CN110483360B - Synthesis method of alfaprost alcohol - Google Patents
Synthesis method of alfaprost alcohol Download PDFInfo
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- CN110483360B CN110483360B CN201910850626.4A CN201910850626A CN110483360B CN 110483360 B CN110483360 B CN 110483360B CN 201910850626 A CN201910850626 A CN 201910850626A CN 110483360 B CN110483360 B CN 110483360B
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 110
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 238000007069 methylation reaction Methods 0.000 claims abstract description 10
- IDHDPWUDFGNQJM-UHFFFAOYSA-N azido dihydrogen phosphate Chemical compound P(=O)(O)(O)ON=[N+]=[N-] IDHDPWUDFGNQJM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 150000003138 primary alcohols Chemical class 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 238000005406 washing Methods 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 31
- 238000001914 filtration Methods 0.000 claims description 31
- 239000000758 substrate Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 27
- 238000010791 quenching Methods 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- 230000000171 quenching effect Effects 0.000 claims description 18
- 150000007529 inorganic bases Chemical class 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- FTUAIEDAAMWBHD-UHFFFAOYSA-N Coriolide Natural products CCCCCC(O)C=CC=C/CCCCCCC=C=O FTUAIEDAAMWBHD-UHFFFAOYSA-N 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 239000010936 titanium Substances 0.000 claims description 11
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 10
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 229910052719 titanium Inorganic materials 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical group CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 7
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 6
- 125000003172 aldehyde group Chemical group 0.000 claims description 6
- -1 alkynyl compound Chemical class 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 claims description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- 230000001939 inductive effect Effects 0.000 claims description 3
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 230000033116 oxidation-reduction process Effects 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000012071 phase Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UQURIQWAEZGLAC-UHFFFAOYSA-N 2-cyclohexylpropanal Chemical compound O=CC(C)C1CCCCC1 UQURIQWAEZGLAC-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- BNGCVNHMPJGSOA-UHFFFAOYSA-N azidophosphonic acid Chemical compound OP(O)(=O)N=[N+]=[N-] BNGCVNHMPJGSOA-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention relates to the field of medicine preparation, in particular to a synthesis method of alfa-prost, wherein levo-benzoyl-colelactone is used as a raw material, and is subjected to primary alcohol oxidation and then reacts with azido phosphate to prepare a compound a3, chiral addition of the compound a3 and aldehyde is induced by chiral ligand amine to generate a compound a4, and reduction and Wittig reaction are carried out to generate a compound a 6; finally, the terminal carboxyl of the compound a6 is subjected to methylation reaction to prepare the alfaprost alcohol. The synthesis method of alfaprost alcohol provided by the invention directly takes levo-benzoyl colactone as a raw material, and the raw material is simple and easy to obtain and simple to operate; the reaction steps are short, the yield of the whole process route is about 55-60%, and the industrial production is easy to realize; the technological conditions of each step of reaction are easy to realize, the post-treatment is simple, and the intermediate is easy to purify; only one-step chiral reaction is carried out, isomer impurities are easy to control, and the obtained product has high optical purity.
Description
Technical Field
The invention relates to the field of medicine preparation, and particularly relates to a synthesis method of alfaprost alcohol.
Background
Alfrostol is a more stable and PGF2αAnalogs with equal selectivity, widely used as luteinizing agents in cattle and mares, the pharmaceutical effect of which is PGF2αTen times that of; meanwhile, the compound is used as PGF in countries of Europe and America and the like because the chemical structure of the compound is more stable2αAnd a plurality of pharmaceutical companies in the world have application in researching the treatment of the neuropsychiatric diseases caused by the reduction of adipose tissues by the alfaprost alcohol and the analogues thereof.
The prior chemical synthesis method of alfrostol has few methods and two effective synthesis processes, the first is Hannah Baars (org. Lett. 2017, 19, 6008.) which discloses a method for preparing a target product by using succinaldehyde as a raw material through 11 steps of reaction, the method has long steps and very low reaction yield, the final yield of the whole route is only 2.68%, and the individual links of the process have urgent requirements on anhydrous and anaerobic operation and can not be realized under simple process conditions, so the preparation process is only limited to a laboratory research stage at present and is not suitable for industrial amplification production.
The second one is Carmelo Gandolfi (US 4035415) which discloses a method for synthesizing alfaprost alcohol, the process takes protected benzoyl colactone as raw material to synthesize alfaprost alcohol through ten steps of reaction, the route is long, and the yield is low; and uses violent poisons such as bromine and flammable and explosive dangerous goods such as sodium hydride, so that the large-scale production can be carried out only by further process optimization.
Therefore, the existing synthesis process of alfaprost alcohol has low yield and long synthesis route, and is not suitable for industrial scale-up production.
Disclosure of Invention
In order to solve the problems of low yield, long synthesis route and unsuitability for industrial scale-up production of the synthesis process of the alfaprost alcohol mentioned in the background art, the invention provides a synthesis method of the alfaprost alcohol, wherein,
the invention provides a synthesis method of alfaprost alcohol, which comprises the following steps:
step a, adding levo-benzoyl coriolide and an oxidant into a solvent, carrying out primary alcohol oxidation reaction, quenching, extracting, washing, drying, filtering and concentrating to obtain coriolide containing aldehyde groups, namely a compound a 2;
specifically, adding levo-benzoyl colactone and dichloromethane into a reaction container, cooling to the temperature of not higher than 0 ℃, then adding an oxidant to carry out primary alcohol oxidation reaction, and controlling the reaction temperature of not higher than 10 ℃; after the reaction is finished, saturated Na is added2S2O3Quenching the solution, extracting the water phase by using dichloromethane, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain the aldehyde group-containing coriolide, namely the compound a 2.
B, reacting the compound a2, azido phosphate and a solvent under the catalysis of inorganic base, and extracting, washing, drying, filtering and concentrating to obtain an alkynyl compound, namely a compound a 3;
specifically, adding a compound a2, a solvent and an inorganic base into a reaction kettle, cooling to 0-5 ℃, adding azido phosphate for reaction, keeping the temperature at 0-5 ℃, adding a saturated sodium chloride solution for quenching after the reaction is finished, and extracting a water phase by using ethyl acetate; and combining organic phases, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering and concentrating to obtain a light yellow alkynyl compound, namely the compound a 3.
C, under the action of organic strong base, inducing the compound a3 by chiral ligand amine and a titanium reagent, carrying out chiral addition reaction with aldehyde, extracting, washing, drying, filtering and concentrating to obtain a compound a 4;
specifically, adding a compound a3 and tetrahydrofuran into a reaction kettle, cooling to-75 ℃, sequentially adding an organic strong base, chiral ligand amine, a titanium reagent and a tetrahydrofuran solution of cyclohexyl propionaldehyde to react, and maintaining the reaction temperature at-75 to-40 ℃; after the compound a3 is induced by chiral ligand, carrying out chiral addition reaction with aldehyde, after the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting a water phase by using ethyl ester, combining organic phases, respectively washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain a compound a 4;
d, taking tetrahydrofuran as a solvent, carrying out redox on the compound a4 by adopting a reducing agent, and then carrying out quenching, extraction, washing, drying, filtration and concentration to obtain a compound a 5;
specifically, tetrahydrofuran and a compound a4 are added into a reaction vessel, after the temperature is cooled to be not higher than-70 ℃, a reducing agent is added for reduction reaction, the reaction temperature is controlled to be not higher than-40 ℃, after the reaction is finished, methanol is added for quenching, a saturated sodium potassium tartrate solution is added, an aqueous phase is extracted by ethyl acetate, organic phases are combined, then a saturated sodium chloride solution is used for washing, drying cannot be carried out by sodium sulfate, filtering and concentrating are carried out, and a light yellow compound a5 is obtained.
Step e, carrying out Wittig reaction on the compound a5 and the upper side chain intermediate, extracting, washing, drying, filtering and concentrating to obtain a compound a 6;
specifically, carrying out a Wittig reaction on a compound a5 and an upper side chain intermediate at a reaction temperature of-40 to-20 ℃, adding a saturated sodium chloride solution to quench after the reaction is finished, extracting a water phase by using ethyl acetate, washing by using sodium hydroxide, combining all the water phases, acidifying by using phosphoric acid until the pH is =5, extracting by using ethyl acetate, combining organic phases, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, concentrating to obtain a light yellow liquid, adding ethyl acetate to crystallize, filtering, and concentrating to obtain a compound a 6;
and f, carrying out methylation reaction on the terminal carboxyl of the compound a6, and then carrying out extraction, washing, drying, filtering, concentrating and column chromatography to obtain the alfaprost alcohol.
Specifically, methylation reaction is carried out on the terminal carboxyl group of the compound a6, the reaction temperature is 0-50 ℃, saturated sodium chloride is added for quenching after the reaction is finished, ethyl acetate is added for extraction, organic phases are combined, the mixture is washed by the saturated sodium chloride, dried by anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography to obtain the alfrostenol.
On the basis of the scheme, in the step a, the oxidant is one of dess-martin, TEMPO, dimethyl sulfoxide and oxalyl chloride; the molar equivalent of the oxidant is 1.0-2.0 times of the reaction substrate.
On the basis of the scheme, in a further step a, the solvent is dichloromethane.
On the basis of the scheme, in the step b, the solvent is one or more of methanol, ethanol and isopropanol; the inorganic base is potassium carbonate or cesium carbonate.
On the basis of the scheme, in the step b, the using molar equivalent of the azido phosphate is 1-5 times of the reaction substrate, and the using molar equivalent of the inorganic base is 2-10 times of the reaction substrate.
On the basis of the scheme, in the step c, the organic strong base is one of LiHMDS, NaHMDS, KHMDS and LDA.
On the basis of the scheme, in the step c, the molar equivalent of the organic strong base is 0.8-1.2 times of that of the reaction substrate; the used molar equivalent of the chiral ligand amine is 0.1-0.5 time of that of a reaction substrate; the molar equivalent of the titanium reagent is 1-2 times of the reaction substrate.
On the basis of the above scheme, further, in step d, the reducing agent is diisobutylaluminum hydride or red aluminum, and the molar equivalent of the reducing agent used is 3.0-4.0 times of the reaction substrate.
On the basis of the scheme, further, the Wittig reaction comprises the following steps: the upper side chain intermediate 4-carboxybutyltriphenylphosphonium bromide, a solvent and tetrahydrofuran are reacted with organic strong base to generate Wittig salt, then tetrahydrofuran solution of a compound a5 is added into a reaction system, the reaction temperature is-40 to-20 ℃, and the Wittig reaction is carried out to obtain a compound a 6.
On the basis of the scheme, in the step e, the organic strong base is one of LiHMDS, NaHMDS and KHMDS, and the using equivalent of the organic strong base is 3.5-12 times of that of the substrate.
On the basis of the scheme, in the step e, the solvent is HMPA, and the concentration of the HMPA is 0.1-1 mol/L; HMPA is used as a reaction solvent and an ion trapping agent, so that the reaction yield can be effectively improved.
On the basis of the above scheme, further, in step f, the methylation reaction comprises: dissolving the compound a6 in a solvent, adding an inorganic base, cooling to a temperature of not higher than 10 ℃, and then adding methyl iodide or diazomethane for reaction to obtain the target product, namely alpha-proethanol.
On the basis of the above scheme, further, in step f, the inorganic base is potassium carbonate or cesium carbonate, and the molar equivalent of the inorganic base used is 1-2 times of the reaction substrate.
On the basis of the scheme, further, the molar equivalent of the methyl iodide is 2-5 times of that of the reaction substrate; the molar equivalent of diazomethane is 2-5 times of the reaction substrate.
On the basis of the scheme, in the step f, the solvent is one of tetrahydrofuran, acetone and N, N-dimethylformamide.
Compared with the prior art, the synthesis method of alfaprost alcohol provided by the invention has the following effects:
1. the levo-benzoyl coriolide is directly used as a raw material, and the raw material is simple and easy to obtain and simple to operate;
2. the reaction steps are short, the yield of the whole process route is about 55-60%, and the industrial production is easy to realize;
3. the technological conditions of each step of reaction are easy to realize, the post-treatment is simple, and the intermediate is easy to purify;
4. only one-step chiral reaction is carried out, isomer impurities are easy to control, and the obtained product has high optical purity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a hydrogen spectrum of alfa-prost alcohol provided by the present invention;
FIG. 2 is a carbon spectrum of alfa-prost alcohol provided by the present invention;
FIG. 3 is a mass spectrum of alfa-prost alcohol provided by the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the following description will clearly and completely describe the embodiments of the present invention, and obviously, the described embodiments are a part of the embodiments of the present invention, but not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention provides a synthesis method of alfaprost alcohol, which comprises the following steps:
step a, adding levo-benzoyl coriolide and an oxidant into a solvent, carrying out primary alcohol oxidation reaction, quenching, extracting, washing, drying, filtering and concentrating to obtain coriolide containing aldehyde groups, namely a compound a 2;
the process route is as follows:
specifically, the levo-benzoylic acid compound isAdding lactone, namely a compound a1 and dichloromethane into a reaction container, cooling to the temperature of not higher than 0 ℃, then adding an oxidant to carry out primary alcohol oxidation reaction, and controlling the reaction temperature of not higher than 10 ℃; after the reaction is finished, saturated Na is added2S2O3Quenching the solution, extracting the water phase by using dichloromethane, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain the aldehyde group-containing coriolide, namely the compound a 2.
B, reacting the compound a2, azido phosphate and a solvent under the catalysis of inorganic base, and extracting, washing, drying, filtering and concentrating to obtain an alkynyl compound, namely a compound a 3;
the process route is as follows:
specifically, adding a compound a2, a solvent and an inorganic base into a reaction kettle, cooling to 0-5 ℃, adding azido phosphate for reaction, keeping the temperature at 0-5 ℃, adding a saturated sodium chloride solution for quenching after the reaction is finished, and extracting a water phase by using ethyl acetate; and combining organic phases, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering and concentrating to obtain a light yellow alkynyl compound, namely the compound a 3.
C, under the action of organic strong base, inducing the compound a3 by chiral ligand amine and a titanium reagent, carrying out chiral addition reaction with aldehyde, extracting, washing, drying, filtering and concentrating to obtain a compound a 4;
the process route is as follows:
specifically, adding a compound a3 and tetrahydrofuran into a reaction kettle, cooling to-75 ℃, sequentially adding organic strong base, chiral ligand amine, titanium reagent and tetrahydrofuran solution of cyclohexyl propionaldehyde to react, and maintaining the reaction temperature at-75 ℃ to-40 ℃; after the compound a3 is induced by chiral ligand, carrying out chiral addition reaction with aldehyde, after the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting a water phase by using ethyl ester, combining organic phases, respectively washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain a compound a 4;
d, taking tetrahydrofuran as a solvent, carrying out redox on the compound a4 by adopting a reducing agent, and then carrying out quenching, extraction, washing, drying, filtration and concentration to obtain a compound a 5;
the process route is as follows:
specifically, tetrahydrofuran and a compound a4 are added into a reaction vessel, after the temperature is cooled to be not higher than-70 ℃, a reducing agent is added for reduction reaction, the reaction temperature is controlled to be not higher than-40 ℃, after the reaction is finished, methanol is added for quenching, a saturated sodium potassium tartrate solution is added, an aqueous phase is extracted by ethyl acetate, organic phases are combined, then a saturated sodium chloride solution is used for washing, drying cannot be carried out by sodium sulfate, filtering and concentrating are carried out, and a light yellow compound a5 is obtained.
Step e, carrying out Wittig reaction on the compound a5 and the upper side chain intermediate, extracting, washing, drying, filtering and concentrating to obtain a compound a 6;
the process route is as follows:
specifically, carrying out a Wittig reaction on a compound a5 and an upper side chain intermediate at a reaction temperature of-40 ℃ to-20 ℃, adding a saturated sodium chloride solution to quench after the reaction is finished, extracting a water phase by using ethyl acetate, washing by using sodium hydroxide, combining all the water phases, acidifying by using phosphoric acid until the pH is =5, extracting by using ethyl acetate, combining organic phases, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, concentrating to obtain a light yellow liquid, adding ethyl acetate to crystallize, filtering, and concentrating to obtain a compound a 6;
and f, carrying out methylation reaction on the terminal carboxyl of the compound a6, and then carrying out extraction, washing, drying, filtering, concentrating and column chromatography to obtain the alfaprost alcohol.
The process route is as follows:
specifically, methylation reaction is carried out on the terminal carboxyl group of the compound a6, the reaction temperature is 0-50 ℃, saturated sodium chloride is added for quenching after the reaction is finished, ethyl acetate is added for extraction, organic phases are combined, the mixture is washed by the saturated sodium chloride, dried by anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography to obtain the alfrostenol.
Preferably, in step a, the oxidant is one of dess-martin, TEMPO, dimethyl sulfoxide and oxalyl chloride; the molar equivalent of the oxidant is 1.0-2.0 times of the reaction substrate.
Preferably, in step a, the solvent is dichloromethane.
Preferably, in the step b, the solvent is one or more of methanol, ethanol and isopropanol; the inorganic base is potassium carbonate or cesium carbonate.
Preferably, in step b, the molar equivalent of the azido phosphate is 1-5 times of the reaction substrate, and the molar equivalent of the inorganic base is 2-10 times of the reaction substrate.
Preferably, in step c, the organic strong base is one of LiHMDS, NaHMDS, KHMDS and LDA.
Preferably, in step c, the molar equivalent of the organic strong base used is 0.8-1.2 times that of the reaction substrate; the used molar equivalent of the chiral ligand amine is 0.1-0.5 time of that of a reaction substrate; the molar equivalent of the titanium reagent is 1-2 times of the reaction substrate.
Preferably, in step d, the reducing agent is diisobutylaluminum hydride or aluminum oxide, and the molar equivalent of the reducing agent is 3.0-4.0 times that of the reaction substrate. .
Preferably, the Wittig reaction comprises: the upper side chain intermediate 4-carboxybutyltriphenylphosphonium bromide, a solvent and tetrahydrofuran are reacted with organic strong base to generate Wittig salt, then tetrahydrofuran solution of a compound a5 is added into a reaction system, and the reaction temperature is-40 ℃ to-20 ℃, namely the Wittig reaction is carried out to obtain a compound a 6.
Preferably, in step e, the organic strong base is one of LiHMDS, NaHMDS and KHMDS, and the using equivalent of the organic strong base is 3.5-12 times of the reaction substrate.
Preferably, in step e, the solvent is HMPA, and the concentration of the HMPA is 0.1-1 mol/L; HMPA is used as a reaction solvent and an ion trapping agent, so that the reaction yield can be effectively improved.
Preferably, in step f, the methylation reaction comprises: dissolving the compound a6 in a solvent, adding an inorganic base, cooling to a temperature of not higher than 10 ℃, and then adding methyl iodide or diazomethane for reaction to obtain the target product, namely alpha-proethanol.
Preferably, in step f, the inorganic base is potassium carbonate or cesium carbonate, and the molar equivalent of the inorganic base is 1-2 times of the raw material.
Preferably, in step f, the molar equivalent of methyl iodide used is 2-5 times that of the reaction substrate; the molar equivalent of diazomethane is 2-5 times of the reaction substrate.
Preferably, in step f, the solvent is one of tetrahydrofuran, acetone and N, N-dimethylformamide.
The invention also provides the following embodiments:
step a, preparation of Compound a2
Adding levo-benzoyl coriolide (500 g, 1.81 mol) and dichloromethane (5L) into a 10L three-neck flask equipped with thermometer and mechanical stirring; then, cooling the mixed system to an internal temperature not higher than 0 ℃ by using an ice salt bath, and stirring for 10 min at a constant temperature;
then slowly adding the dessimutan reagent (2.17 mol) into the reaction system, controlling the reaction temperature to be not higher than 10 ℃, and stirring for 2 hours at constant temperature after the addition of the dessimutan reagent is finished. After the reaction is finished, saturated Na is added into the system2S2O3The reaction was quenched (1000 mL), the aqueous phase was extracted with dichloromethane (0.5L x 2), the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the pale yellow compound a2(480 g,1.75 mol) which was used directly in the next reaction with a yield of 96.7%.
Step b, preparation of Compound a3
In a 10L reactor equipped with a thermometer, mechanical stirring and dropping funnel, a2(480 g,1.75 mol), methanol (5L) and potassium carbonate (483 g,3.50 mol) were charged in this order. Stirring was started and the temperature of the reaction was reduced to 0-5 ℃. Subsequently, azidophosphonate (402 g, 2.10 mol) was slowly added dropwise to the above system, over 30 min, and stirred at 0-5 ℃ for 12 h. After the reaction was complete, 10L of saturated sodium chloride solution was added to quench the reaction and the aqueous phase was extracted with ethyl acetate (2L 4). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give the pale yellow compound a3(387 g, 1.43 mol) in 81.9% yield.
Step c preparation of Compound a4
After the compound a3(387 g, 1.43 mol) and tetrahydrofuran (4L) were charged into a 10L reactor, the temperature in the reactor was lowered to-75 ℃ and 1M toluene solution of NaHMDS (1.72L, 1.72 mol) was slowly added dropwise thereto at a controlled rate to maintain the reaction temperature of-75 to-65 ℃. After the addition, chiral ligand amine (112 g, 0.143 mol) and titanium reagent (1.43 mol) are added to react for 1 hour at constant temperature, finally, tetrahydrofuran (1L) solution of cyclohexyl propionaldehyde (200 g, 1.43 mol) is slowly dripped into the reaction system, and the reaction temperature is controlled to be-75 to-65 ℃. After the dropwise addition, the reaction is carried out for 24 hours at constant temperature. After completion of the TLC detection reaction, 3L of saturated ammonium chloride solution was added for quenching, and the separated aqueous phase was extracted with ethyl acetate (1L. multidot.3). And (3) combining organic phases, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain 780 g of crude product, wherein the yield of the crude product is 101%.
Step d, preparation of Compound a5
Compound a4 (780 g, 1.44 mol) and tetrahydrofuran (5L) were added to a 10L three-necked flask equipped with a constant pressure dropping funnel, thermometer and mechanical stirring. The above mixed system was then cooled to an internal temperature of not higher than-70 ℃ and a 1.5M diisobutylaluminum hydride (3.86L) toluene solution was added dropwise.
The reaction temperature is controlled not to be higher than-40 ℃. After the dropwise addition, stirring at constant temperature for 30 min. After the reaction is finished, adding methanol (100 mL) into the system for quenching, transferring the system into a saturated sodium potassium tartrate solution (5L), and stirring at room temperature for 1 h; the aqueous phase was extracted with ethyl acetate (2L x 3), the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the pale yellow compound a5(383 g,1.24 mol) in 87.0% yield over two steps.
Step e preparation of Compound a6
In a 20L reactor equipped with a thermometer, mechanical stirring and dropping funnel, the pendant side chain intermediate, 4-carboxybutyltriphenylphosphonium bromide (3150 g, 7.5 mol), HMPA (200 mL) and tetrahydrofuran (6L) were added in that order. And starting stirring, reducing the temperature in the reaction kettle to-40 ℃, slowly dropwise adding NaHMDS (15 mol, 7.5L) into the reaction system, reacting at constant temperature for 30 min, then heating to-25 ℃, and stirring for 1 h.
Then, the intermediate compound a5(383 g,1.24 mol) obtained in the step d is dissolved in 2L of tetrahydrofuran, slowly and dropwise added into the reaction system, and after the dropwise addition is finished, the mixture is stirred at constant temperature for 1 hour. Then slowly heating to room temperature, and stirring for reaction for 12 h. After the reaction was completed, 4L of saturated sodium chloride solution was slowly added, the mixture was allowed to stand for separation, the aqueous phase was extracted with ethyl acetate (2L × 3), and the organic phases were combined and washed with 10% by mass of sodium hydroxide (2L). Combining all aqueous phases, acidifying to pH =5 with 15% phosphoric acid, extracting with ethyl acetate (3L × 3), combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating to obtain about 910 g of light yellow liquid; then 3L of ethyl acetate is added and stirred for 1h, a large amount of white solid is separated out, the mixture is filtered, a filter cake is washed by 0.5L of ethyl acetate, and the filtrate is concentrated to be dry, so that about 560g of crude compound a6 is obtained.
Step (six) preparation of alpha-Protohol
The compound a6 (crude product 560 g) obtained above is dissolved in acetone (4L) and transferred to a 10L three-necked flask, cesium carbonate (808 g, 2.48 mol) is added, then cooling is carried out to be not higher than 10 ℃, methyl iodide (352 g, 2.48 mol) is added dropwise, and the isothermal reaction is carried out for 2h after the dropwise addition is finished. TLC, filtration, washing the filter cake with acetone, and concentrating the filtrate to dryness. Then, the above system was added with saturated sodium chloride (4L) and ethyl acetate (4L) and stirred for 30 min. Extracting the separated water phase with ethyl acetate once, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product of about 570 g, and performing column chromatography to obtain a pure alfrost alcohol (438 g, 1.08 mol) which is a light yellow liquid with the purity of more than 98%, the isomer impurity content of less than 0.5%, the yield of the two steps is 87.4%, and the total yield of the process route is 59.6%.
In the chemical field, hydrogen spectrum, carbon spectrum and mass spectrum are all necessary spectrograms for identifying substance structure, and the prepared target product is analyzed by hydrogen spectrum, carbon spectrum and mass spectrum to obtain three spectrograms as shown in figure 1, figure 2 and figure 3, wherein [ alpha ], [ alpha ]]D25 = 35.6 (c 1.0, CHCl3) (ii) a Meanwhile, analytical data of the spectrogram are as follows:
analytical data for hydrogen spectra in FIG. 1:
1 (600 MHz, CDCl3) H(ppm)= 5.50–5.46 (m, 1H), 5.40–5.35 (m, 1H), 4.32-4.29 (brs, 1H), 4.20–4.17 (m, 1H), 4.14–4.12 (m, 1H), 3.65 (s, 3H), 2.62 (ddd, J = 8.8, 4.8, 1.2 Hz, 1H), 2.35-2.28 (m, 4H), 2.23–2.18 (m, 1H), 2.17–2.07 (m, 2H), 1.82–1.78 (m, 2H), 1.72–1.60 (m, 9H), 1.34–1.08 (m, 6H), 0.90–0.83 (m, 2H)；
analytical data for carbon spectra in FIG. 2:
13(150MHz,CDCl3)H(ppm)=174.5,129.8,128.8,86.3,83.9,78.8,72.7,62.8,52.0,51.7,44.0,42.7,37.4,35.5,33.4,33.3,33.0,26.7,26.6,26.5,26.0,24.8。
FIG. 3 analytical data for Mass Spectrometry:
calcd. for C24H38NaO5 [M+Na]+ 429.2611,found 429.2610
νmax(film): 3350, 2912, 2858, 1743, 1442, 1327, 1233, 1179, 1042, 932 cm−1。
by referring to fig. 1, 2 and 3 and by combining the spectrum analysis data, it can be confirmed that the target product is alfaprost. The data obtained in the embodiment show that the synthesis method of alfaprost alcohol provided by the invention has short reaction steps, the yield is about 55-60%, and the industrial production is easy to realize; the technological conditions of each step of reaction are easy to realize, the post-treatment is simple, and the intermediate is easy to purify; only one-step chiral reaction is carried out, isomer impurities are easy to control, and the obtained product has high optical purity.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for synthesizing alfaprost alcohol is characterized by comprising the following steps:
step a, adding levo-benzoyl coriolide and an oxidant into a solvent, controlling the reaction temperature to be not higher than 10 ℃, and carrying out primary alcohol oxidation reaction to obtain coriolide containing aldehyde groups, namely a compound a 2;
b, reacting the compound a2, azido phosphate and a solvent under the catalysis of inorganic base, and keeping the temperature at 0-5 ℃ to obtain an alkynyl compound, namely a compound a 3;
c, under the action of organic strong base, inducing a compound a3 by chiral ligand amine and a titanium reagent, carrying out chiral addition reaction on the compound a3 and aldehyde, and maintaining the reaction temperature at-75 ℃ to-40 ℃ to obtain a compound a 4;
d, taking tetrahydrofuran as a solvent, carrying out oxidation reduction on the compound a4 by adopting a reducing agent, and controlling the reaction temperature to be not higher than-40 ℃ to obtain a compound a 5;
step e, carrying out Wittig reaction on the compound a5 and the side chain intermediate at the reaction temperature of-40 ℃ to-20 ℃ to obtain a compound a 6;
step f, carrying out methylation reaction on the terminal carboxyl of the compound a6 at the reaction temperature of 0-50 ℃, and obtaining alfaprost alcohol;
wherein the titanium reagent is Ti (O-i-Pr)4;
The structural formula of the chiral ligand amine is shown in the specification
。
2. The method for synthesizing alfaprost alcohol according to claim 1, wherein in the step a, after primary alcohol oxidation reaction, quenching, extracting, washing, drying, filtering and concentrating are carried out to obtain the aldehyde group-containing coriolide, namely compound a 2;
in the step b, after the reaction, quenching, extracting, washing, drying, filtering and concentrating are carried out to obtain an alkynyl compound, namely a compound a 3;
in the step c, after the chiral addition reaction, quenching, extracting, washing, drying, filtering and concentrating are carried out to obtain a compound a 4;
in the step d, the compound a5 is obtained after the reduction reaction through quenching, extraction, washing, drying, filtration and concentration;
in the step e, after the Wittig reaction, extracting, washing, drying, filtering and concentrating to obtain a compound a 6;
in the step f, the alfaprost alcohol is obtained after the methylation reaction through extraction, washing, drying, filtration, concentration and column chromatography.
3. The method of claim 1, wherein in step a, the oxidizing agent is one of dess-martin, TEMPO, dimethyl sulfoxide and oxalyl chloride; the molar equivalent of the oxidant is 1.0-2.0 times of the reaction substrate.
4. The method for synthesizing alfaprost alcohol according to claim 1, wherein in step b, the molar equivalent of the azido phosphate is 1-5 times of the reaction substrate, and the molar equivalent of the inorganic base is 2-10 times of the reaction substrate.
5. The method for synthesizing alfacaprost as claimed in claim 1, wherein in step c, the molar equivalent of the organic strong base is 0.8-1.2 times of that of the reaction substrate; the molar equivalent of the chiral ligand amine is 0.1-0.5 times of the reaction substrate, and the molar equivalent of the titanium reagent is 1-2 times of the reaction substrate.
6. The method for synthesizing alfrostanol as claimed in claim 1, wherein the reducing agent is diisobutylaluminum hydride or red aluminum in step d, and the molar equivalent of the reducing agent is 3.0-4.0 times of the reaction substrate.
7. The method for synthesizing alfaprost alcohol as claimed in claim 1, wherein said Wittig reaction comprises: 4-carboxybutyltriphenylphosphonium bromide, a solvent and tetrahydrofuran are reacted with organic strong base to generate Wittig salt, and then tetrahydrofuran solution of a compound a5 is added into a reaction system, namely Wittig reaction is carried out to obtain a compound a 6.
8. The method for synthesizing alfaprost alcohol as claimed in claim 7, wherein the solvent is HMPA at a concentration of 0.1-1 mol/L in step e.
9. The method for synthesizing alfapprost as claimed in claim 1, wherein in step f, the methylation reaction comprises: dissolving the compound a6 in a solvent, adding an inorganic base, cooling to a temperature of not higher than 10 ℃, and then adding methyl iodide or diazomethane for reaction to obtain the target product, namely alpha-proethanol.
10. The method for synthesizing alfaprost alcohol according to claim 9, wherein the molar equivalent of methyl iodide used is 2 to 5 times that of the reaction substrate; the molar equivalent of diazomethane is 2-5 times of the reaction substrate; the solvent is one of tetrahydrofuran, acetone and N, N-dimethylformamide.
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