CN114249706A - Preparation method of intermediate for synthesizing prostacyclin derivative - Google Patents
Preparation method of intermediate for synthesizing prostacyclin derivative Download PDFInfo
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- CN114249706A CN114249706A CN202011011017.9A CN202011011017A CN114249706A CN 114249706 A CN114249706 A CN 114249706A CN 202011011017 A CN202011011017 A CN 202011011017A CN 114249706 A CN114249706 A CN 114249706A
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- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 150000003815 prostacyclins Chemical class 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 27
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 20
- 229940125898 compound 5 Drugs 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012267 brine Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 9
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 8
- QVHRAGBOMUXWRI-UHFFFAOYSA-N 3-hydroxy-2-prop-2-enylbenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1CC=C QVHRAGBOMUXWRI-UHFFFAOYSA-N 0.000 claims description 7
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 3
- 238000010626 work up procedure Methods 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims 1
- -1 cyclic prostaglandin Chemical class 0.000 abstract description 9
- 238000006859 Swern oxidation reaction Methods 0.000 abstract description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract description 3
- 150000007530 organic bases Chemical class 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical compound [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229960001726 treprostinil sodium Drugs 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229940118867 remodulin Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- FMCGSUUBYTWNDP-MWLCHTKSSA-N (1s,2r)-2-(dimethylamino)-1-phenylpropan-1-ol Chemical compound CN(C)[C@H](C)[C@@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-MWLCHTKSSA-N 0.000 description 1
- SEDRQGRABDFZKO-UHFFFAOYSA-N 3-prop-2-enoxybenzaldehyde Chemical compound C=CCOC1=CC=CC(C=O)=C1 SEDRQGRABDFZKO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000003790 Foot Ulcer Diseases 0.000 description 1
- 241000463109 Haloprofundus marisrubri Species 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007654 ischemic lesion Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an intermediate for synthesizing a cyclic prostaglandin derivative, which uses n-butyl lithium as an organic base when preparing a compound 6, namely (6S) -1- (2-allyl-3- (benzyloxy) phenyl) -6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-alkyne-1-alcohol, so that the reaction efficiency is improved, and high yield and purity are obtained. In the preparation of compound 7, namely (6S) -1- (2-allyl-3- (benzyloxy) phenyl-6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-yn-1-one, a selective Oxidation reagent (Swern Oxidation) is used in the reaction to convert hydroxyl into ketone, so that the reaction efficiency is improved, and the yield and the purity are improved.
Description
Technical Field
The invention relates to a preparation process of treprostinil sodium, in particular to a preparation method of an intermediate for synthesizing a prostaglandin derivative.
Background
Treprostinil sodium (Remodulin) is a derivative of prostacyclin and was first described in U.S. Pat. No. 4306075. It is approved for intravenous, subcutaneous route of administration (u.s 5153222) and as inhalant (u.s.pat.nos. 6521212 and 6756033) for the treatment of pulmonary hypertension and peripheral vascular disease. It is also used to treat cancers such as lung, liver, brain, pancreas, kidney, prostate, breast, colon, and head and neck (u.s 6803386); treatment of ischemic lesions (u.s 2005/0165111); improving renal function (7199157); treating neuropathic foot ulcer (U.S 2005/0282903), pulmonary fibrosis (US 2008/12/028471), peripheral angiopathy (U.S 6054486), interstitial lung disease (U.S 2008/0280986), and asthma (U.S 2008/12/028471)). U.S. Pat. nos.7417070, 7384978 and U.S. publication nos.2007/0078095, 2005/0282901 and 2008/0249167 describe oral dosage forms of treprostinil and other prostacyclin analogs. Due to the great use and importance of treprostinil sodium in the medical field, there is a great need to develop efficient synthetic methods that can be used for large-scale commercial production of treprostinil sodium and other prostacyclin derivatives.
Example 1 of chinese patent document CN103261142B (application No. 201180038065. X) discloses the preparation of chiral benzyl alcohol (a-1) by charging zinc trifluoromethanesulfonate (2.16g, 0.0059mol) and (+) -N-methylephedrine (0.814g, 0.0045mol) in toluene (10mL) into a 50mL two-necked round-bottomed flask equipped with a mechanical stirrer. Triethylamine (0.459g, 0.0045mol) was added to the mixture, and the gel-like mixture was stirred at ambient temperature for 30-60 minutes. The mixture was then treated with a solution of alkyne (1.08g, 0.0045mol) in toluene (1mL), stirred at ambient temperature for 15 minutes, and subsequently treated with a solution of acetaldehyde (0.250g, 0.0014 mol). The progress of the reaction was monitored by Thin Layer Chromatography (TLC) (completion of the reaction was monitored by Thin Layer Chromatography (TLC) using a thin layer silica gel plate; eluent: 20% ethyl acetate in hexane). After stirring the mixture for 3 hours, TLC indicated the reaction was complete. At this stage, the reaction mixture was quenched by slow addition of saturated ammonium chloride (10 ml). The mixture is stirred for 5 to 10 minutes, and the organic layer containing the desired compound is separated. The aqueous layer was washed with ethyl acetate (10 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product (2.0 g). The crude product was purified by column chromatography using 250-400 mesh silica gel. The product was eluted from the column using a gradient solvent (5% -20%) containing ethyl acetate in hexane. All fractions containing the desired product were mixed and concentrated in vacuo to give pure chiral benzyl alcohol a-1.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of an intermediate for synthesizing a prostacyclin derivative, which has high reaction efficiency, high yield and high purity.
The technical scheme for realizing the aim of the invention is a preparation method of an intermediate for synthesizing the prostacyclin derivative, wherein the intermediate is a compound 6, the structural formula is as follows, and the preparation method comprises the following steps:
(a) 2- (allyl) -3- (benzyloxy) benzaldehyde is prepared by reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide.
(b) Reacting a compound 5 shown as the following formula with 2- (allyl) -3- (benzyloxy) benzaldehyde to obtain a compound 6
In the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran and then cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
A process for preparing an intermediate for synthesizing a prostacyclin derivative, which is compound 7 having the following structural formula, comprising the steps of:
(a) 2- (allyl) -3- (benzyloxy) benzaldehyde is prepared by reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide.
(b) Reacting a compound 5 shown in the following formula with 2- (allyl) -3- (benzyloxy) benzaldehyde to obtain a compound 6;
(c) compound 6 is subjected to a Stevens oxidation reaction and the hydroxyl group is oxidized to give compound 7.
In the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran THF, and then is cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
In the above step (c), in N 2Under protection, at-78 + -2 deg.C (COCl)2Dissolving in anhydrous DCM, and stirring for 20-40 minutes at the temperature; then dropwise adding DMSO and anhydrous DCM, stirring after the dropwise adding is finished, and removing gas generated by the reaction mixture; dissolving a compound 6 in anhydrous DCM, dropwise adding the mixture into the reaction mixture, and stirring after dropwise addition; then TEA was added, the reaction stirred, and the reaction quenched by addition of brine to afford Compound 7.
A process for preparing an intermediate for synthesizing a prostacyclin derivative, which is compound 8 having the following structural formula, comprising the steps of:
(a) 2- (allyl) -3- (benzyloxy) benzaldehyde is prepared by reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide.
(b) Compound 5 is reacted with 2- (allyl) -3- (benzyloxy) benzaldehyde to give compound 6.
(c) Compound 6 is subjected to a Stevens oxidation reaction and the hydroxyl group is oxidized to give compound 7.
(d) The keto group of compound 7 is reduced to give compound 8.
In the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran THF, and then is cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
In the above step (c), in N 2Under protection, at-78 + -2 deg.C (COCl)2Dissolving in anhydrous DCM, and stirring for 20-40 minutes at the temperature; then dropwise adding DMSO and anhydrous DCM, stirring after the dropwise adding is finished, and removing gas generated by the reaction mixture; dissolving a compound 6 in anhydrous DCM, dropwise adding the mixture into the reaction mixture, and stirring after dropwise addition; then TEA was added, the reaction stirred, and the reaction quenched by addition of brine to afford Compound 7.
In the above step (d), in N2Under protection, dispersing the CBS-THF solution in anhydrous THF at-40 +/-2 ℃; then BH is added dropwise3-a THF solution; then 1/4-1/6 of the total amount of the THF solution of the compound 7 is dripped; then add BH alternately3-THF solution and compound 7/THF solution; stirring the reaction materials at-40 +/-2 ℃ for 2-4 hours, adding MeOH for quenching reaction, and stirring 8E14 hours; work-up gives compound 8.
The invention has the positive effects that:
(1) according to the invention, when the compound 4, namely 2- (allyl) -3- (benzyloxy) benzaldehyde, DMF (dimethyl formamide) and inorganic base are used together, so that the reaction efficiency is improved, and a product with high yield and high purity is obtained without chromatographic separation.
(2) According to the invention, when the compound 6, namely (6S) -1- (2-allyl-3- (benzyloxy) phenyl) -6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-alkyne-1-alcohol, is prepared, n-butyllithium is used as an organic base, so that the reaction efficiency is improved, and high yield and purity are obtained.
(3) In the invention, when the compound 7, namely (6S) -1- (2-allyl-3- (benzyloxy) phenyl-6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-alkyne-1-ketone is prepared, a selective Oxidation reagent (Swern Oxidation) is used for converting hydroxyl into ketone in the reaction, so that the reaction efficiency is improved, and the yield and the purity are improved.
Detailed Description
(example 1)
The intermediate prepared in this example for the synthesis of prostacyclin derivatives is (6S) -1- (2-allyl-3- (benzyloxy) phenyl) -6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-yn-1-ol, of the formula:
the preparation method comprises the following steps:
preparing 3- (allyloxy) benzaldehyde according to the following reaction formula:
the preparation process comprises the following steps:
150g (409.4 mmol) of 3-hydroxybenzaldehyde and 113.2g (818.9 mmol) of K2CO3Putting into a round bottom containing 200mL of DMF for sinteringIn a bottle and stirred at a temperature of 70 ℃ for one hour. After completion of the stirring, the mixture was cooled to room temperature (10 ℃ C. -35 ℃ C.), and 70mL (818.9 mmol) of allyl bromide was added to the round-bottom flask and stirred for 8-14 hours.
The reaction was monitored by thin layer chromatography (hexane: ethyl acetate (5: 1)).
After completion of the reaction, 300mL of water was added to the resulting mixture, followed by extraction with diethyl ether (200 mL × 2); the resulting organic phase was washed with brine (200 mL x 2), followed by Na2SO4Drying and then evaporating the solvent in vacuo gave 70g of an oily residue; LCMS: 99.48 percent.
For the compounds thus obtained1H. LCMS data characterization.
1 (CDCl3): 4.54-4.56(d, 2H, CH2), 5.25-5.42(m, 2H, =CH2), 5.95-6.08(m, 1H, =CH), 7.13-7.41(m, 4H, ArH), 9.92(s, H, CHO)。
: agilent ZORBAX XDB C18 (3.0X 150mm2, 3.5 μm; flow rate 0.7 mL/min), mobile phase acetonitrile (10% -90% -10%), 1% formic acid solution (90% -10% -90%), retention time 11.317 minutes, purity 99.48%.
Preparing 2-allyl-3-hydroxybenzaldehyde according to the following reaction formula:
the preparation process comprises the following steps:
in N2Under protection, the compound 2 prepared in the step (r) is dissolved in 40 g of PEG-600, and a reaction vessel is a thick-wall pressure-resistant flask. The reaction mass was stirred at 220 ℃ for 0.5h and then cooled to room temperature.
To the mixture obtained after the reaction, 40mL of water was added, followed by extraction with diethyl ether (200 mL × 2). Extracting the organic phase with Na2SO4Drying and then evaporation of the solvent in vacuo gave an oily residue which was purified on a flash column. The purified product was recrystallized from a mixture of hexane and DCM (4: 1) to give white crystals (2).92 g, yield 14.6%).
For the compounds thus obtained1H. LCMS data characterization.
1 (CDCl3): 3.90-3.92(d, 2H, CH2), 5.01-5.15(m, 2H, =CH2), 5.29(s, 1H, OH), 5.98-6.11(m, 1H, =CH), 7.08-7.10(d, 1H, ArH), 7.26-7.33(dd, 1H, ArH), 7.44-7.47(d, 1H, ArH), 10.19(s, 1H, CHO). LCMS: Agilent ZORBAX XDB C18(3.0×150mm2, 3.5 µm; flow rate, 0.7 mL/min; mobile phase, Acetonitrile (10%-90%-10%): 1% formic acid solution (90%-10%-90%); retention time: 8.453min(purity 95.43%)。
: agilent ZORBAX XDB C18 (3.0X 150mm2, 3.5 μm; flow rate 0.7 mL/min), mobile phase acetonitrile (10% -90% -10%), 1% formic acid solution (90% -10% -90%), retention time 8.453 minutes (purity 95.43%).
The use of the environment-friendly PEG-600 in the step can effectively reduce the time and temperature of the rearrangement reaction, and the prepared product has high purity.
③ preparing 2- (allyl) -3- (benzyloxy) benzaldehyde with the following reaction formula:
the preparation process comprises the following steps:
in N2Under protection, 2.85g (17.57 mmol) of compound 3 and 9.71g (70.29 mmol) of K2CO3And 0.26g (1.76 mmol) NaI in 15mL anhydrous DMF and the reaction mass was stirred at room temperature for 1 h.
4.18 mL (35.14 mmol) of benzyl bromide BnBr was dissolved in 5mL of anhydrous DMF and added dropwise to the reaction mass.
After the addition was completed, stirring was carried out for 3 hours, and TLC showed that the reaction was completed.
To the mixture obtained after the reaction, 20mL of water was added, followed by extraction with diethyl ether (200 mL × 2). The organic phase obtained by extraction was washed with brine (50 mL × 2) and water (50 mL × 2) in this order, and after washing, Na was added2SO4DryingThe solvent was then evaporated in vacuo to give the crude product. The crude product was recrystallized from hexane to obtain 2.1g of transparent crystals (yield 57.6%).
For the compounds thus obtained1H. LCMS data characterization.
1HNMR (DMSO-d6):3.87(d, 2H, CH2), 4.86-4.99(m, 2H, =CH2), 5.20 (s, 2H, CH2), 5.91-6.04(m, 1H, =CH),7.31-7.48(m, 8H, ArH)。
LCMS：Agilent ZORBAX XDB C18（3.0×150mm23.5 μm; the flow rate is 0.7 mL/min; mobile phase acetonitrile (10% -90% -10%): 1% formic acid solution (90% -10% -90); retention time 16.457 minutes, purity 98.80% was measured.
The step of using DMF and inorganic base together can improve the reaction efficiency, obtain products with high yield and high purity, and does not need chromatographic separation and purification.
(iv) preparation of (6S) -1- (2-allyl-3- (benzyloxy) phenyl) -6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-yn-1-ol according to the following reaction scheme:
the preparation process comprises the following steps:
1.42g (5.95 mmol) of Compound 5 was dissolved in 3mL of anhydrous tetrahydrofuran THF, then cooled to-8 ℃ to-12 ℃ (in this example, -10 ℃); then, 4.1 mL (6.54 mmol) of N-butyllithium was added dropwise to the solution of Compound 5, and the mixture was stirred under N2Stirring under an atmosphere at-10 ℃ for 40 to 80min, in this example for 1h, the solution turned yellow.
To the above yellow solution was added dropwise 1g (3.96 mmol) of compound 4, and the solution became pale orange and then turned back yellow. The end of the reaction was monitored by thin layer chromatography (hexane: ethyl acetate (7: 1)).
After the reaction was complete, 10mL of saturated NH4The Cl solution was added to the reacted mixture, and then 5mL of water was added dropwise. The organic layer was separated after separation and used for Et2O（200mL * 2）The aqueous layer was extracted. Mixing the extracts with Na2SO4Drying and subsequent evaporation of the solvent in vacuo gave the crude product as a yellow oil which was isolated on flash column to give 1.69g (87% yield) of compound 6 as a clear oil.
Prepared compound 6 with1H. LCMS data characterization.
1HNMR (CDCl3):0.88(t, 3H), 1.27-1.81(m, 17H), 2.26-2.44(dt, 2H), 3.43-3.92(m, 4H), 4.66-4.67(d, 1H), 4.92-4.93(m, 2H), 5.01-5.08(m, 2H), 5.64(s, 1H), 5.96-6.09(m, 1H), 6.89-6.93(d, 1H), 7.18-7.44(m, 7H)。
LCMS: agilent ZORBAX XDB C18 (3.0X 150mm2, 3.5 μm; flow rate 0.7 mL/min), mobile phase acetonitrile (76%): 1% formic acid solution (24%); retention times 11.62 and 12.62min (two diastereomers), purity 90.19% was measured.
The n-butyllithium is used as the organic base in the step, so that the reaction efficiency is improved, and high yield and purity are obtained.
(example 2)
The intermediate prepared in this example for the synthesis of prostacyclin derivatives is (6S) -1- (2-allyl-3- (benzyloxy) phenyl-6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-yn-1-one, of the formula:
the reaction formula is as follows:
the preparation process comprises the following steps:
in N 20.87 mL (10.19 mmol) of (COCl) at-78 ℃ under protection2Dissolved in 20mL of anhydrous dichloromethane (abbreviated as DCM herein) and stirred at that temperature for 30 minutes; 4.34mL (61.4 mmol) of DMSO and 4.5mL of anhydrous DCM are then added dropwise; stirring for 30 minutes after the dropwise addition is finished, and then removingRemoving gas generated from the reaction mixture.
1.325g (2.7 mmol) of compound 6 prepared in example 1 was dissolved in 4.5mL of anhydrous DCM and added dropwise to the above reaction mixture, stirring for 30 minutes after completion of the addition; then, 0.68mL (4.85 mmol) of triethylamine (hereinafter referred to as TEA) was added.
After 20 min, 6.96 mL (49.91 mmol) of TEA was added and stirred at-78 deg.C for 3 h. Brine was added to quench the reaction. DCM and TEA were removed in vacuo at room temperature.
50mL of water was added to the DCM and TEA removed material, followed by Et2O (50 mL × 3) extraction. The combined organic layers were extracted with saturated NaHCO3(50 mL x 2) and brine (50 mL x 2) and then over Na2SO4And (5) drying. The solvent was evaporated in vacuo to give a crude oil which was purified by flash column. Evaporation of the solvent in vacuo gave 2.1g of compound 7 as a brown oil in 84% yield.
Prepared compound 7 with1H. LCMS data characterization.
1(CDCl3): 0.86(t, 3H), 1.28-1.65(m, 16H), 2.51(t, 1H), 2.62(t, 1H), 3.45-3.51(m, 1H), 3.71-3.93(m, 4H), 4.62-4.63(m, 1H), 4.94-4.97(m ,2H), 4.99-5.10(m, 2H), 5.92-6.09(m ,1H), 7.08-7.12(d, 1H), 7.22-7.45(m,6H), 7.76(t, 1H)。
：AgilentZORBAX XDB C18（3.0×150mm23.5 μm; the flow rate is 0.7 mL/min; mobile phase, acetonitrile (10% -90% -10%): 1% formic acid solution (90% -10% -90%); retention times 9.743 and 10.163 minutes (two diastereomers), purity 86.51% was determined.
In this example, a selective Oxidation reagent (Swern Oxidation) was used to convert the hydroxyl group to a ketone, which improves the reaction efficiency and also achieves higher yield and purity.
(example 3)
The intermediate prepared in this example for the synthesis of prostacyclin derivatives is (1S, 6S) -1- (2-allyl-3- (benzyloxy) phenyl) -6- ((tetrahydro-2H-pyran-2-yl) oxy) undecyl-2-yn-1-ol, formula:
the reaction formula is as follows:
the preparation process comprises the following steps:
in N21M CBS-THF solution (0.491 mL; 0.491 mmol) was dispersed in 1mL anhydrous THF at-40 deg.C with protection; then 0.4 equivalent of 1M BH is added dropwise3THF solution (0.164 mL; 0.164 mmol).
After 5 minutes, 0.2mL of 1mL of Compound 7 prepared in example 2 in THF was added dropwise; BH was then added alternately every 2 minutes3-THF solution and THF solution of compound 7.
The reaction mass was stirred at-40 ℃ for 3 hours, quenched with MeOH and stirred overnight (8-14 hours).
The temperature of the reacted material was reduced to-10 ℃ and 2mL of 5% NH was added thereto4The Cl solution, after stirring for 10 min, was filtered through celite and washed with ethyl acetate EtOAc. The organic layer was separated and washed with 5% NH4The Cl solution (20 mL. times.2) and brine (20 mL. times.2) were washed, the combined aqueous layers were extracted with EtOAc (50 mL), and the combined washed organic layers were Na 2SO4After drying, the solvent was evaporated in vacuo to give a yellow oily material, which was purified using a conventional silica column, and after column purification the fractions containing the desired compound were evaporated in vacuo to give 75 mg of compound 8 as a yellow oil (yield 37%).
Prepared compound 8 by1H. LCMS data characterization.
1HNMR (CDCl3): 0.88(t, 3H), 1.25-1.79(m, 17H), 2.30-2.42(m, 2H), 3.44-3.91(m, 4H), 4.65(d, 1H), 4.94-4.98(m, 2H), 5.0-5.08(m, 2H), 5.64(m, 1H), 6.02(m, 1H), 6.91(d, 1H), 7.20-7.43, m, 7H)。
LCMS: agilent ZORBAX XDB C18 (3.0X 150mm2, 3.5 μm; flow rate 0.7 mL/min; mobile phase, acetonitrile (76%): 1% formic acid solution (24%); retention times 9.310 and 10.143 min (two diastereomers); purity 97.16% was measured.
With respect to the obtained compound 8, treprostinil sodium (Remodulin) was prepared as an intermediate of prostacyclin derivatives by a method taught in CN 103261142B.
Claims (9)
1. A process for producing an intermediate for synthesizing a prostacyclin derivative, which is compound 6 having the following structural formula, characterized by comprising the steps of:
(a) reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide to prepare 2- (allyl) -3- (benzyloxy) benzaldehyde;
(b) reacting a compound 5 shown as the following formula with 2- (allyl) -3- (benzyloxy) benzaldehyde to obtain a compound 6
2. The process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 1, wherein: in the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran THF, and then is cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
3. A process for producing an intermediate for synthesizing a prostacyclin derivative, which is compound 7 having the following structural formula, characterized by comprising the steps of:
(a) reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide to prepare 2- (allyl) -3- (benzyloxy) benzaldehyde;
(b) reacting a compound 5 shown in the following formula with 2- (allyl) -3- (benzyloxy) benzaldehyde to obtain a compound 6;
(c) compound 6 is subjected to a Stevens oxidation reaction and the hydroxyl group is oxidized to give compound 7.
4. The process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 3, wherein:
in the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran THF, and then is cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
5. The process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 3, wherein:
in step (c), in N 2Under protection, at-78 + -2 deg.C (COCl)2Dissolving in anhydrous DCM, and stirring for 20-40 minutes at the temperature; then adding DMSO and anhydrous DCM dropwise, stirring after dropwise addition, removing reaction mixtureA gas generated by the compound; dissolving a compound 6 in anhydrous DCM, dropwise adding the mixture into the reaction mixture, and stirring after dropwise addition; then TEA was added, the reaction stirred, and the reaction quenched by addition of brine to afford Compound 7.
6. A process for preparing an intermediate for synthesizing a prostacyclin derivative, which is compound 8 having the following structural formula, characterized by comprising the steps of:
(a) reacting 2-allyl-3-hydroxybenzaldehyde with benzyl bromide to prepare 2- (allyl) -3- (benzyloxy) benzaldehyde;
(b) reacting the compound 5 with 2- (allyl) -3- (benzyloxy) benzaldehyde to obtain a compound 6;
(c) carrying out Stevens oxidation reaction on the compound 6, and oxidizing hydroxyl to obtain a compound 7;
(d) reducing the ketone group of the compound 7 to obtain a compound 8;
7. the process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 6, wherein:
in the step (b), the compound 5 is dissolved in anhydrous tetrahydrofuran THF, and then is cooled to-8 to-12 ℃; then N-butyllithium was added dropwise to the solution of compound 5 and added under N2Stirring at the atmosphere of-8 to-12 ℃ until the solution turns yellow; 2- (allyl) -3- (benzyloxy) benzaldehyde is added dropwise into the yellow solution, and compound 6 is obtained after the reaction is finished.
8. The process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 6, wherein:
in step (c), in N 2Under protection, at-78 + -2 deg.C (COCl)2Dissolving in anhydrous DCM, and stirring for 20-40 minutes at the temperature; then dropwise adding DMSO and anhydrous DCM, stirring after the dropwise adding is finished, and removing gas generated by the reaction mixture; dissolving a compound 6 in anhydrous DCM, dropwise adding the mixture into the reaction mixture, and stirring after dropwise addition; then TEA was added, the reaction stirred, and then quenched by addition of brine to afford compound 7 after work-up.
9. The process for producing an intermediate for synthesizing a prostacyclin derivative according to claim 6, wherein:
in step (d), in N2Under protection, dispersing the CBS-THF solution in anhydrous THF at-40 +/-2 ℃; then BH is added dropwise3-a THF solution; then 1/4-1/6 of the total amount of the THF solution of the compound 7 is dripped; then add BH alternately3-THF solution and compound 7/THF solution; stirring the reaction materials at-40 +/-2 ℃ for 2-4 hours, adding MeOH for quenching reaction, and stirring for 8-14 hours; after work-up, compound 8 is obtained.
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| CN104892555A (en) * | 2014-03-04 | 2015-09-09 | 江苏豪森药业股份有限公司 | The preparation method of treprostinil intermediate |
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| WO2002053517A2 (en) * | 2001-01-05 | 2002-07-11 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| CN1494524A (en) * | 2001-01-05 | 2004-05-05 | �Ƹ��� | Process for stereo selective synthesis of prostacyclin derivatives |
| CN104892555A (en) * | 2014-03-04 | 2015-09-09 | 江苏豪森药业股份有限公司 | The preparation method of treprostinil intermediate |
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