CN105418634B - The preparation method of biotin intermediate impurity - Google Patents
The preparation method of biotin intermediate impurity Download PDFInfo
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- CN105418634B CN105418634B CN201510931936.0A CN201510931936A CN105418634B CN 105418634 B CN105418634 B CN 105418634B CN 201510931936 A CN201510931936 A CN 201510931936A CN 105418634 B CN105418634 B CN 105418634B
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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 44
- 239000012535 impurity Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229960002685 biotin Drugs 0.000 title claims abstract description 22
- 235000020958 biotin Nutrition 0.000 title claims abstract description 22
- 239000011616 biotin Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 12
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 14
- 239000011777 magnesium Substances 0.000 claims description 14
- 229910052749 magnesium Inorganic materials 0.000 claims description 14
- 230000004224 protection Effects 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 239000011630 iodine Substances 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 239000010410 layer Substances 0.000 claims description 10
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000007259 addition reaction Methods 0.000 claims description 7
- 150000002460 imidazoles Chemical class 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000009423 ventilation Methods 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 229940005605 valeric acid Drugs 0.000 claims description 5
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical class BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000007704 transition Effects 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
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 229940046001 vitamin b complex Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention provides a kind of preparation methods of biotin intermediate impurity of structural formula as shown in following formula (V), and using thiolactone and Grignard Reagent as raw material, the intermediate impurities of high-purity are obtained through addition, hydrolysis.Method is simple for preparation method of the present invention, is especially suitable for laboratory and prepares.
Description
Technical field
The present invention relates to the synthesis technology of compound, specifically, being related to the preparation method of biotin intermediate impurity.
Background technology
Biotin is also known as biotin, biotin, is water soluble vitamin, also belongs to vitamin B complex, B7.It is synthesis dimension
The necessary material of raw element C, is fat and the indispensable substance of protein eubolism.Be it is a kind of maintenance human body natural growth,
Development and the necessary nutrient of normal human's functional health.The synthesis of biotin through intermediate thiolactone by double forms, hydrogenation,
The reaction synthesizing biotinylated such as de- benzyl, cyclization, wherein double be formatted as wherein important reaction step, if hydrolysis not exclusively may be used
Not Olefination impurity can be introduced, is had an adverse effect to subsequent reactions.In order to effectively control the issuable impurity of the step,
The impurity reference substance of high-purity is needed to be detected for analyzing；It is used for the content that impurity is effectively controlled in production process, so as to
The effectively quality of control product.
According to the stabilization synthetic method that the high-purity product is also not yet found in the document retrieved at present, the side of document report
Method is hydrolyzed using sulfuric acid, and dehydration easily occurs and mainly generates such as following formula (VI) compound represented, and cannot be obtained high-purity
Spend transition state hydroxylate.
Invention content
The object of the present invention is to provide a kind of preparation methods of biotin intermediate impurity, can stablize output high-purity
Grignard impurity uses, so as to effectively control the matter of product as reference substance for the content that impurity is effectively controlled in production process
Amount.
In order to realize the object of the invention, it is miscellaneous that the present invention provides a kind of biotin intermediate of structural formula as shown in following formula (V)
The preparation method of matter,
The synthetic route of this method is as follows：
Specifically, the preparation method of above-mentioned biotin intermediate impurity includes the following steps：
B) addition reaction
Under nitrogen protection, in the presence of solvent by thiolactone of the structural formula as shown in formula (III) and structural formula such as formula (II)
Shown mono-Grignard Reagent reaction, is made structural formula such as formula (IV) compound represented；
C) it is inserted into hydrolysis
By the structural formula obtained by step b) as shown in formula (IV) compound and CO2After reaction, then through weak acid hydrolysis
Biotin intermediate impurity of the structural formula as shown in formula (V) is made.
In the preparation method of above-mentioned biotin intermediate impurity, wherein step b) addition reactions：
The solvent is selected from ethers, preferably ether or tetrahydrofuran, more preferably tetrahydrofuran.
The addition of the magnesium is 2 of the addition of thiolactone described in step a)：0.9~1 times；
Or 1~1.1 times of the addition that the Grignard Reagent theoretical addition amount is thiolactone.
The weak acid includes one or more of acid or glacial acetic acid.
Wherein, Grignard Reagent preparation method of the structure above as shown in formula (II) includes：A) grignard reacts, this method
Synthetic route is as follows：
It specifically includes：Under nitrogen protection, structural formula such as formula is made in Isosorbide-5-Nitrae-dibromobutane in the presence of solvent and magnesium
(II) mono-Grignard Reagent shown in.
The list grignard reaction, wherein：
The solvent is selected from ethers, preferably ether or tetrahydrofuran, more preferably tetrahydrofuran.
The solvent is 5~10: 1 with 1,4- dibromobutanes mass volume ratio；The quality of the mass volume ratio in terms of g,
Volume is in terms of mL.
The molar ratio of the magnesium and 1,4- dibromobutanes is 2:1~0.8；Preferably 2:1~0.9；
The magnesium is preferably magnesium chips.
Preferably, the reaction temperature is 60 DEG C~70 DEG C.
Preferably, the reaction time is 2~3h.
It is preferred that iodine or iodine grain are added in the reactor as initiator；The addition of the further preferred iodine or iodine grain
Measure 1%~3% for magnesium or magnesium chips quality.
More specifically, the preparation method of above-mentioned biotin intermediate impurity, includes the following steps：
A) grignard reacts
Under nitrogen protection, magnesium chips and tetrahydrofuran are added in into reaction vessel, is heated to reflux, then be added dropwise into reaction vessel
Isosorbide-5-Nitrae-dibromobutane and tetrahydrofuran, and iodine grain is added in as initiator, 2~3h of back flow reaction；It is made and contains above-mentioned Dan Geshi
The reaction solution of reagent；
B) addition reaction
Reaction solution made from step a) is cooled to -30 DEG C, under nitrogen protection, (i.e. step 1) is obtained to the reaction solution
Reaction solution containing above-mentioned mono-Grignard Reagent) in be added dropwise the tetrahydrofuran solution for dissolving the thiolactone, control dropping temperature≤-
20 DEG C, 1~2h of insulation reaction is added dropwise, the reaction was continued to room temperature (referring generally to 15~25 DEG C)；It is preferred that dropping temperature is -30 DEG C
~-20 DEG C；
C) hydrolysis
Under stirring, CO is passed through at -30 DEG C~-20 DEG C into the reaction solution obtained by step b)2To room temperature, ventilation
2~4h of time, dilute acid soln is added dropwise into reaction solution, in 40~45 DEG C of insulated and stirred 30-60min, adds in toluene extraction, point
Layer；Add water washing into organic layer (i.e. toluene layer), gained organic layer after washing is evaporated to get (light red solid)；
Wherein, acetum of the preferred dilute acid soln for mass concentration 10%~25% in step c).
It is preferred that adding water washing into the organic layer (i.e. toluene layer) 1-3 times.
It is preferred that the temperature that the organic layer is evaporated is 70~75 DEG C, pale yellow oil is obtained.
Thiolactone chemical name of the present invention is (3aS, 6aR) -1,3- dibenzyl tetrahydrochysene -1H- thiophene [3,4-d] miaow
Azoles -2,4- diketone.
Shown in the chemical structural formula such as following formula (V) of biotin intermediate impurity prepared by the present invention, its chemical name is
5- ((3aS, 4S, 6aR) -1,3- dibenzyl -4- hydroxyls -2- oxo -1H- thiophene [3,4-d] imidazoles -4-yl) valeric acid, appearance：It is light
Yellow oily liquid.
The present invention provides a kind of preparation method of biotin intermediate impurity, using thiolactone and mono-Grignard Reagent as raw material,
The intermediate impurities of high-purity are obtained through addition, hydrolysis.Preparation method provided by the invention is simple and easy to do, is especially suitable for laboratory
It prepares.Present invention process can stablize the grignard impurity of output high-purity as reference substance, for effectively being controlled in production process
The content of impurity uses, so as to effectively control the quality of product.
Description of the drawings
Fig. 1 is the mass spectrogram of experimental example 1.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Unless otherwise specified, embodiment
Used in the conventional means that are well known to those skilled in the art of technological means, raw materials used is commercial goods.
Embodiment 1
Biotin intermediate impurity 5- ((3aS, 4S, 6aR) -1,3- dibenzyl -4- hydroxyl -2- oxo -1H- thiophene [3,4-
D] imidazoles -4-yl) valeric acid preparation method, include the following steps：
A) grignard reacts
Under nitrogen protection, magnesium chips 5.8g, anhydrous tetrahydro furan 60ml are added in into reaction bulb, is heated to reflux 30min, to anti-
It answers and iodine grain 1 (0.3g) is added in bottle, Isosorbide-5-Nitrae-dibromobutane, the 125ml tetrahydrofurans of 25g are added dropwise into reaction bulb, drips
Bi Jixu back flow reactions 3h；The reaction solution containing the Grignard Reagent as shown in structural formula (I) is made.
B) addition reaction
21.8g thiolactone ((3aS, 6aR) -1,3- dibenzyl tetrahydrochysene -1H- thiophene [3,4-d] miaows are added in into reaction bulb
Azoles -2,4- diketone adds tetrahydrofuran 200ml dissolvings, is transferred in dropping funel, and step a) systems are added dropwise under nitrogen protection
(it is cooled to -30 DEG C in advance) in standby reaction solution, -30 DEG C of initial temperature is added dropwise, process temperature is added dropwise and is no more than -20 DEG C, is added dropwise
Complete heat preservation 1h.
C) hydrolysis
Under stirring, CO is passed through at -30 DEG C2To room temperature, duration of ventilation 3h is added dropwise into reaction solution made from step b)
The acetum 200ml of mass concentration 15% is added dropwise in 40~50 DEG C of insulated and stirred 30min.Add in toluene 100ml extractions
Reaction solution, toluene layer addition are separately added into 50ml water washings 2 times.Toluene layer is evaporated to obtain yellow oily liquid, 70 DEG C of vacuum decompressions
5h is dried, obtains final product 44g.Yield is 86%.
It is detected through HPLC, gained final product content is 98.8%.
Embodiment 2
Biotin intermediate impurity 5- ((3aS, 4S, 6aR) -1,3- dibenzyl -4- hydroxyl -2- oxo -1H- thiophene [3,4-
D] imidazoles -4-yl) valeric acid preparation method, with embodiment 1 is differed only in step C) in CO2Be passed through temperature for-
20 DEG C, duration of ventilation 4h, addition, reaction condition and the last handling process and embodiment 1 of unclassified stores are consistent.Finally obtain end
Product pale yellow oily liquid 42.5g.Yield is 83%.
According to the same manner as in Example 1, it is detected through HPLC, gained final product content 98.7%.
Present invention process is especially suitable for laboratory condition synthesis as can be seen from the above embodiments, without harsh reaction condition,
Products obtained therefrom purity is higher, can be used for the detection work of the corresponding intermediate impurities of biotin.
Experimental example 1
The mass spectrogram of final product is shown in Fig. 1 made from embodiment 1.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1. a kind of preparation method of biotin intermediate impurity of structural formula as shown in following formula (V), the synthetic route of this method is such as
Under：
The preparation method includes the following steps：
A) grignard reacts
Under nitrogen protections, magnesium chips and tetrahydrofuran are added in into reaction vessel, is heated to reflux, then be added dropwise into reaction vessel Isosorbide-5-Nitrae-
Dibromobutane and ethers, and iodine grain is added in as initiator, 2~3h of back flow reaction；It is made containing the grignard as shown in formula (II)
The reaction solution of reagent；The ethers is ether or tetrahydrofuran；
The ethers is 5~10: 1 with 1,4- dibromobutanes mass volume ratio；
The molar ratio of the magnesium chips and 1,4- dibromobutanes is 2:1~0.8；
The addition of the iodine grain is the 1%~3% of magnesium chips quality；
The reaction temperature is 60 DEG C~70 DEG C；
The reaction time is 2~3h；
B) addition reaction
Reaction solution made from step a) is cooled to -30 DEG C, under nitrogen protection, is added dropwise into the reaction solution and dissolves the thiolactone
Tetrahydrofuran solution, control dropping temperature≤- 20 DEG C, 1~2h of insulation reaction is added dropwise；
The Grignard Reagent theoretical addition amount is 1~1.1 times of the addition of thiolactone；
C) hydrolysis
Under stirring, CO is passed through at -30 DEG C~-20 DEG C into the reaction solution obtained by step b)2To room temperature, duration of ventilation 2
~4h, dilute acid soln is added dropwise into reaction solution, in 40~45 DEG C of insulated and stirred 30-60min, adds in toluene extraction, layering；Xiang You
In machine layer plus water washing, by gained organic layer after washing be evaporated to get；The dilute acid soln is mass concentration 10%~25%
Acetum.
2. preparation method according to claim 1, which is characterized in that add water washing 1- in step c) into the organic layer
3 times；And/or
The temperature that the organic layer is evaporated is 70~75 DEG C, is evaporated method to be concentrated in vacuo.
3. preparation method according to claim 2, which is characterized in that again that the product after being evaporated is true in 70 DEG C in step c)
Sky drying.
4. preparation method according to claim 1, which is characterized in that magnesium chips described in step a) and Isosorbide-5-Nitrae-dibromobutane
Molar ratio is 2:1~0.9.
5. preparation method according to claim 1, which is characterized in that in step b)；The dropping temperature for -30 DEG C~-
20℃。
6. biotin intermediate impurity 5- ((3aS, 4S, 6aR) -1,3- dibenzyl -4- hydroxyl -2- oxo -1H- thiophene [3,4-d]
Imidazoles -4-yl) valeric acid preparation method, which is characterized in that include the following steps：
A) grignard reacts
Under nitrogen protection, magnesium chips 5.8g, anhydrous tetrahydro furan 60ml are added in into reaction bulb, 30min is heated to reflux, to reaction bulb
Isosorbide-5-Nitrae-dibromobutane, the 125ml tetrahydrofurans of 25g are added dropwise into reaction bulb by the middle i.e. 0.3g of addition iodine grain 1, be added dropwise after
Continuous back flow reaction 3h；The reaction solution containing the Grignard Reagent as shown in structural formula (II) is made；
B) addition reaction
Added in into reaction bulb 21.8g thiolactones ((3aS, 6aR) -1,3- dibenzyl tetrahydrochysene -1H- thiophene [3,4-d] imidazoles -2,
4- diketone adds tetrahydrofuran 200ml dissolvings, is transferred in dropping funel, and step a) preparations are added dropwise under nitrogen protection
In reaction solution, which is cooled to -30 DEG C in advance, and -30 DEG C of initial temperature is added dropwise, and process temperature is added dropwise and is no more than -20 DEG C, drop
Add into heat preservation 1h；
C) hydrolysis
Under stirring, CO is passed through at -30 DEG C2To room temperature, quality is added dropwise into reaction solution made from step b) in duration of ventilation 3h
The acetum 200ml of concentration 15% is added dropwise in 40~50 DEG C of insulated and stirred 30min；Add in toluene 100ml extraction reactions
Liquid, toluene layer addition are separately added into 50ml water washings 2 times；Toluene layer is evaporated to obtain yellow oily liquid, 70 DEG C of vacuum decompression drying
5h obtains final product.
7. biotin intermediate impurity 5- ((3aS, 4S, 6aR) -1,3- dibenzyl -4- hydroxyl -2- oxo -1H- thiophene [3,4-d]
Imidazoles -4-yl) valeric acid preparation method, which is characterized in that include the following steps：
A) grignard reacts
Under nitrogen protection, magnesium chips 5.8g, anhydrous tetrahydro furan 60ml are added in into reaction bulb, 30min is heated to reflux, to reaction bulb
Isosorbide-5-Nitrae-dibromobutane, the 125ml tetrahydrofurans of 25g are added dropwise into reaction bulb by the middle i.e. 0.3g of addition iodine grain 1, be added dropwise after
Continuous back flow reaction 3h；The reaction solution containing the Grignard Reagent as shown in structural formula (II) is made；
B) addition reaction
Added in into reaction bulb 21.8g thiolactones ((3aS, 6aR) -1,3- dibenzyl tetrahydrochysene -1H- thiophene [3,4-d] imidazoles -2,
4- diketone adds tetrahydrofuran 200ml dissolvings, is transferred in dropping funel, and step a) preparations are added dropwise under nitrogen protection
In reaction solution, which is cooled to -30 DEG C in advance, and -30 DEG C of initial temperature is added dropwise, and process temperature is added dropwise and is no more than -20 DEG C, drop
Add into heat preservation 1h；
C) hydrolysis
Under stirring, CO is passed through at -20 DEG C2To room temperature, quality is added dropwise into reaction solution made from step b) in duration of ventilation 4h
The acetum 200ml of concentration 15% is added dropwise in 40~50 DEG C of insulated and stirred 30min；Add in toluene 100ml extraction reactions
Liquid, toluene layer addition are separately added into 50ml water washings 2 times；Toluene layer is evaporated to obtain yellow oily liquid, 70 DEG C of vacuum decompression drying
5h obtains final product.
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| CN107973806A (en) * | 2016-10-21 | 2018-05-01 | 大丰海嘉诺药业有限公司 | A kind of method for preparing D-Biotin bromide intermediate |
| CN110577547B (en) * | 2019-08-05 | 2021-05-11 | 浙江工业大学 | Synthesis method of biotin intermediate |
| EP4353728A1 (en) * | 2021-06-11 | 2024-04-17 | Tokuyama Corporation | Hydroxy thienoimidazole derivative, vinyl sulfide derivative, n-butylidene sulfide derivative, and production method for saturated straight-chain hydrocarbon-substituted thienoimidazole derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0270076A1 (en) * | 1986-12-02 | 1988-06-08 | Lonza Ag | Imidazole derivatives and a process for their preparation |
| US4877882A (en) * | 1986-04-19 | 1989-10-31 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Process for the preparation of D-(+)-biotin |
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