
Ether is extracted.Merge organic phase, and organic phase is washed with 1mol/L NaOH (17mL × 3).Saturated common salt water washing, anhydrous slufuric acid
Sodium is dried, and is depressurized and is spin-dried at 25 DEG C, obtains 1.75g pale yellow oils, yield 91%.
Using its content of external standard method, qualified reference substance is first prepared, is determined after its content, in this, as reference material
Matter, it is 99% that content is drawn with external standard method.
1H NMR：(400MHz, CD3CN)：5.46(br,1H),4.70(td,1H),4.03(d,2H),3.69-3.57(m,
2H),3.45-3.32(dt,1H),2.77(br,1H),2.61-2.51(m,1H),2.49-2.39(m,1H),2.30(br 1H),
2.12-1.92(m,1H),1.87(dt,1H),1.81-1.72(m,1H),1.61-1.50(m,1H),1.48(d,3H),1.23-
1.09(m,7H),1.05-0.90(m,2H)；
MS(ES+)m/z:326.24[M+H]+。
Embodiment 2：
The THF of sodium borohydride (312mg, 8.25mmol) and 16mL is added in 100mL there-necked flask.By raw material II
(2.00g, 5.89mmol) is dissolved in 15mL THF, is added drop-wise to by constant pressure funnel in reaction system, and process temperature control is -2
~-5 DEG C, during will produce a large amount of bubbles, stir about 45min is generated until bubble-free.By 13mL containing iodine (0.60g,
THF solution 2.36mmol) is transferred in constant pressure funnel.It is slowly dropped in reaction system.Drop continues to stir 1h after finishing.
Post processing, by 0.8mL at 0 DEG C, 1mol/L HCl are slowly dropped in the reaction system of stirring, are added after appropriate water, second
Ether is extracted.Merge organic phase, and organic phase is washed with 11mol/L NaOH (17mL × 3).Saturated common salt water washing, anhydrous slufuric acid
Sodium is dried, and is depressurized and is spin-dried at 25 DEG C, obtains 1.65g pale yellow oils.
It is 98.7% to determine its content with reference to embodiment 1.
MS(ES+)m/z:326.24[M+H]+。
Embodiment 3：
50mL single port bottles, condenser pipe.Intermediate III b (1.00g, 3.07mmol) is dissolved in 10ml dichloromethane, it is rear to add
Into 50mL single port bottle, manganese dioxide (0.32g, 3.68mmol), back flow reaction 8h are added.After TLC detection reactions completely, drop
Temperature is to suction filtration after 20~25 DEG C, filter cake eluent methylene chloride (3mL × 3), is concentrated to dryness below 30 DEG C of filtrate.Add into residue
Enter 5mL ether, suction filtration after 0.5h is stirred in 20~25 DEG C, gained filter cake is dried in vacuo 10~12h in 30 DEG C.Obtain 0.87g white
Color solid.
1H NMR：(400MHz, CD3CN)：9.74(d,1H),5.40(br,1H),4.77-4.66(m,1H),4.09-3.98
(m,2H),3.49-3.37(m,1H),2.75-2.64(m,2H),2.55-2.48(m,1H),1.95-1.87(m,2H),1.89-
1.77(m,2H),1.61-1.49(m,1H),1.32-1.13(m,9H),1.08-0.82(m,2H)；
MS(ES+)m/z:324.33[M+H]+。
Using its content of external standard method, qualified reference substance is first prepared, is determined after its content, in this, as reference material
Matter, it is 99.2% that content is drawn with external standard method.
Claims (5)
1. the synthetic method of a kind of sulfuric acid Walla handkerchief sand intermediate compound I, it is characterised in that synthetic route is as follows：
Comprise the following steps：
(1) initiation material II reacts with sodium borohydride in polar organic solvent, then is acted on iodine, hydrolyzes to obtain intermediate III b,
Wherein compound II is -5~5 DEG C with the temperature that sodium borohydride reacts；
(2) intermediate III b and activated manganese dioxide flow back in dichloromethane, obtain intermediate compound I.
2. synthetic method according to claim 1, it is characterised in that compound II is four with the solvent that sodium borohydride reacts
Hydrogen furans, the temperature of reaction is -5~5 DEG C.
3. synthetic method according to claim 1, it is characterised in that compound II is -2 with the temperature that sodium borohydride reacts
~0 DEG C.
4. synthetic method according to claim 1, it is characterised in that in step (1), sodium borohydride and compound II and iodine
Molar ratio be (2.6~3.5)：(1.5~2.5)：1.
5. synthetic method according to claim 1, it is characterised in that add sodium borohydride in anhydrous tetrahydro furan, then
The anhydrous tetrahydrofuran solution of raw material II is added drop-wise in reaction system, process temperature control is at -2~0 DEG C, stirring to bubble-free life
Into, the tetrahydrofuran solution of iodine is slowly added drop-wise in reaction system, reacted, sodium borohydride and compound II and iodine
Molar ratio is 2.69：2：1.
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| CN105919966A (en) * | 2016-06-12 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Vorapaxar sulfate preparation and application thereof |
| CN106749138B (en) * | 2016-12-07 | 2019-08-16 | 扬子江药业集团四川海蓉药业有限公司 | A kind of preparation method of sulfuric acid Walla pa sand intermediate aldehydes |
| CN108947947A (en) * | 2017-05-17 | 2018-12-07 | 北京新领先医药科技发展有限公司 | A kind of preparation method of Walla pa sand intermediate |
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| AR061727A1 (en) * | 2006-06-30 | 2008-09-17 | Schering Corp | DIETILE SYNTHESIS [[5- (3-FLUOROPHENYL) -PIRIDIN -2IL] METHYL] PHOSPHONATE |
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Address after: Cheng Wei Road Nanjing city Jiangsu province 210012 Xianlin University No. 9 building C3 Patentee after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: Cheng Wei Road Nanjing city Jiangsu province 210012 Xianlin University No. 9 building C3 Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |