CN105348241A - Synthetic method of vorapaxar sulfate intermediate - Google Patents

Synthetic method of vorapaxar sulfate intermediate Download PDF

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Publication number
CN105348241A
CN105348241A CN201510916334.8A CN201510916334A CN105348241A CN 105348241 A CN105348241 A CN 105348241A CN 201510916334 A CN201510916334 A CN 201510916334A CN 105348241 A CN105348241 A CN 105348241A
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sodium borohydride
intermediate
synthetic method
iodine
compound ii
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CN201510916334.8A
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Chinese (zh)
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CN105348241B (en
Inventor
包金远
刘保庆
张孝清
蒋玉伟
黄辉
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南京华威医药科技开发有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic 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
    • C07D307/92Naphthofurans; Hydrogenated naphthofurans

Abstract

The invention belongs to a synthetic method of a vorapaxar sulfate intermediate, which comprises the steps of: taking a compound II as an initial raw material, reacting with sodium borohydride, acting with iodine and hydrolyzing to obtain an intermediate IIIb; then refluxing in dichloromethane through manganese dioxide to obtain an intermediate I. By means of sodium borohydride and iodine, the compound II can optionally directly reduce carboxylic acid into alcohol under the reaction temperature conditions, lactone in the structure is not affected, and the preparing process has the characteristics of high selection in reduction, easiness in control over reaction conditions, safety in operation, stable intermediate, suitability for industrialized production and the like.

Description

The synthetic method of the husky intermediate of a kind of sulfuric acid Walla handkerchief

Technical field

The invention belongs to pharmaceutical intermediate preparing technical field, particularly a kind of anti-coagulant sulfuric acid Walla handkerchief sand (vorapaxar) intermediate and preparation method thereof.

Background technology

Mo Shadong anti-coagulant sulfuric acid May 8 in 2014 Walla handkerchief sand (vorapaxar) obtains FDA approval, the patient of blocking is had, to reduce the risk of further heart attack, apoplexy, cardiovascular death and needs operation for the patient that had a heart attack or leg arteries.Vorapaxar is proteinase activated receptors 1 (PAR-1) antagonist of a kind of pioneering (first-in-class), it is a kind of anti-platelet agent, be intended to reduce platelet aggregation tendency, suppress the formation of blood clotting grumeleuse, have the wide market requirement and social value.

The structural formula of sulfuric acid Walla handkerchief sand is as follows:

The route of existing bibliographical information is as follows, and as can be seen from structure, starting raw material contains 7 hand-type centers; after two fragments molecules docking; obtain drug molecule sulfuric acid Walla handkerchief husky, the difficult point of this operational path is the husky midbody compound I of sulfuric acid Walla handkerchief ((1R, 3aR; 4aR; 6R, 8aR, 9S; 9aS)-9-formyl radical-1-methyl-3-oxo ten dihydro naphtho-[2,3-c] furans-6-base) urethanum preparation on.

The synthetic route of Vorapaxar technique

Patent of invention WO2006/076564 adopts intermediate II to react, and carboxylic acid first changes into the derivative acyl chlorides of carboxylic acid.And then be reduced into aldehyde with dry Pd/C.This method has following shortcoming: a, dry Pd/C are highly combustible, and particularly in the season of drying, there is very large danger, and affect very large by the property in season when factory amplifies.In b, literature procedures, first generate intermediate acid chloride IIIa, this intermediate very unstable, very responsive to water, this is by very high to the anhydrous requirement of reaction solvent.Because the water of a part will consume bimolecular acyl chlorides, generate acid anhydrides, will the productive rate of reaction be had a strong impact on.Aqueous vapor to be avoided in the post-processing operation of intermediate as far as possible, add the operation easier of aftertreatment.Its route is as follows:

The present inventor once attempted intermediate II first being changed into its carboxylic acid derivative chloride compounds ((1R; 3aR; 4aR; 6R; 8aR, 9S, 9aR)-9-(chloroformyl)-1-methyl-3-oxo ten dihydro-naphtho [2; 3-c] furans-6-base) urethanum, be then reduced into aldehyde with by three (trimethyl carbinol) lithium aluminium hydride.But experimental result is unsatisfactory, product purity is poor, and by product is more, and possible reason is that the ester group position of intermediate also can be reduced into alcohol by three (trimethyl carbinol) lithium aluminium hydride, incompatible with the lactone in structure.The present inventor attempts intermediate II to be first reduced into its alkylol cpd ((1R, 3aR, 4aR, 6R, 8aR, 9S, 9aS)-9-(methylol)-1-methyl-3-oxo ten dihydro-naphtho [2,3-c] furans-6-base) urethanum IIb, and then selective oxidation is to aldehyde.Attempt using reductive agent lithium aluminum hydride, borine and ruthenium agent etc., experimental result is undesirable equally, by product is more, product purification difficult, and possible reason is that lactone by the lactone reduction in midbody compound structure or can reduce by these catalyzer together with urethanum.

In addition, directly the carboxyl functional group of intermediate II is reduced into the reaction of aldehyde I, does not also there is actual operation.First-selection, need the activity reducing reductive agent, generally select diisobutyl aluminium hydride (DIBAL-H) as reductive agent, this reductive agent laboratory uses more, and its price is higher, is rarely used in industrial production, industrial also without more cheap substitute; Secondly, reaction is difficult to control reaction and is only docked to aldehyde, and does not continue to be reduced into alcohol, even if add the reductive agent of equivalent.Finally, diisobutyl aluminium hydride can by the lactone reduction in structure.

Due to the special construction of starting material compound II, no matter by direct-reduction or conventional indirect reduction, all can not effectively convert it into target compound I.Can be applicable to amplifying the method only having bibliographical information of producing, and condition is harsh, intermediate is unstable.The focus of our innovation there is provided a kind of there is high-selectivity reduction, reaction conditions is easy to controls, operational safety, intermediate are stablized, product purity better, be applicable to the sulfuric acid Walla handkerchief sand intermediate compound I of suitability for industrialized production; i.e. ((1R; 3aR; 4aR, 6R, 8aR; 9S; 9aS)-9-formyl radical-1-methyl-3-oxo ten dihydro naphtho-[2,3-c] furans-6-base) urethanum, preparation technology.

Summary of the invention

The synthetic method of the husky intermediate compound I of a kind of sulfuric acid Walla handkerchief; i.e. ((1R; 3aR; 4aR, 6R, 8aR; 9S; 9aS)-9-formyl radical-1-methyl-3-oxo ten dihydro naphtho-[2,3-c] furans-6-base) synthetic method of urethanum, can be achieved through the following technical solutions:

The synthetic route of the husky intermediate compound I of sulfuric acid Walla handkerchief is as follows:

Comprise the steps:

(1) starting raw material II and sodium borohydride react in polar organic solvent, then with iodine effect, be hydrolyzed to obtain intermediate III b;

(2) intermediate III b and activated manganese dioxide reflux in methylene dichloride, obtain intermediate compound I.

Further,

In step (1), the solvent that Compound II per and sodium borohydride react is tetrahydrofuran (THF).

In step (1), the temperature that Compound II per and sodium borohydride react is-5 ~ 5 DEG C.

In step (1), the molar ratio of sodium borohydride and Compound II per and iodine is (2.6 ~ 3.5): (1.5 ~ 2.5): 1.

In a kind of scheme, added by sodium borohydride in anhydrous tetrahydro furan, be then added drop-wise in reaction system by the anhydrous tetrahydrofuran solution of raw material II, process temperature control, at-2 ~ 0 DEG C, is stirred to bubble-free and generates.Be added drop-wise to slowly in reaction system by the tetrahydrofuran solution of iodine, react, the molar ratio of sodium borohydride and Compound II per and iodine is 2.69:2:1.

The present invention take Compound II per as starting raw material, reacts with sodium borohydride, then with iodine effect, be hydrolyzed to obtain intermediate III b; Then reflux in methylene dichloride through Manganse Dioxide, obtain intermediate compound I.Compound II per is by sodium borohydride and iodine, under temperature of reaction condition of the present invention, optionally carboxylic acid is directly reduced to alcohol, and the lactone not ester impact in structure, the confession preparation technology that the present invention carries, has high-selectivity reduction, reaction conditions is easy to control, operational safety, intermediate are stable, be applicable to the features such as suitability for industrialized production.

Specific embodiment

For ease of understanding, below will be described in detail the present invention by specific embodiment.It is important to note that specific embodiment is only to illustrate, obvious those of ordinary skill in the art according to illustrating, can make various correction to the present invention herein within the scope of the present invention.

Embodiment 1:

The THF of sodium borohydride (300mg, 7.93mmol) and 15mL is joined in the there-necked flask of 100mL.Be dissolved in the THF of 15mL by raw material II (2.00g, 5.89mmol), be added drop-wise in reaction system by constant pressure funnel, process temperature control, at-2 ~ 0 DEG C, will produce a large amount of bubble in process, and stir about 0.5h is until bubble-free generates.13mL is transferred in constant pressure funnel containing the THF solution of iodine (0.75g, 2.95mmol).Slowly be added drop-wise in reaction system.Drip after finishing and continue to stir 1h.Aftertreatment, is slowly added drop-wise to 0.8mL, 1mol/LHCl in the reaction system of stirring at 0 DEG C, after adding appropriate water, and extracted with diethyl ether.Merge organic phase, and wash organic phase with 1mol/LNaOH (17mL × 3).Saturated common salt water washing, anhydrous sodium sulfate drying, at 25 DEG C, decompression is spin-dried for, and obtains 1.75g pale yellow oil, productive rate 91%.

Use its content of external standard method, first prepare qualified reference substance, after determining its content, in this, as reference material, show that content is 99% with external standard method.

1HNMR:(400MHz,CD 3CN):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(br1H),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 joined in the there-necked flask of 100mL.Be dissolved in the THF of 15mL by raw material II (2.00g, 5.89mmol), be added drop-wise in reaction system by constant pressure funnel, process temperature control, at-2 ~-5 DEG C, will produce a large amount of bubble in process, and stir about 45min is until bubble-free generates.13mL is transferred in constant pressure funnel containing the THF solution of iodine (0.60g, 2.36mmol).Slowly be added drop-wise in reaction system.Drip after finishing and continue to stir 1h.Aftertreatment, is slowly added drop-wise to 0.8mL, 1mol/LHCl in the reaction system of stirring at 0 DEG C, after adding appropriate water, and extracted with diethyl ether.Merge organic phase, and wash organic phase with 11mol/LNaOH (17mL × 3).Saturated common salt water washing, anhydrous sodium sulfate drying, at 25 DEG C, decompression is spin-dried for, and obtains 1.65g pale yellow oil.

Measuring its content with reference to embodiment 1 is 98.7%.

MS(ES+)m/z:326.24[M+H] +

Embodiment 3:

50mL single port bottle, prolong.Intermediate III b (1.00g, 3.07mmol) is dissolved in 10ml methylene dichloride, after add in the single port bottle of 50mL, add Manganse Dioxide (0.32g, 3.68mmol), back flow reaction 8h.After TLC detection reaction is complete, suction filtration after being cooled to 20 ~ 25 DEG C, filter cake eluent methylene chloride (3mL × 3), filtrate less than 30 DEG C is concentrated into dry.In residue, add 5mL ether, suction filtration after stirring 0.5h in 20 ~ 25 DEG C, gained filter cake is in 30 DEG C of vacuum-drying 10 ~ 12h.Obtain 0.87g white solid.

1HNMR:(400MHz,CD 3CN):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] +

Use its content of external standard method, first prepare qualified reference substance, after determining its content, in this, as reference material, show that content is 99.2% with external standard method.

Claims (5)

1. a synthetic method for the husky intermediate compound I of sulfuric acid Walla handkerchief, is characterized in that synthetic route is as follows:
comprise the steps:
(1) starting raw material II and sodium borohydride react in polar organic solvent, then with iodine effect, be hydrolyzed to obtain intermediate III b;
(2) intermediate III b and activated manganese dioxide reflux in methylene dichloride, obtain intermediate compound I.
2. synthetic method according to claim 1, it is characterized in that the solvent that Compound II per and sodium borohydride react is tetrahydrofuran (THF), the temperature of reaction is-5 ~ 5 DEG C.
3. synthetic method according to claim 1, is characterized in that the temperature that Compound II per and sodium borohydride react is-2 ~ 0 DEG C.
4. synthetic method according to claim 1, is characterized in that in step (1), and the molar ratio of sodium borohydride and Compound II per and iodine is (2.6 ~ 3.5): (1.5 ~ 2.5): 1.
5. synthetic method according to claim 1, is characterized in that sodium borohydride to add in anhydrous tetrahydro furan, is then added drop-wise in reaction system by the anhydrous tetrahydrofuran solution of raw material II, and process temperature control, at-2 ~ 0 DEG C, is stirred to bubble-free and generates.Be added drop-wise to slowly in reaction system by the tetrahydrofuran solution of iodine, react, the molar ratio of sodium borohydride and Compound II per and iodine is 2.69:2:1.
CN201510916334.8A 2015-12-11 2015-12-11 A kind of synthetic method of the husky intermediate of sulfuric acid Walla handkerchief CN105348241B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN106749138A (en) * 2016-12-07 2017-05-31 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 handkerchief sand intermediate aldehydes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137647A (en) * 2005-01-14 2008-03-05 先灵公司 Synthesis of himbacine analogs
CN101193880A (en) * 2005-01-14 2008-06-04 先灵公司 Exo- and diastereo- selective syntheses of himbacine analogs
CN101511852A (en) * 2006-06-30 2009-08-19 先灵公司 Synthesis of diethyl{ i5'' (3 -fluorophenyl) -pyridine-2-yl] methyl} phosphonate used in the synthesis of himbacine analogs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137647A (en) * 2005-01-14 2008-03-05 先灵公司 Synthesis of himbacine analogs
CN101193880A (en) * 2005-01-14 2008-06-04 先灵公司 Exo- and diastereo- selective syntheses of himbacine analogs
CN101511852A (en) * 2006-06-30 2009-08-19 先灵公司 Synthesis of diethyl{ i5'' (3 -fluorophenyl) -pyridine-2-yl] methyl} phosphonate used in the synthesis of himbacine analogs

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN106749138A (en) * 2016-12-07 2017-05-31 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 handkerchief sand intermediate aldehydes
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

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Address after: Cheng Wei Road Nanjing city Jiangsu province 210012 Xianlin University No. 9 building C3

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