CN115557958A - Method for preparing biotin intermediate optical active lactone - Google Patents
Method for preparing biotin intermediate optical active lactone Download PDFInfo
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- CN115557958A CN115557958A CN202110753405.2A CN202110753405A CN115557958A CN 115557958 A CN115557958 A CN 115557958A CN 202110753405 A CN202110753405 A CN 202110753405A CN 115557958 A CN115557958 A CN 115557958A
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- imide
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- sodium borohydride
- biotin
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 title claims abstract description 71
- 150000002596 lactones Chemical class 0.000 title claims abstract description 36
- 229960002685 biotin Drugs 0.000 title claims abstract description 33
- 235000020958 biotin Nutrition 0.000 title claims abstract description 32
- 239000011616 biotin Substances 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000003287 optical effect Effects 0.000 title abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 150000003949 imides Chemical class 0.000 claims abstract description 47
- 230000002829 reductive effect Effects 0.000 claims abstract description 33
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 20
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 20
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000746 purification Methods 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 7
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 241000531375 Dexamine Species 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000006722 reduction reaction Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000003472 neutralizing effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000005564 crystal structure determination Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 2
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229930003756 Vitamin B7 Natural products 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229940068840 d-biotin Drugs 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000011912 vitamin B7 Nutrition 0.000 description 2
- 239000011735 vitamin B7 Substances 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a method for preparing biotin intermediate optically active lactone, which comprises the following steps of 1) reducing biotin intermediate imide by using sodium borohydride to obtain an imide reduced product, wherein the sodium borohydride is added in batches; 2) Purifying the imide reduced product obtained in the step 1); 3) Reducing and ring-opening the imide reduced product purified in the step 2) by using sodium borohydride to obtain biotin intermediate amine alcohol, wherein the sodium borohydride is added in batches; 4) And hydrolyzing the biotin intermediate amino alcohol with acid to obtain biotin intermediate optically active lactone. According to the invention, imide is reduced to obtain a selective reduction product, chiral impurities are removed through crystallization and refining to obtain a pure reduction product, the reduction product is continuously reduced to obtain the aminoalcohol, the aminol can be directly hydrolyzed without separation and purification to obtain the optically active lactone (IV) with qualified optical purity, the total yield is improved, the operation is simplified, waste materials are reduced, and the optically active lactone (IV) has great industrial value.
Description
Technical Field
The invention relates to the field of vitamin intermediates, in particular to a method for preparing biotin intermediate optically active lactone.
Background
(+) -Biotin (Biotin), also known as vitamin H or coenzyme R, has the chemical name of (3aS, 4S, 6aR) -hexahydro-2-oxo-1H-thieno [3,4-d ] imidazole-4-pentanoic acid, is widely distributed on animal and plant tissues, is separated from liver extracts and egg yolks, is a component of various carboxylase prosthetic groups, and is a substance necessary for the growth and development of animals and plants.
Since the first synthesis of d-biotin by Merck corporation of 1944, more than 40 chemical total syntheses of biotin have been performed. The starting materials comprise L-cysteine, fumaric acid, d-glucose, d-arabinose, pimelic acid and the like, wherein the most classical technology is Goldberg-Sterbach of Roche company, the industrial production of biotin is realized for the first time, and most of the current industrial technology comes from the improvement of the technology. One key intermediate in this route is the optically active lactone (IV), which reacts with potassium thioacetate in DMF, maintains the configuration and gives optically active thiolactone (V) in higher yields. The d-biotin can be directly synthesized by utilizing the photoactive thiolactone through several steps of reactions, and the synthetic route is as follows:
therefore, the synthesis of optically active lactone (IV) is extremely important as a key intermediate.
In 1975, sumitomo developed an asymmetric synthesis of optically active lactones (IV): reacting meso-diacid with (S, S) - (+) -threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol (by-product of antibiotic chloramphenicol) to obtain imide (II), and reacting with NaBH 4 Reducing and ring-opening to obtain amino alcohol (IIIA), and recrystallizing to remove optical by-product (IIIB); then the amino alcohol (IIIA) is hydrolyzed by acid to obtain the needed optically active lactone (IV), the yield is 65 percent after recrystallization, and the e.e value reaches 98 percent. The key point for controlling the optical purity of the lactone is the purity of the amino alcohol (IIIA), and the synthetic route is as follows:
the asymmetric reduction of the two carbonyl groups of the imide (II) due to the different chemical environment leads, at the same time as the target product (IIIA), to the inevitable production of a small amount of the other diastereomer (IIIB). If the separation is not carried out, optical isomer Impurities (IVB) obtained by hydrolyzing the diastereoisomer (IIIB) can be carried into a final product all the time, and the content of biotin in the product is influenced; when the separation and purification are carried out, the yield is greatly lowered.
Disclosure of Invention
An object of the present invention is to provide a method for producing a biotin intermediate optically active lactone, comprising the steps of:
1) Reducing biotin intermediate imide shown as a formula (II) with sodium borohydride to obtain an imide reducing substance shown as a formula (I), wherein the sodium borohydride is added in batches;
2) Purifying the imide reducing substance obtained in the step 1);
3) Reducing and ring-opening the imide reduced product purified in the step 2) by using sodium borohydride to obtain biotin intermediate aminoalcohol shown as a formula (III), wherein the sodium borohydride is added in batches;
4) Hydrolyzing the biotin intermediate amino alcohol with acid to obtain biotin intermediate optically active lactone shown as a formula (IV);
wherein R is a chiral amine and Bn is benzyl.
After the asymmetric reduction reaction of imide (II, structural formula is shown below) is deeply analyzed, naBH is considered 4 The selective reduction of the carbonyl groups at the 4 and 6 positions of the imide is due primarily to steric effects. The carbonyl group at position 6 is preferentially reduced to an alcohol due to the small steric hindrance.
The chemical name of the imide reducer shown as the formula (I) is (3aS, 6aR) -1,3-dibenzyl-5- [ (1S, 2S) - (+) -threo-1 ' -hydroxymethyl-2 ' -p-nitrophenyl-2 ' -hydroxy-ethyl ] -hexahydro-1H-pyrrolo [3,4-d ] imidazole-6-hydroxy-2,4-diketone:
wherein Bn is benzyl.
In a preferred embodiment of the process of the invention, R is preferably dexamine, (1s, 2s) - (+) -threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol.
In a preferred embodiment of the method of the present invention, preferably, in step 1), the molar ratio of the amount of sodium borohydride to the amount of biotin intermediate imide is 0.3 to 0.5:1, the ratio of the volume usage amount of the aqueous ethanol solvent to the weight usage amount of the biotin intermediate imide is 3-6:1, reacting in an aqueous ethanol solvent at a temperature of between 15 ℃ below zero and 0 ℃.
In a preferred embodiment of the method of the present invention, preferably, in step 2), the purification of the imide reduced product is recrystallization purification.
In a preferred embodiment of the method of the present invention, preferably, in step 3), the molar ratio of the amount of sodium borohydride to the amount of the purified imide reduced product is 2.0 to 2.2:1, the ratio of the volume usage amount of the aqueous ethanol to the weight usage amount of the imide reducing substance is 3-6:1, reacting in an aqueous ethanol solvent at 5-10 ℃.
In a preferred embodiment of the method of the present invention, preferably, in step 3), the biotin intermediate aminoalcohol may be further purified.
In a preferred embodiment of the method of the present invention, preferably, the temperature of the hydrolysis is 90-100 ℃, and the acid is selected from one of acetic acid, hydrochloric acid, and sulfuric acid.
In a preferred embodiment of the method of the present invention, preferably, in step 1) and step 3), the aqueous ethanol solvent is a 95% ethanol aqueous solution.
In a preferred embodiment of the method of the present invention, the solvent for recrystallization is preferably methanol, ethanol or isopropanol.
In a preferred technical scheme of the method, preferably, in the step 4), after hydrolysis, thin layer detection is performed, after completion, heating is stopped, cooling is performed to room temperature, and neutralization is performed to neutrality by using an alkaline solution; then extracting with organic solvent, washing with water twice, drying, recovering solvent under reduced pressure, and recrystallizing to obtain white crystalline powder lactone (IV); the alkali liquor is selected from one of aqueous solutions of sodium hydroxide, sodium carbonate and sodium bicarbonate; the organic solvent is selected from one of toluene, n-hexane, cyclohexane, diethyl ether and dichloromethane.
According to the invention, imide is reduced to obtain a selective reduction product, chiral impurities are removed through crystallization and refining to obtain a pure reduction product, the reduction product is continuously reduced to obtain the aminoalcohol, the aminol can be directly hydrolyzed without separation and purification to obtain the optically active lactone (IV) with qualified optical purity, the total yield is improved, the operation is simplified, waste materials are reduced, and the optically active lactone (IV) has great industrial value.
Drawings
FIG. 1A is a schematic representation of the imide reduction product (I) 1 H-NMR spectrum;
FIG. 1B is of the imide reduction product (I) 13 C-NMR spectrum;
FIG. 2A is an infrared spectrum of an optically active lactone (IV) of a biotin intermediate;
FIG. 2B is a drawing of the biotin intermediate optically active lactone (IV) 1 H-NMR spectrum;
FIG. 2C is a drawing of the biotin intermediate optically active lactone (IV) 13 C-NMR spectrum;
FIG. 2D is a DEPT135 spectrum of the biotin intermediate optically active lactone (IV);
FIG. 3 is a perspective view showing the crystal structure determination of the imide-reduced product (I) by the analytical test center at Zhejiang university.
Detailed Description
The following detailed description is to be read in conjunction with the appended preferred embodiments, which are provided only for illustrating the technical solutions of the present invention and are not to be construed as limiting the present invention.
The analytical instruments and equipment used in the various embodiments of the present invention are: nuclear magnetic resonance apparatus, AVANCE DMXIII 400M (TMS internal standard, bruker Corp.); infrared spectrometer, NICOLET 360FT-IR.
Example 1: preparation of imide reduced product (I)
Putting 21.2g of imide (0.04 mol) into a three-neck flask, adding 80ml of 95% ethanol aqueous solution serving as a solvent, adding 0.65g of sodium borohydride (0.017 mol) in batches at-10 ℃, completing the addition within about 1 hour, maintaining the temperature of-15-0 ℃ for reaction for about 1 hour, detecting the reaction completion by thin-layer chromatography, neutralizing the reaction to be neutral by acetic acid, evaporating the solvent, adding 50ml of isopropanol, heating for dissolution, cooling to 5 ℃ for crystallization, separating out a large amount of white solid, performing suction filtration, and drying to obtain 18.9g of a product, wherein the molar yield is 88.7%, and mp 96-97 ℃.
1 H NMR (400mhz, dmso) δ 8.181 (d, J =8.4hz, 2h), 7.621 (d, J =8.4hz, 2h), 7.179-7.380 (m, 10H), 6.675 (d, J =6.0hz, 1h), 6.159-6.171 (m, 1H), 5.209-5.236 (m, 1H), 5.063-5.090 (m, 1H), 4.815-4.891 (m, 2H), 3535 zxft 4935 (d, J =15.2hz, 1h), 4.164 (d, J =15.2hz, 15H), 3.906-1zxft 3584 (m, 3584H), 3584 (d, 5384, 5325 zxft 6225H), 5623 zxft, 4262H, 5623H, 4262H, 4225, 5623H, and the like.
13 C NMR (101MHz, DMSO). Delta. 170.40,159.01,150.40,146.66,137.39,136.91,128.61,128.49,127.98,127.92,127.82,127.35,127.25,123.07,79.21,70.15,60.23,58.37,55.17,52.13,46.38,45.35 as shown in FIG. 1B.
Example 2: continuously reducing and hydrolyzing the imide reducing product (I) to prepare lactone
Adding 80ml of 95% aqueous ethanol into a 250ml three-neck flask, stirring in a cold bath at 5 ℃, adding 10.6g (0.020 mol) of the reduced substance prepared in the previous example (example 1), stirring for a few minutes, starting to add 1.6g (0.042 mol) of sodium borohydride in batches, finishing adding about half an hour, insoluble reduced substance at the beginning, clarifying the solution when finishing adding the batches, continuing to stir for about 48 hours at the constant temperature, neutralizing to neutrality by using acetic acid after finishing the thin-layer detection reaction, and evaporating the solvent to obtain a crude product. 59g (0.12 mol) of 20% sulfuric acid aqueous solution is added into a bottle, the mixture is magnetically stirred and refluxed for 4 hours at 90-100 ℃, after the thin layer detection reaction is finished, heating is stopped, the mixture is cooled to room temperature, the mixture is neutralized to be neutral by dilute alkali solution (10% sodium hydroxide aqueous solution), then the mixture is extracted for three times by 150ml of dichloromethane, organic layers are combined, the organic layers are washed twice by water and dried by 2g of anhydrous sodium sulfate, the solvent is recovered under reduced pressure, and then the mixture is recrystallized by 95% ethanol aqueous solution. 5.8g of white solid powder is obtained, the molar yield is 90.0 percent, mp is between 116 and 117 ℃, and the specific optical rotation [ alpha ] is] D 20 = 59.4 °, e.e value 98.9%.
In the reaction of the 2 steps, the imide is firstly reduced to a reduced substance, and after refining, reduction ring opening, hydrolysis and recrystallization, the product lactone meeting the content requirement is obtained, and the molar total yield of the 2 steps is 79.8 percent.
And (3) structure confirmation:
IR 3033.75 (Ar-H), 1769.88 (C = O, ester), 1700.57 (C = O, ketone), 1443.71 (C = C, benzene), 1211.33 (C-O, ester), 697.62 (delta Ar-H), as shown in FIG. 2A.
1 HNMR(CDCl 3 ) 7.252-7.400 (m, 10H, benzene ring H), 5.062 (d, 1H, J = 14.8H) Z ,C7H)，4.646(d,1H,J＝15.2H Z ,C8H)，4.389(d,1H,J＝14.4H Z ,C7H)，4.360(d,1H,J＝14.8H Z ,C8 H)，4.162(s,2H,C6 H)，4.1066～4.133(C3aH)，3.925(d,1H,J＝8.8H Z C6 aH) as shown in fig. 2B.
13 CNMR(CDCl 3 ) 172.76 (C4), 158.12 (C2), 135.94 (C10), 135.83 (C9), 127.80-128.94 (benzene ring C except 9, 10), 70.04 (C6), 54.33 (C6 a), 52.39 (C3 a), 46.83 (C7), 45.15 (C8), as shown in fig. 2C.
DEPT (θ =135 °): 127.80-128.94, 70.03 (D), 54.33, 52.39, 46.827 (D), 45.149 (D), as shown in FIG. 2D.
And (3) culturing of the single crystal: a small amount of the lactone crystal powder obtained above was placed in a vial, dissolved in ethanol, sealed with filter paper, and left for five weeks to precipitate colorless transparent crystals, which were subjected to crystal structure determination by the analytical test center of Zhejiang university, and the measured stereo structure was shown in FIG. 3.
Example 3: continuously reducing and hydrolyzing the imide reducing product (I) to prepare lactone
The imide reduced product (I) prepared in example 1 is subjected to reductive ring opening by the method of the above example (example 2) to obtain a crude product of the aminoalcohol (III). Recrystallization from 50ml of isopropanol gave 10.1g of a white solid. 12g (0) of 37% hydrochloric acid was added to the bottle.12 mol), magnetically stirring and refluxing for 4h, stopping heating after the thin-layer detection reaction is finished, cooling to room temperature, neutralizing to be neutral by using dilute alkali liquor (10% sodium hydroxide aqueous solution), extracting for three times by using 150ml of dichloromethane, combining organic layers, washing twice by using water, drying by using 2g of anhydrous sodium sulfate, recovering the solvent under reduced pressure, and recrystallizing by using 95% ethanol. 5.5g of white solid powder is obtained, the yield is 85.3 percent, the temperature is mp 116-117 ℃, and the specific optical rotation [ alpha ] is] D 20 = 60.0 °, e.e value 100%.
In the embodiment 1 and the embodiment 3, the imide is firstly reduced to a reduced substance, and after purification, reduction ring opening, purification, hydrolysis and recrystallization, the lactone product meeting the content requirement is obtained, and the total molar yield of 2 steps is 75.7 percent. And (3) structure confirmation:
IR 3033.75 (Ar-H), 1769.88 (C = O, ester), 1700.57 (C = O, ketone), 1443.71 (C = C, benzene), 1211.33 (C-O, ester), 697.62 (delta Ar-H), as shown in FIG. 2A.
1 HNMR(CDCl 3 ) 7.252-7.400 (m, 10H, benzene ring H), 5.062 (d, 1H, J =14.8H Z ,C7H)，4.646(d,1H,J＝15.2H Z ,C8H)，4.389(d,1H,J＝14.4H Z ,C7H)，4.360(d,1H,J＝14.8H Z ,C8 H)，4.162(s,2H,C6 H)，4.1066～4.133(C3aH)，3.925(d,1H,J＝8.8H Z C6 aH) as shown in fig. 2B.
13 CNMR(CDCl 3 ) 172.76 (C4), 158.12 (C2), 135.94 (C10), 135.83 (C9), 127.80-128.94 (benzene ring C except 9, 10), 70.04 (C6), 54.33 (C6 a), 52.39 (C3 a), 46.83 (C7), 45.15 (C8), as shown in fig. 2C.
DEPT (θ =135 °): 127.80-128.94, 70.03 (D), 54.33, 52.39, 46.827 (D), 45.149 (D), as shown in FIG. 2D.
And (3) culturing of the single crystal: a small amount of the lactone crystal powder obtained above was placed in a vial, dissolved in ethanol, sealed with filter paper, and left for five weeks to precipitate colorless transparent crystals, which were subjected to crystal structure determination by the analytical test center of Zhejiang university, and the measured stereo structure was shown in FIG. 3.
Comparative example 1: direct hydrolysis for preparing lactone by reduction of imide
100ml of 95% ethanol aqueous solution is added into a 250ml three-neck flask, stirred in a cold bath at minus 10 ℃, 21.2g (0.04 mol) of imide is added, after stirring for a few minutes, 3.8g (0.10 mol) of sodium borohydride is added in batches, the addition is finished in about half an hour, and the reaction is followed by a thin layer. Moving the reaction liquid to room temperature, magnetically stirring for 48 hours, neutralizing acetic acid to be neutral after the thin layer detection reaction is finished, evaporating the solvent under reduced pressure, adding 98g (0.2 mol) of 20% sulfuric acid into the obtained solid, magnetically stirring and refluxing for 4 hours, stopping heating after the thin layer detection reaction is finished, cooling the solid to room temperature, neutralizing with dilute alkali solution to neutrality, extracting with 150ml dichloromethane for three times, mixing organic layers, washing with water twice, drying with anhydrous sodium sulfate, recovering solvent under reduced pressure, and recrystallizing with 95% ethanol to obtain white crystalline powder 10.9g, with total yield of 84.6%, mp 116-118 deg.C, specific optical rotation [ alpha ]] D 20 = 50.2 °, e.e. value 83.7%. The optical purity thereof is not satisfactory.
The nuclear magnetic data are in accordance with example 2.
Comparative example 2: reduction of imide to amine alcohol, recrystallization of amine alcohol and hydrolysis to prepare lactone
184ml of ethanol and 16ml of water are added into a 250ml three-neck flask, the mixture is stirred in a cold bath at-10 ℃, 42.4g (0.08 mol) of imide is added, after stirring for a few minutes, 7.6g (0.21 mol) of sodium borohydride is added in batches, the addition is finished in about half an hour, and the reaction is followed by a thin layer. Moving the reaction solution to room temperature, magnetically stirring for 48 hours, neutralizing with acetic acid to neutrality after thin-layer detection reaction is finished, evaporating the solvent to dryness, recrystallizing with 50ml of isopropanol to obtain 26.2g of white solid, hydrolyzing according to the method, recrystallizing with 95% ethanol aqueous solution to obtain 15.0g of white crystalline powder, wherein the total yield is 58.0%, mp 116-117 ℃, and the specific optical rotation [ alpha ] is] D 20 = 60.0 °, e.e value 100%.
The nuclear magnetic data are in accordance with example 2.
When the process of the invention is compared with the processes of comparative examples 1 and 2, it can be concluded that: the method of the invention can not only obtain the product with the content meeting the requirement, but also ensure higher yield, and has great industrial value.
It should be noted that the above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention.
Claims (10)
1. A method for preparing a biotin intermediate optically active lactone, the method comprising the steps of:
1) Reducing biotin intermediate imide shown as a formula (II) with sodium borohydride to obtain an imide reducing substance shown as a formula (I), wherein the sodium borohydride is added in batches;
2) Purifying the imide reduced product obtained in the step 1);
3) Reducing and ring-opening the imide reduced product purified in the step 2) by using sodium borohydride to obtain biotin intermediate aminoalcohol shown as a formula (III), wherein the sodium borohydride is added in batches;
4) Hydrolyzing the biotin intermediate amino alcohol with acid to obtain biotin intermediate optically active lactone shown as a formula (IV);
wherein R is chiral amine and Bn is benzyl.
2. The method of claim 1, wherein R is dexamine, (1S, 2S) - (+) -threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol.
3. The process according to claim 1 or 2, wherein in step 1), the molar ratio of the amount of sodium borohydride to the amount of biotin intermediate imide is from 0.3 to 0.5:1, the ratio of the volume usage amount of the aqueous ethanol solvent to the weight usage amount of the biotin intermediate imide is 3-6:1, reacting in an aqueous ethanol solvent at a temperature of between 15 ℃ below zero and 0 ℃.
4. The method according to claim 1 or 2, characterized in that in step 2), the purification of the imide-reduced product is a recrystallization purification.
5. The method according to claim 1 or 2, wherein in step 3), the molar ratio of the amount of sodium borohydride to the amount of the purified imide-reduced product is 2.0-2.2:1, the ratio of the volume usage amount of the aqueous ethanol to the weight usage amount of the imide reducing substance is 3-6:1, reacting in an aqueous ethanol solvent at 5-10 ℃.
6. The process of claim 1, 2 or 5, wherein in step 3) the biotin intermediate aminoalcohol may be further purified.
7. The method according to claim 1, wherein in the step 4), the temperature of the hydrolysis is 90-100 ℃, and the acid is selected from one of acetic acid, hydrochloric acid and sulfuric acid.
8. The method according to claim 3 or 5, wherein in step 1) and step 3), the aqueous ethanol solvent is a 95% ethanol aqueous solution.
9. The process according to claim 1 or 2, characterized in that the solvent of recrystallization is methanol, ethanol or isopropanol.
10. The method according to claim 1, 2 or 7, wherein in step 4), after hydrolysis, thin layer detection is performed, after completion, heating is stopped, cooling is performed to room temperature, and neutralization is performed to neutrality with alkaline solution; then extracting with organic solvent, washing with water twice, drying, recovering solvent under reduced pressure, and recrystallizing to obtain white crystalline powder lactone (IV); the alkali liquor is selected from one of aqueous solutions of sodium hydroxide, sodium carbonate and sodium bicarbonate; the organic solvent is selected from one of toluene, n-hexane, cyclohexane, diethyl ether and dichloromethane.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3876656A (en) * | 1972-06-22 | 1975-04-08 | Sumitomo Chemical Co | Method for synthesis of optically active lactones |
| CN101973996A (en) * | 2010-09-30 | 2011-02-16 | 绍兴文理学院 | Imide biotin intermediate monoester and preparation method and use thereof |
| CN109563102A (en) * | 2016-08-04 | 2019-04-02 | 株式会社德山 | The manufacturing method of the intermediate of biotin and the manufacturing method of biotin |
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3876656A (en) * | 1972-06-22 | 1975-04-08 | Sumitomo Chemical Co | Method for synthesis of optically active lactones |
| CN101973996A (en) * | 2010-09-30 | 2011-02-16 | 绍兴文理学院 | Imide biotin intermediate monoester and preparation method and use thereof |
| CN109563102A (en) * | 2016-08-04 | 2019-04-02 | 株式会社德山 | The manufacturing method of the intermediate of biotin and the manufacturing method of biotin |
Non-Patent Citations (1)
| Title |
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| 韩卫华，等: "生物素中间体内酯合成进展", 化学通报, pages 566 - 573 * |
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