CN114957202A - Preparation method of DL-homocysteine thiolactone hydrochloride - Google Patents
Preparation method of DL-homocysteine thiolactone hydrochloride Download PDFInfo
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- CN114957202A CN114957202A CN202210900373.9A CN202210900373A CN114957202A CN 114957202 A CN114957202 A CN 114957202A CN 202210900373 A CN202210900373 A CN 202210900373A CN 114957202 A CN114957202 A CN 114957202A
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- homocysteine thiolactone
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- thiolactone hydrochloride
- thiobutyrolactone
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- ZSEGSUBKDDEALH-UHFFFAOYSA-N 3-aminothiolan-2-one;hydron;chloride Chemical compound Cl.NC1CCSC1=O ZSEGSUBKDDEALH-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 29
- 238000006467 substitution reaction Methods 0.000 claims abstract description 23
- CFPHMAVQAJGVPV-UHFFFAOYSA-N 2-sulfanylbutanoic acid Chemical compound CCC(S)C(O)=O CFPHMAVQAJGVPV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- WOQPIIAJLDWJCH-UHFFFAOYSA-N oxolane-2-thione Chemical group S=C1CCCO1 WOQPIIAJLDWJCH-UHFFFAOYSA-N 0.000 claims description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052736 halogen Chemical group 0.000 claims description 7
- 238000005658 halogenation reaction Methods 0.000 claims description 7
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical group [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012445 acidic reagent Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 239000003208 petroleum Substances 0.000 description 23
- 238000001914 filtration Methods 0.000 description 22
- 238000001035 drying Methods 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 13
- 238000004537 pulping Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- GMOZFDYOIWEEGL-UHFFFAOYSA-N 3-bromooxolane-2-thione Chemical compound BrC1C(=S)OCC1 GMOZFDYOIWEEGL-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 239000012346 acetyl chloride Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910052718 tin Inorganic materials 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 239000004470 DL Methionine Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- FFEARJCKVFRZRR-UHFFFAOYSA-N methionine Chemical compound CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 235000006109 methionine Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000011135 tin Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZTVZLYBCZNMWCF-UHFFFAOYSA-N homocystine Chemical compound [O-]C(=O)C([NH3+])CCSSCCC([NH3+])C([O-])=O ZTVZLYBCZNMWCF-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of DL-homocysteine thiolactone hydrochloride, which relates to the technical field of biological medicine, and comprises the following steps: the DL-homocysteine thiolactone hydrochloride is obtained by taking mercaptobutyric acid as a starting material and carrying out acid catalytic condensation, bromine substitution and amino substitution. According to the method, mercaptobutyric acid is used as a raw material for the first time to prepare DL-homocysteine thiolactone hydrochloride, and a new method is provided for synthesizing the DL-homocysteine thiolactone hydrochloride. And DL-homocysteine thiolactone hydrochloride is used as a raw material to further prepare the cetivone, thereby providing a new way for preparing the cetivone. The preparation process is simple, safe, stable, controllable and suitable for industrial production.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to a preparation method of DL-homocysteine thiolactone hydrochloride.
Background
The cetivone is an important medical raw material for cerebrovascular disorder sequelae, senile dementia and the like, and the product form is white crystal powder. The cetivone is generally synthesized by DL-homocysteine thiolactone hydrochloride and acetyl chloride.
DL-homocysteine thiolactone hydrochloride is an important biochemical reagent and drug intermediate, and the product form is white crystalline powder. Generally synthesized by a chemical reduction method, namely, synthesized by reduction reaction of metal zinc or tin, hydrochloric acid and DL-homocystine, the synthesis method can generate a large amount of hydrogen, zinc salt (tin salt) and a large amount of waste water, thereby causing serious environmental pollution and having certain danger in the operation process.
The chinese patent document with application number 200710053041.7 discloses a method for obtaining DL-homocysteine thiolactone hydrochloride by demethylation oxidative coupling of DL-methionine in sulfuric acid solution, the synthetic method generates a large amount of toxic gases such as dimethyl sulfide, sulfur dioxide and the like, generates a large amount of high-salt wastewater, easily causes environmental pollution, and brings higher environmental protection cost pressure to production enterprises.
The chinese patent document No. 201710695613.5 discloses a method for obtaining DL-homocysteine thiolactone hydrochloride by the reduction reaction of DL-methionine and metallic sodium, the synthetic method can generate hydrogen in the reaction process, the danger is large, the operation process is very complicated, and the reaction cost is high.
Disclosure of Invention
The invention aims to provide a method for synthesizing DL-homocysteine thiolactone hydrochloride, which synthesizes DL-homocysteine thiolactone hydrochloride by taking mercaptobutyric acid as a raw material and provides a novel synthesis path of DL-homocysteine thiolactone hydrochloride, which has the advantages of simple and convenient process, easy purification, controllable quality and high yield through a series of reactions of acid catalytic condensation, bromine substitution and amino substitution.
In one aspect, the present application provides a method for preparing DL-homocysteine thiolactone hydrochloride, which comprises the following steps:
step one, carrying out halogenation reaction on thiobutyrolactone and a halogen substitution reagent to obtain 2-halogenated thiobutyrolactone;
and step two, carrying out amino substitution reaction on the 2-halogenated thio-butyrolactone and an amino substitution reagent to obtain DL-homocysteine thiolactone hydrochloride.
Further, the halogen substitution reagent is bromine;
the molar ratio of the thiobutyrolactone to the halogen substitution reagent is 1: (1.2-2.0).
Preferably, the molar ratio of the thiobutyrolactone to the halogen substitution reagent is 1: 1.5.
In a preferred embodiment, the above-mentioned thiobutyrolactone is reacted with bromine in an amount of solvent such that 1 g of thiobutyrolactone is dissolved in 4 mL of chloroform.
Furthermore, phosphorus tribromide is used as a catalyst in the halogenation reaction.
In a preferred embodiment, the mass ratio of the above-mentioned thiobutyrolactone to phosphorus tribromide is 1: 0.1.
Further, the halogenation reaction conditions are as follows: chloroform is used as a solvent, and the reaction is carried out for 1-10 h at the temperature of 0-20 ℃.
Preferably, the step one further comprises the steps of extracting, separating, concentrating under reduced pressure, pulping, filtering and drying.
Preferably, the halogenation reaction conditions are as follows: reacting for 5 hours at the temperature of 0-10 ℃.
In a preferred embodiment, the first step of the pulping is petroleum ether pulping, and when the petroleum ether is used, the amount of the petroleum ether is 5 mL of petroleum ether for 1 g of the thiobutyrolactone.
Further, the amino substitution reagent is sodium amide;
the molar ratio of the 2-halogenated thiobutyrolactone to the amino substitution reagent is 1: (1.2-1.5).
Preferably, the molar ratio of the 2-halothiobutyrolactone to the amino-substitution reagent is 1: 1.3.
Further, the amino substitution reaction conditions are as follows: tetrahydrofuran is used as a solvent, and the reaction is carried out for 1-5 h at the temperature of 20-50 ℃.
Preferably, the amino substitution reaction conditions are as follows: reacting for 2 hours at the temperature of 30-40 ℃.
In a preferred embodiment, the above tetrahydrofuran solvent is used in an amount such that 1 g of 2-bromothiobutyrolactone is dissolved in 5 mL of tetrahydrofuran.
Further, the step two also comprises a step of adjusting the pH value to 1-7;
the pH adjusting reagent is an acidic reagent, and the acidic reagent is selected from one or two of concentrated hydrochloric acid and concentrated sulfuric acid.
Preferably, the second step further comprises the steps of cooling crystallization, filtering and drying.
Preferably, the pH is adjusted to 5-6, and the pH adjusting reagent is concentrated hydrochloric acid.
Further, the thiobutyrolactone is prepared by carrying out condensation reaction on mercaptobutyric acid;
the condensation reaction adopts acid as a catalyst, and the acid is selected from one or two of concentrated hydrochloric acid and concentrated sulfuric acid.
Preferably, the acid catalyst is concentrated hydrochloric acid.
Further, the condensation reaction conditions are as follows: reacting for 2-4 h at 10-30 ℃ by taking tetrahydrofuran as a solvent;
the preparation method of the thiobutyrolactone also comprises the steps of decompression concentration, pulping, filtering and drying.
Further, the condensation reaction conditions are as follows: reacting for 3 hours at the temperature of 20-25 ℃.
In a preferred embodiment, the reaction of mercaptobutanoic acid as described above under the action of a catalyst is carried out in such amounts that 1 g of mercaptobutanoic acid is dissolved in 2 mL of concentrated hydrochloric acid per 5 mL of tetrahydrofuran as solvent and catalyst.
And the condensation reaction also comprises the steps of decompression concentration and petroleum ether beating, wherein when the petroleum ether is beaten, the using amount of the petroleum ether is 6 mL of petroleum ether used per 1 g of mercaptobutyric acid.
In a preferred embodiment, a process for the preparation of DL-homocysteine thiolactone hydrochloride, said process comprising the steps of:
step one, dissolving mercaptobutyric acid and concentrated hydrochloric acid in tetrahydrofuran, controlling the temperature to be 20-25 ℃, reacting for 3 hours, concentrating under reduced pressure, pulping with petroleum ether, filtering and drying to obtain the thiobutyrolactone.
And step two, dissolving thiobutyrolactone and phosphorus tribromide in chloroform, dropwise adding bromine, controlling the temperature to be 0-10 ℃ to react for 5 hours, dropwise adding water, stirring and separating liquid, carrying out reduced pressure concentration on chloroform, pulping petroleum ether, filtering and drying to obtain the 2-bromothiobutyrolactone.
Dissolving 2-bromothiobutyrolactone in tetrahydrofuran, adding sodium amide, controlling the temperature to be 30-40 ℃, reacting for 2 h, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH to be 5-6, controlling the temperature to be lower than 20 ℃, cooling to 10 ℃, crystallizing for 2 h, filtering and drying to obtain DL-homocysteine thiolactone hydrochloride.
In a preferred embodiment, the present application also provides a method for preparing cetivone, the method comprising the steps of: adding triethylamine as a catalyst into the DL-homocysteine thiolactone hydrochloride prepared by the method, cooling to-10-0 ℃, and dropwise adding acetyl chloride for reaction to obtain cetivone;
the molar ratio of DL-homocysteine thiolactone hydrochloride to acetyl chloride is 1: (1.3-1.8);
the reaction conditions of the DL-homocysteine thiolactone hydrochloride and the acetyl chloride are as follows: taking dichloromethane as a solvent, and reacting for 5-7 h at the temperature of 20-30 ℃;
the preparation method of the cetivone also comprises a step of recrystallization, after recrystallization, the cetivone is dissolved by ethyl acetate, decolored by active carbon, crystallized by dropping petroleum ether, filtered and dried.
Preferably, the molar ratio of DL-homocysteine thiolactone hydrochloride to acetyl chloride is 1: 1.5.
In a preferred embodiment, the molar ratio of the DL-homocysteine thiolactone hydrochloride to triethylamine is 1:4, and the amount of dichloromethane, ethyl acetate, petroleum ether is 10 mL of dichloromethane, 2 mL of ethyl acetate or 6 mL of petroleum ether per 1 g of DL-homocysteine thiolactone hydrochloride.
In a preferred embodiment, a process for the preparation of cetivone, said process comprising the steps of:
dissolving DL-homocysteine thiolactone hydrochloride and triethylamine in dichloromethane, cooling to-10-0 ℃, dropwise adding acetyl chloride, controlling the dropwise adding temperature to be not more than 0 ℃, slowly heating to normal temperature after dropwise adding, reacting for 6 hours, washing an organic phase for 3 times by using saturated saline water, extracting and layering, drying the organic phase by using anhydrous sodium sulfate, filtering, decompressing and concentrating a filtrate, dissolving the remainder ethyl acetate, decoloring and filtering by using activated carbon, dropwise adding petroleum ether, crystallizing at 0-10 ℃, crystallizing for 4 hours, filtering and drying to obtain the cetivone.
The invention has the following beneficial effects:
1. according to the method, mercaptobutyric acid is used as a raw material for the first time to prepare DL-homocysteine thiolactone hydrochloride, so that a new method is provided for preparing DL-homocysteine thiolactone hydrochloride;
2. the application also provides a preparation method of the cetivone, and provides a new way for the synthesis of the cetivone;
3. the synthesis method does not need to use hazardous reagents, does not need to add metal sodium, zinc or tin and the like as reducing agents, does not generate a large amount of hydrogen and wastewater containing zinc or tin, has the advantages of low cost, small environmental pressure, simple operation, small danger, environmental protection, safety and the like, and is suitable for large-scale production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:
FIG. 1 is a hydrogen spectrum of cetivone;
figure 2 is a synthetic route to cetivone.
Detailed Description
In order to more clearly explain the overall concept of the present application, the following detailed description is given by way of example in conjunction with the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present invention. It will be apparent, however, to one skilled in the art, that the present invention may be practiced without one or more of these specific details. In other instances, well-known features have not been described in order to avoid obscuring the invention.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.
In the following embodiments, reagents or instruments used are not indicated by manufacturers, and are all conventional products available by commercial purchase, unless otherwise specified.
Example 1
Step one, 100 g (0.83 mol) of mercaptobutyric acid and 200 mL of concentrated hydrochloric acid are dissolved in 500 mL of tetrahydrofuran, the temperature is controlled to be 20-25 ℃, the reaction is carried out for 3 hours, and the tetrahydrofuran is decompressed and concentrated. 600 mL of petroleum ether was slurried, filtered and dried to give 75 g (0.73 mol) of thiobutyrolactone.
And step two, dissolving 75 g (0.73 mol) of thiobutyrolactone and 7.5 g of phosphorus tribromide in 300 mL of chloroform, dropwise adding 176 g (1.1 mol) of bromine, controlling the temperature to be 0-10 ℃ and reacting for 5 h, dropwise adding 500 mL of water, stirring and separating liquid, carrying out reduced pressure concentration on chloroform, pulping 375 mL of petroleum ether, filtering and drying to obtain 120 g (0.66 mol) of 2-bromothiobutyrolactone.
Step three, dissolving 120 g (0.66 mol) of 2-bromothiobutyrolactone in 600 mL of tetrahydrofuran, adding 33.6 g (0.86 mol) of sodium amide, controlling the temperature to be 30-40 ℃, reacting for 2 h, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid, adjusting the pH to be 5-6, controlling the temperature to be lower than 20 ℃, cooling to 10 ℃, crystallizing for 2 h, filtering and drying to obtain 91 g (0.59 mol) of DL-homocysteine thiolactone hydrochloride.
91 g of DL-homocysteine thiolactone hydrochloride is obtained, the yield of the product is 71.08%, and the purity is as follows: more than or equal to 98.0 percent.
Example 2
Step one, 0.83 mol of mercaptobutyric acid and 200 mL of concentrated hydrochloric acid are dissolved in 500 mL of tetrahydrofuran, the temperature is controlled to be 20-25 ℃, the reaction is carried out for 3 h, and the tetrahydrofuran is decompressed and concentrated. Pulping 600 mL of petroleum ether, filtering and drying to obtain 0.73 mol of thiobutyrolactone.
And step two, dissolving 0.73 mol of thiobutyrolactone and 7.5 g of phosphorus tribromide in 300 mL of chloroform, dropwise adding 0.949 mol of bromine, controlling the temperature to be 0-10 ℃ and reacting for 6 h, dropwise adding 500 mL of water, stirring and separating, carrying out reduced pressure concentration on chloroform, pulping 375 mL of petroleum ether, filtering and drying to obtain 0.64 mol of 2-bromothiobutyrolactone.
And step three, dissolving 0.64 mol of 2-bromothiobutyrolactone in 600 mL of tetrahydrofuran, adding 0.792 mol of sodium amide, controlling the temperature to 30-40 ℃, reacting for 3 hours, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid to adjust the pH to 5-6, controlling the temperature to be lower than 20 ℃, cooling to 10 ℃, crystallizing for 2 hours, filtering and drying to obtain DL-homocysteine thiolactone hydrochloride.
90.2g of DL-homocysteine thiolactone hydrochloride is obtained, the yield of the product is 70.48 percent, and the purity is as follows: more than or equal to 98.0 percent.
Example 3
Step one, 0.83 mol of mercaptobutyric acid and 200 mL of concentrated hydrochloric acid are dissolved in 500 mL of tetrahydrofuran, the temperature is controlled to be 20-25 ℃, the reaction is carried out for 3 h, and the tetrahydrofuran is decompressed and concentrated. Pulping with 600 mL of petroleum ether, filtering and drying to obtain 0.73 mol of thiobutyrolactone.
And step two, dissolving 0.73 mol of thiobutyrolactone and 7.5 g of phosphorus tribromide in 300 mL of chloroform, dropwise adding 1.241 mol of bromine, controlling the temperature to be 0-10 ℃ for reaction for 7 h, dropwise adding 500 mL of water, stirring, separating, concentrating the chloroform under reduced pressure, pulping 375 mL of petroleum ether, filtering and drying to obtain 0.64 mol of 2-bromothiobutyrolactone.
And step three, dissolving 0.64 mol of 2-bromothiobutyrolactone in 600 mL of tetrahydrofuran, adding 0.924 mol of sodium amide, controlling the temperature to 30-40 ℃, reacting for 4 hours, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid to adjust the pH to 5-6, controlling the temperature to be lower than 20 ℃, cooling to 10 ℃, crystallizing for 2 hours, filtering and drying to obtain DL-homocysteine thiolactone hydrochloride.
86.45g of DL-homocysteine thiolactone hydrochloride are obtained, the yield of the product is 67.53%, and the purity is as follows: not less than 98.077.80 percent.
Example 4
Step one, 0.83 mol of mercaptobutyric acid and 200 mL of concentrated hydrochloric acid are dissolved in 500 mL of tetrahydrofuran, the temperature is controlled to be 20-25 ℃, the reaction is carried out for 3 h, and the tetrahydrofuran is decompressed and concentrated. Pulping with 600 mL of petroleum ether, filtering and drying to obtain 0.73 mol of thiobutyrolactone.
And step two, dissolving 0.73 mol of thiobutyrolactone and 7.5 g of phosphorus tribromide in 300 mL of chloroform, dropwise adding 1.387 mol of bromine, controlling the temperature to be 0-10 ℃ and reacting for 8 hours, dropwise adding 500 mL of water, stirring and separating, carrying out reduced pressure concentration on chloroform, pulping 375 mL of petroleum ether, filtering and drying to obtain 0.63 mol of 2-bromothiobutyrolactone.
Dissolving 0.63 mol of 2-bromothiobutyrolactone in 600 mL of tetrahydrofuran, adding 0.89 mol of sodium amide, controlling the temperature to be 30-40 ℃, reacting for 2 h, cooling to 10 ℃, dropwise adding concentrated hydrochloric acid to adjust the pH to be 5-6, controlling the temperature to be lower than 20 ℃, cooling to 10 ℃, crystallizing for 2 h, filtering and drying to obtain DL-homocysteine thiolactone hydrochloride.
77.80g of DL-homocysteine thiolactone hydrochloride is obtained, the yield of the product is 60.78 percent, and the purity is as follows: more than or equal to 98.5 percent.
Example 5
DL-homocysteine thiolactone hydrochloride was prepared in the manner of example 1.
91 g (0.59 mol) DL-homocysteine thiolactone hydrochloride and 240 g (2.37 mol) triethylamine are dissolved in 900 mL dichloromethane, the temperature is reduced to-10 ℃ to 0 ℃, 70 g (0.89 mol) acetyl chloride is dripped, the dripping temperature is controlled not to exceed 0 ℃, after the dripping is finished, the temperature is slowly raised to normal temperature for reaction for 6 h, 300 mL saturated saline water is used for washing an organic phase for 3 times, extraction and layering are carried out, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, the filtrate is decompressed and concentrated, 180 mL ethyl acetate of the remainder is dissolved, 5g of activated carbon is decolored and filtered, 540 mL petroleum ether is dripped, 0 ℃ to 10 ℃ is used for crystallization for 4 h, 83 g (0.52 mol) cetivone is obtained by filtration and drying, the product yield is 88.13%, and the purity: more than or equal to 98.0 percent.
The hydrogen spectrogram of the cetivone is shown in figure 1, and the synthesis route of the cetivone is shown in figure 2.
The above description is only an example of the present application and is not intended to limit the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement or the like made within the spirit and principle of the present application shall be included in the scope of the claims of the present application.
Claims (10)
1. A method for preparing DL-homocysteine thiolactone hydrochloride, which is characterized by comprising the following steps:
step one, carrying out halogenation reaction on thiobutyrolactone and a halogen substitution reagent to obtain 2-halogenated thiobutyrolactone;
and step two, carrying out amino substitution reaction on the 2-halogenated thio-butyrolactone and an amino substitution reagent to obtain DL-homocysteine thiolactone hydrochloride.
2. The method of claim 1, wherein the halogen substitution reagent is bromine;
the molar ratio of the thiobutyrolactone to the halogen substitution reagent is 1: (1.2-2.0).
3. The process according to claim 1, characterized in that phosphorus tribromide is used as catalyst in the halogenation reaction.
4. The process according to claim 1, characterized in that the halogenation reaction conditions are: chloroform is used as a solvent, and the reaction is carried out for 1-10 h at the temperature of 0-20 ℃.
5. The method of claim 1, wherein the amino substitution reagent is sodium amide;
the molar ratio of the 2-halogenated thiobutyrolactone to the amino substitution reagent is 1: (1.2-1.5).
6. The method of claim 1, wherein the amino substitution reaction conditions are: tetrahydrofuran is used as a solvent, and the reaction is carried out for 1-5 h at the temperature of 20-50 ℃.
7. The method according to claim 1, wherein the second step further comprises a step of adjusting the pH to 1-7;
the pH adjusting reagent is an acidic reagent, and the acidic reagent is selected from one or two of concentrated hydrochloric acid and concentrated sulfuric acid.
8. The method according to claim 1, wherein the thiobutyrolactone is prepared by condensation reaction of mercaptobutanoic acid;
the condensation reaction adopts acid as a catalyst, and the acid is selected from one or two of concentrated hydrochloric acid and concentrated sulfuric acid.
9. The method of claim 8, wherein the condensation reaction conditions are: tetrahydrofuran is used as a solvent, and the reaction is carried out for 2-4 h at the temperature of 10-30 ℃.
10. The method of claim 9, wherein the condensation reaction conditions are: reacting for 3 hours at the temperature of 20-25 ℃.
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|---|---|---|---|---|
| JPS632043A (en) * | 1986-06-23 | 1988-01-07 | Fuji Photo Film Co Ltd | Preparation of photographic silver halide emulsion |
| CN107325073A (en) * | 2017-08-15 | 2017-11-07 | 成都百事兴科技实业有限公司 | A kind of new synthetic method of DL homocysteine thiolactones hydrochloride |
| CN109824649A (en) * | 2019-03-11 | 2019-05-31 | 南京红杉生物科技有限公司 | Homocysteinic acid thiolactone hydrochloride and its preparation method and application |
| CN111004209A (en) * | 2019-12-24 | 2020-04-14 | 浙江工业大学 | Continuous production method of DL-homocysteine thiolactone hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS632043A (en) * | 1986-06-23 | 1988-01-07 | Fuji Photo Film Co Ltd | Preparation of photographic silver halide emulsion |
| CN107325073A (en) * | 2017-08-15 | 2017-11-07 | 成都百事兴科技实业有限公司 | A kind of new synthetic method of DL homocysteine thiolactones hydrochloride |
| CN109824649A (en) * | 2019-03-11 | 2019-05-31 | 南京红杉生物科技有限公司 | Homocysteinic acid thiolactone hydrochloride and its preparation method and application |
| CN111004209A (en) * | 2019-12-24 | 2020-04-14 | 浙江工业大学 | Continuous production method of DL-homocysteine thiolactone hydrochloride |
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Denomination of invention: Preparation method of DL homocysteine thiolactone hydrochloride Granted publication date: 20221028 Pledgee: Shandong Shanghe Rural Commercial Bank Co.,Ltd. Pledgor: Jinan xuanzheng Pharmaceutical Co.,Ltd. Registration number: Y2024980008293 |