CN109503620A - The preparation method of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds - Google Patents
The preparation method of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds, it include: (3S, 7aR) -6- substituted benzyl -7- alkoxy -3- substituted-phenyl imidazolidine simultaneously [1, 5-c] (3H) -one of thiazole -5 reacted with 1- hexamethylene alkenyloxy group trimethyl silane, generate (3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3- substituted-phenyl imidazolidine simultaneously [1, 5-c] thiazole -5 (3H) -one, then ring-opening reaction is successively carried out, reduction ring-opening reaction, cyclization and elimination reaction, obtain the 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds.The preparation method has few side reaction, high income, environmentally friendly, the mild advantage easily-controllable, post-processing is simple of reaction condition, suitable industrialized production.
Description
Technical field
The present invention relates to a kind of medical material preparation fields, and in particular to a kind of D-biotin intermediate 5- (2- oxo four
Hydrogen Thienoimidazole -4 (2H)-alkenyl) penta acid compounds preparation method.
Background technique
D-biotin (biotin) is also known as biotin, biotin, and chemical name is (3aS, 4S, 6aR)-hexahydro -2- oxo -
1H- thieno [3,4-d] imidazoles -4- valeric acid, belongs to water-soluble B vitamin, is used as medicine and feed addictive.D- biology
Element is distributed in animal and plant tissue, can be isolated from liver extract and yolk, be a variety of carboxylase prothetic groups at
Point, it is the necessary material of growth and development of plants and animals.D-biotin is typically now obtained using chemical synthesis.
The structure of D-biotin is as follows:
The specific synthetic method of D-biotin is as follows:
Chen Fener et al. has reported a kind of D-biotin in " Chemical Journal of Chinese Universities ", 2001,22 (7), 1141-1146
Synthetic method: with -2 ketone of 1,3- dibenzyl imidazole-cis- 4,5- dicarboxylic acids for raw material, through cis- 1,3- dibenzyl-tetrahydro -2H- furan
It mutters simultaneously [3,4-d] imidazoles -2,4,6- triketone etc., (3aS, 6aR) -1,3- dibenzyl-tetrahydro -4H- thieno [3,4-d] imidazoles -
2,4 (1H)-diketone etc., (3aR, 8aS, 8bS) -1,3- dibenzyl -2- oxo-decahydro imidazo [4,5-c] thieno [1,2-a]
Sulfonium bromide, dibenzylbiotin diester, debenzylation protection, decarboxylation obtain D-biotin product.This synthetic route must be used
The sulfiding reagents such as thioacetic acid potassium, environmental protection pressure are very big.
Subhash P.Chavan et al. is in 2005,70 (5) " Journal of Organic Chemistry ", 1901-
1903 have reported a kind of D-biotin synthetic method: using cysteine hydrochloride as raw material, through (3S, 7aR) -6- benzyl -7- hydroxyl
Base -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one and bis- (trimethyl silicane oxygen) the hexamethylene alkene reactions of 1,2-, obtain
(3S, 7aR) -6- benzyl -7- (1- hydroxyl -2- oxocyclohexyl) -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one,
Obtaining 6- with peroxidating Oxidation of t-Butanol, esterification, ((3S, 7aR) -6- benzyl -5- oxo -- 3- phenyl imidazolidine is simultaneously [1,5-c]
Thiazole -7- base) -6- oxo methyl caproate, with zinc powder/acetic acid reductive ring open, then with acetic acid/piperidines cyclization obtain 5- ((3aS,
6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4 (2H)-alkenyl)-methyl valerate, repeated hydrogenation,
Debenzylation obtains D-biotin.The route will use special raw material: 1,2- bis- (trimethyl silicane oxygen) cyclohexene, synthesize difficulty
Greatly, buying is difficult；Tertbutanol peroxide is used, industrial implementation risk is big, and intermediate methyl esterization also needs to use dangerous
Diazomethane.(3S, 7aR) -6- benzyl -7- hydroxyl -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one to 5-
((3aS, 6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4 (2H)-alkenyl)-methyl valerate report
The yield led is 48.02%.
For Chen Kexi et al. in " organic chemistry " 2006,26 (9), 1309-1312 has reported a kind of D-biotin synthetic method:
Using cysteine hydrochloride as raw material, through (3S, 7aR) -6- benzyl -7- hydroxyl -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5
(3H) -one and 1- trimethyl silicane oxygen -1- hexamethylene alkene reaction, obtain (3S, 7S, 7aR) -6- benzyl -7- (2- oxocyclohexyl) -3-
Phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one, is aoxidized to obtain 6- ((3S, 7R, 7aR) -6- benzyl-with benzoyl hydroperoxide
5- oxo -3- phenyl hexahydro imidazo [1,5-c] thiazole -7- base) -6 hydroxycaproic acid, 6- is obtained with chromium trioxide oxidation, esterification
((3S, 7R, 7aR) -6- benzyl -5- oxo -3- phenyl hexahydro imidazo [1,5-c] thiazole -7- base) -6- oxo methyl caproate,
With zinc powder/acetic acid/piperidines open loop-cyclization obtain 5- ((3aS, 6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,
4-d] imidazoles -4 (2H)-alkenyl)-methyl valerate, repeated hydrogenation, debenzylation obtain D-biotin.The route will use risk high
Benzoyl hydroperoxide as oxidant, make oxidant using chromium trioxide again, the waste disposal containing chromium after chromium trioxide use
Difficulty is big, and processing cost is high.(3S, 7aR) -6- benzyl -7- hydroxyl -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one
To 5- ((3aS, 6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4 (2H)-alkenyl)-valeric acid first
The yield of ester report is 53.62%.
The method that Subhash P.Chavan and the Chen Ke report of good news is led is all made of zinc powder reduction under acid condition, cyclization, reaction
Impurity is more, and side reaction is serious, and separating-purifying is difficult.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the problems of the above-mentioned prior art, provides one kind and be not required to use
The raw material of stench does not use hazardous materials, and raw material is easy to get, side reaction is few, high income, environmentally friendly, and reaction condition is mildly easy
Control and 5- ((3aS, the 6aR) -1- substituted benzyl -3- substituted benzyl -2- oxo tetrahydro -1H- thieno [3,4-d] for being suitble to production
Imidazoles -4 (2H)-alkenyl) valeric acid synthetic method.
For this purpose, The technical solution adopted by the invention is as follows:
A kind of preparation method of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl), including with
Lower step:
(1) (3S, 7aR) -6- substituted benzyl -7- alkoxy -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5
(3H) -one is reacted with 1- hexamethylene alkenyloxy group trimethyl silane, generates (3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohex
Base) -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one；
(2) (3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3- substituted-phenyl tetrahydro miaow that step (1) obtains
Simultaneously [1,5-c] thiazole -5 (3H) -one carries out ring-opening reaction to azoles, and generating 6-, ((3S, 7aR) -6- substituted benzyl -5- oxo -3- replaces
Phenyl hexahydro imidazo [1,5-c] thiazole -7- base -6- oxo caproate；
6- that (3) step (2) obtains ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro imidazo [1,
5-c] thiazole -7- base -6- oxo caproate progress reduction ring-opening reaction, generate 6- ((5R) -1- substituted benzyl -3- substituted benzyl -
5- (thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxo caproic acid；
(4) 6- ((5R) -1- substituted benzyl -3- substituted benzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole-that step (3) obtains
4- yl) -6- oxo caproic acid successively carries out cyclization and elimination reaction, generate the 5- (2- oxo thiophane and imidazoles -4
(2H)-alkenyl) penta acid compounds；
(3S, 7aR) -6- substituted benzyl -7- alkoxy -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5
Shown in the structure such as formula (1) of (3H) -one:
(3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3- substituted-phenyl imidazolidine simultaneously [1,5-
C] shown in thiazole -5 (3H) -one such as formula (2):
Described 6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro imidazo [1,5-c] thiazole -
Shown in 7- base -6- oxo caproate such as formula (3):
Described 6- ((5R) -1- substituted benzyl -3- substituted benzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxygen
For shown in caproic acid such as formula (4):
Shown in described 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) the penta acid compounds such as formula (5):
In formula (1)~(5), R1To replace or unsubstituted phenyl, the substituent group on the phenyl are C1~C4Alkyl,
C1~C4Alkoxy or halogen；
R2To replace or unsubstituted benzyl, the substituent group on the benzyl are C1~C4Alkyl, C1~C4Alkoxy or
Halogen；
R3For H, C1~C5Alkyl or benzyl；
M+For Li+、Na+、K+, ammonium ion, (CH3)3NH+Or (CH3CH 2)3NH+。
Preferably, R1For phenyl, p-methylphenyl, rubigan, p-methoxyphenyl, o-tolyl, Chloro-O-Phenyl or neighbour
Anisyl；R2For benzyl, to methylbenzyl, p-chlorobenzyl, to methoxybenzyl, adjacent methylbenzyl, o-chlorobenzyl or adjacent methoxybenzyl；
R3For hydrogen, methyl, ethyl, propyl, allyl, isopropyl, butyl, isobutyl group, sec-butyl, amyl, isopentyl, tertiary amyl or benzyl
Base.
In route of the invention, key is step (2) and step (4), and respective the reaction mechanism is as follows.
The reaction mechanism of step (2):
In the step, general formula (2) compound forms carbanion under alkali effect, and carbanion is formed in conjunction with oxygen
Peroxidating intermediate, for this intermediate under the effect of reproducibility co-catalyst, peroxide bridge breaks to form hydroxyl；Hydroxy intermediate is into one
Step obtains lactone under manganese dioxide, oxygen effect, and general formula (3) compound is obtained after basic hydrolysis.This reaction process raw material valence
Honest and clean to be easy to get, technical process is mild, oxidationreduction at hydroxyl, at lactone, open loop one-pot synthesis, it is easy to operate, be conducive to industrial real
It applies；It is aoxidized using air (oxygen), technique clean-up performance is high.
The reaction mechanism of step (4):
In the step, for general formula (4) compound under alkali effect, sulfydryl forms sulfydryl anion, sulfydryl anion and carbonyl
Carbon combines cyclization and generates negative oxygen ion simultaneously, and negative oxygen ion forms hydroxyl under promoter effect, and hydroxyls dehydrate forms double bond, acid
General formula (5) compound is obtained after change.This reaction process raw material is cheap and easy to get, and technical process is mild, and cyclization is dehydrated into one pot of double bond
Synthesis, it is easy to operate, be conducive to industrial implementation.
Each step is illustrated further below.
In step (1), reaction is catalyzed using lewis acid and lewis acid compound, the lewis acid and Louis
Acid compound preferably has alchlor, triethylamine hydrochloride-alchlor, zinc chloride, zinc chloride ether, boron trifluoride ether, three
Boron fluoride acetonitrile, titanium tetrachloride or tin tetrachloride.
In step (1), reaction carries out in a solvent, and solvent is alkyl halide, alkane, ester or ketone；Preferred solvent is dichloro
Methane, toluene or butyl acetate.
In step (1), reaction temperature is -80~100 DEG C, and preferred reaction temperature is -40~30 DEG C.
In step (2), for the ring-opening reaction under the catalysis of manganese dioxide and co-catalyst, air or oxygen aoxidizes item
It is carried out under part；
The co-catalyst be hypophosphite, pyrophosphate, alkylphosphines, phosphite ester, thioether, mercaptan, thiophenol or
Phenol；Preferably sodium hypophosphite, sodium pyrophosphate, triphenylphosphine, triphenyl phosphite, thioanisole or phenol；
The air or oxygen pressure is 0~10MPa (gauge pressure)；Preferred air or oxygen pressure is 0~1MPa (table
Pressure).
In step (2), the ring-opening reaction carries out in the presence of alkali；
The alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, trimethylamine, aqueous solution or alcohol in triethylamine
It is one or more in solution；
The solvent of the alcoholic solution is C1-C6Alcohol；Preferably methanol, ethyl alcohol, propyl alcohol, butanol, isobutanol, the tert-butyl alcohol, penta
Alcohol, isoamyl alcohol or cyclohexanol.
In step (2), reaction temperature is -30~120 DEG C, preferably -10~50 DEG C.
In step (2), after co-catalyst fully reacting first is added, adds manganese dioxide and continue in air or oxygen ring
It is reacted in border.Wherein, when using oxygen, when oxygen pneumatic no longer declines, manganese dioxide can be added, and the reaction was continued；When using empty
When gas, fresh air air pressure is added and does not decline, pressure does not decline, and manganese dioxide can be added, and the reaction was continued.
With molar amount, (3S, 7aR) -6- substituted benzyl -7- (2- the oxocyclohexyl) -3- substituted-phenyl tetrahydro miaow
Simultaneously the ratio between [1,5-c] thiazole -5 (3H) -one, co-catalyst, manganese dioxide are 1:0.5~1.5:0.01~0.05 to azoles.
In step (3), the reduction ring-opening reaction uses zinc powder or aluminium powder as reducing agent, and reaction is under inorganic base effect
It carries out；
The mole dosage of the zinc powder is 6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro miaow
1.0~10.0 times, preferably 2.0~5.0 times of azoles simultaneously [1,5-c] thiazole -7- base -6- oxo caproate；
The inorganic base is sodium hydroxide, potassium hydroxide；
Reaction temperature is -10~100 DEG C, preferably 10~60 DEG C；
PH value in reaction is 7.0~14.0, preferably 11.0~13.0.
In step (4), the cyclization carries out in the presence of alkali, and the alkali is lithium hydroxide, sodium hydroxide or hydrogen
Potassium oxide；
After cyclization reaction, the auxiliary agent in situ that is added carries out the elimination reaction；
The auxiliary agent is sodium bicarbonate, saleratus or ammonium acetate.
In step (4), the solvent of the cyclization reaction is alkane, ester or ketone；Preferably toluene, hexamethylene, acetic acid second
Ester, butyl acetate, methyl iso-butyl ketone (MIBK)；
Promote to react by reflux dewatering in reaction process.
Compared with the existing technology, non-toxic the invention has the following advantages that raw material is inexpensive, be easy to get, safety is good, reaction
Mild condition is easy to control, reduces production cost and environmentally protective；Reaction condition is mildly easily-controllable, high income, and separation is easy, and obtains
5- ((3aS, 6aR) -1- substituted benzyl -3- substituted benzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4 of high-purity
(2H)-alkenyl) valeric acid compound.
Specific embodiment
Embodiment 1:(3S, 7aR) -6- benzyl -7- (2- oxocyclohexyl) -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -
The preparation of 5 (3H) -one
In the 500mL there-necked flask with mechanical stirring, thermometer, methylene chloride 200mL is added, puts into compound (1a)
32.6g(0.1mol)(R1=phenyl, R2=benzyl, R3=H), 1- hexamethylene alkenyloxy group trimethyl silane 18.7g is added
(0.11mol), nitrogen protection, stirring are cooled to -45 DEG C, boron trifluoride ether 14.2g (0.1mol) are added dropwise with half an hour, control
Temperature -45~-10 DEG C are stirred to react 2~3 hours；Reaction is finished, and is warming up to -5~0 DEG C, and water 50mL, layering is added dropwise, and water layer adds two
Chloromethanes 100mL × 2 are extracted twice, and are merged methylene chloride organic phase saturated sodium bicarbonate aqueous solution 50mL × 2 and are washed twice,
The above dichloromethane layer is steamed, product drying obtains target product (2a) (3S, 7aR) -6- benzyl -7- (2- oxocyclohex
Base) -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one (R1=phenyl, R2=benzyl), weight 39.9g, content
98.9%, yield 98.1%.
Embodiment 14:6- ((3S, 7aR) -6- benzyl -5- oxo -3- phenyl hexahydro imidazo [1,5-c] thiazole -7- base -
The preparation of 6- oxo sodium n-caproate
In the 500mL autoclave pressure with mechanical stirring, thermometer, ethyl alcohol 300mL is added, investment is prepared by embodiment 1
Compound (2a) (3S, 7aR) -6- benzyl -7- (2- oxocyclohexyl) -3- phenyl imidazolidine simultaneously [1,5-c] thiazole -5
(3H) -one 40.6g (0.1mol) (R1=phenyl, R2=benzyl), it is added sodium hydroxide 4.0g (0.1mol), co-catalyst triphen
Base phosphine 26.2g (0.1mol) is passed through air to 0.3MPa (gauge pressure), and stirring is warming up to 40 DEG C of reactions, as reaction carries out, pressure
Declined, continues supplement indentation air, when pressure does not decline, unload and be depressed into 0MPa (gauge pressure), re-fill air to 0.3MPa
(gauge pressure), pressure then react if do not declined and finish (can not unload when oxygen and be depressed into end of reaction early period) early period.Pressure is shed, is added
Manganese dioxide 0.4g (0.005mol) is passed through air to 0.3MPa (gauge pressure) end of reaction, is filtered to remove manganese dioxide and triphen
Base phosphine oxide, filtrate steam ethyl alcohol, and the distillation later period is added 300mL water, obtains target product (3a) 6- ((3S, 7aR) -6- benzyl -5-
Oxo -3- phenyl hexahydro imidazo [1,5-c] thiazole -7- base -6- oxo caproic acid sodium water solution (R1=phenyl, R2=benzyl), inspection
Mark contains target product (3a) 41.6g, HPLC purity 98.0%, yield 90.3% surely.
Embodiment 27:6- ((5R) -1,3- dibenzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxo caproic acid
Preparation
In the 500mL there-necked flask with mechanical stirring, thermometer, investment presses the compound of 14 method of embodiment preparation
(3a) 6- ((3S, 7aR) -6- benzyl -5- oxo -3- phenyl hexahydro imidazo [1,5-c] thiazole -7- base -6- oxo sodium n-caproate water
Solution 320mL contains compound (3a) 46.0g (0.1mol) (R1=phenyl, R2=benzyl), 500 mesh zinc powders are added at room temperature
32.7g (0.5mol), nitrogen protection, stirring are warming up to 40 DEG C, are added dropwise 30%NaOH (26.6g, 0.2mol), and control pH value exists
11.0~13.0,40~45 DEG C of temperature are controlled, is stirred to react 5~6 hours；Reaction is finished, and heat filtering removing, filter cake 100mL are multiplied
Water washing, filtrate adjust pH value=3.5-4.0 with 30%HCl solution, toluene 200mL × 2 are added to be extracted twice, and toluene extract liquor is used
Water 50mL × 2 wash twice, and obtain target product (4a) 6- ((5R) -1,3- dibenzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4-
Base) -6- oxo caproic acid toluene solution (R1=phenyl, R2=benzyl), detection calibration is pure containing target product (4a) 41.9g, HPLC
Degree 98.2%, yield 95.1%.
Embodiment 40:5- ((3aS, 6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4
(2H)-alkenyl) valeric acid preparation
With mechanical stirring, water segregator, thermometer 500mL four-hole bottle in, investment compound (4a) 6- ((5R) -1,
3- dibenzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxo caproic acid toluene solution 420mL, (4a) containing compound
44.0g(0.1mol)(R1=phenyl, R2=benzyl), it is added portionwise at room temperature sodium hydroxide 8.0g (0.2mol), continues room temperature and stir
Half an hour is mixed, reflux is warming up to and takes moisture out of, reaction goes out for 2~3 hours to no moisture, is cooled to 60 DEG C hereinafter, bicarbonate is added
Sodium (8.4g, 0.1mol) continues temperature rising reflux band water and reacts 1~2 hour, and end of reaction is cooled to 30 DEG C hereinafter, filtering, filter
Cake is washed with toluene 100mL, and merging filtrate 30%HCl solution adjusts pH value=3.5~4.0, layering, and water layer adds toluene 50mL
× 2 are extracted twice, and combining methylbenzene layer is washed twice with water 50mL × 2, are evaporated toluene, recrystallize, and filtering obtains target product
(5a) 5- ((3aS, 6aR) -1,3- dibenzyl -2- oxo tetrahydro -1H- thieno [3,4-d] imidazoles -4 (2H)-alkenyl) valeric acid
(R1=phenyl, R2=benzyl), drying, weight 37.0g, content 99.0%, yield 84.7%.
The above is only several implementation methods of the invention, catalyst combination also changeable for those skilled in the art changes
Become solvent combination, changes response parameter etc., all changes and improvements are accordingly to be regarded as falling into protection scope of the present invention.
Claims (10)
1. a kind of preparation method of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl), feature exist
In, comprising the following steps:
(1) (3S, 7aR) -6- substituted benzyl -7- alkoxy -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one
It is reacted with 1- hexamethylene alkenyloxy group trimethyl silane, generates (3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3-
Substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -one；
(2) (3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3- substituted-phenyl imidazolidine that step (1) obtains is simultaneously
[1,5-c] thiazole -5 (3H) -one carries out ring-opening reaction, generates 6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl
Hexahydro imidazo [1,5-c] thiazole -7- base -6- oxo caproate；
(3) 6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro imidazo [1,5-c] that step (2) obtains
Thiazole -7- base -6- oxo caproate carries out reduction ring-opening reaction, generates 6- ((5R) -1- substituted benzyl -3- substituted benzyl -5-
(thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxo caproic acid；
(4) 6- ((5R) -1- substituted benzyl -3- substituted benzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4- that step (3) obtains
Base) -6- oxo caproic acid successively carries out cyclization and elimination reaction, generate the 5- (2- oxo thiophane and imidazoles -4 (2H) -
Alkenyl) penta acid compounds；
(3S, 7aR) -6- substituted benzyl -7- alkoxy -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiazole -5 (3H) -
Shown in the structure of ketone such as formula (1):
(3S, 7aR) -6- substituted benzyl -7- (2- oxocyclohexyl) -3- substituted-phenyl imidazolidine simultaneously [1,5-c] thiophene
Shown in azoles -5 (3H) -one such as formula (2):
6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro imidazo [1,5-c] thiazole -7- base -
Shown in 6- oxo caproate such as formula (3):
Described 6- ((5R) -1- substituted benzyl -3- substituted benzyl -5- (thiopurine methyltransferase) -2- oxo-imidazole -4- base) -6- oxo oneself
Shown in acid such as formula (4):
Shown in described 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) the penta acid compounds such as formula (5):
In formula (1)~(5), R1To replace or unsubstituted phenyl, the substituent group on the phenyl are C1~C4Alkyl, C1~C4
Alkoxy or halogen；
R2To replace or unsubstituted benzyl, the substituent group on the benzyl are C1~C4Alkyl, C1~C4Alkoxy or halogen；
R3For H, C1~C5Alkyl or benzyl；
M+For Li+、Na+、K+, ammonium ion, (CH3)3NH+Or (CH3CH 2)3NH+。
2. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (1), reaction carries out under lewis acidic catalysis；
The lewis acid is alchlor, triethylamine hydrochloride-alchlor, zinc chloride, zinc chloride ether, boron trifluoride second
Ether, boron trifluoride acetonitrile, titanium tetrachloride or tin tetrachloride.
3. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (1), reaction carries out in a solvent；The solvent is alkyl halide, alkane, ester or ketone；
The solvent is preferably methylene chloride, toluene or butyl acetate.
4. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (1), reaction temperature is -80~100 DEG C, and preferred reaction temperature is -40~30 DEG C.
5. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (2), the ring-opening reaction under the catalysis of manganese dioxide and co-catalyst, air or
It is carried out under the conditions of dioxygen oxidation；
The co-catalyst is hypophosphite, pyrophosphate, alkylphosphines, phosphite ester, thioether, mercaptan, thiophenol or phenol；
The co-catalyst is preferably sodium hypophosphite, sodium pyrophosphate, triphenylphosphine, triphenyl phosphite, thioanisole or phenol；
The air or oxygen pressure is 0~10MPa；Preferred air or oxygen pressure is 0~1MPa.
6. 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds according to claim 1 or 5
Preparation method, which is characterized in that in step (2), the ring-opening reaction carries out in the presence of alkali；
The alkali is that lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, trimethylamine, the aqueous solution of triethylamine or alcohol are molten
Liquid；
The solvent of the alcoholic solution is C1-C6Alcohol；Preferably methanol, ethyl alcohol, propyl alcohol, butanol, isobutanol, the tert-butyl alcohol, amylalcohol,
Isoamyl alcohol or cyclohexanol.
7. 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) penta acid compounds according to claim 1 or 5
Preparation method, which is characterized in that in step (2), reaction temperature is -30~120 DEG C, preferably -10~50 DEG C.
8. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (3), the reduction ring-opening reaction uses zinc powder or aluminium powder as reducing agent, reacts in nothing
The effect of machine alkali is lower to be carried out；
The mole dosage of the zinc powder or aluminium powder is 6- ((3S, 7aR) -6- substituted benzyl -5- oxo -3- substituted-phenyl hexahydro
1.0~10.0 times, preferably 2.0~5.0 times of imidazo [1,5-c] thiazole -7- base -6- oxo caproate；
The inorganic base is sodium hydroxide or potassium hydroxide；
Reaction temperature is -10~100 DEG C, preferably 10~60 DEG C；
PH value in reaction is 7.0~14.0, preferably 11.0~13.0.
9. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (4), the cyclization carries out in the presence of alkali, and the alkali is lithium hydroxide, hydrogen
Sodium oxide molybdena or potassium hydroxide；
After cyclization reaction, the auxiliary agent in situ that is added carries out the elimination reaction；
The auxiliary agent is sodium bicarbonate, saleratus or ammonium acetate.
10. the system of penta acid compounds of 5- (2- oxo thiophane and imidazoles -4 (2H)-alkenyl) according to claim 1
Preparation Method, which is characterized in that in step (4), the solvent of the cyclization reaction is alkane, ester or ketone；Preferably toluene, hexamethylene
Alkane, ethyl acetate, butyl acetate, methyl iso-butyl ketone (MIBK)；
Promote to react by reflux dewatering in reaction process.
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| CN114957621A (en) * | 2022-05-13 | 2022-08-30 | 嘉应学院 | Conjugated polymer containing dinitrogen benzoacenaphthenequinoneimide and preparation method and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4130713A (en) * | 1977-08-05 | 1978-12-19 | Hoffmann-La Roche Inc. | Biotin intermediates |
| EP0387747A1 (en) * | 1989-03-15 | 1990-09-19 | Lonza Ag | Process for the preparation of 1,3-substituted tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-on-4-ylidene-pentanoic ester |
| EP1219625A1 (en) * | 2000-12-27 | 2002-07-03 | Council of Scientific and Industrial Research | Novel substituted 2-(6-benzyl-5-oxo-3-phenyl-(S3,7S,7AR)- pherhydroimidazol (1,5-C) (1,3) thiazol-7YL) compounds |
| CN103242342A (en) * | 2013-04-27 | 2013-08-14 | 浙江新和成股份有限公司 | Preparation method of 1, 3-alkyl tetrahydrothieno[3,4-d] imidazole-2(3H)-4-diketone compound |
| WO2015134561A1 (en) * | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
| CN106748693A (en) * | 2016-11-16 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of synthetic method of α hydroxyacetone compounds |
| CN107021969A (en) * | 2017-04-19 | 2017-08-08 | 浙江大学 | The method that catalysis oxidation prepares biotin precursor ketone acid |
-
2018
- 2018-12-25 CN CN201811590991.8A patent/CN109503620B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4130713A (en) * | 1977-08-05 | 1978-12-19 | Hoffmann-La Roche Inc. | Biotin intermediates |
| EP0387747A1 (en) * | 1989-03-15 | 1990-09-19 | Lonza Ag | Process for the preparation of 1,3-substituted tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-on-4-ylidene-pentanoic ester |
| EP1219625A1 (en) * | 2000-12-27 | 2002-07-03 | Council of Scientific and Industrial Research | Novel substituted 2-(6-benzyl-5-oxo-3-phenyl-(S3,7S,7AR)- pherhydroimidazol (1,5-C) (1,3) thiazol-7YL) compounds |
| CN103242342A (en) * | 2013-04-27 | 2013-08-14 | 浙江新和成股份有限公司 | Preparation method of 1, 3-alkyl tetrahydrothieno[3,4-d] imidazole-2(3H)-4-diketone compound |
| WO2015134561A1 (en) * | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
| CN106748693A (en) * | 2016-11-16 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of synthetic method of α hydroxyacetone compounds |
| CN107021969A (en) * | 2017-04-19 | 2017-08-08 | 浙江大学 | The method that catalysis oxidation prepares biotin precursor ketone acid |
Non-Patent Citations (2)
| Title |
|---|
| FEI XIONG等: "Highly Enantioselective Methanolysis of Meso-Cyclic Anhydride Mediated by Bifunctional Thiourea Cinchona Alkaloid Derivatives: Access to Asymmetric Total Synthesis of (+)-Biotin", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| 陈克喜等: "d-生物素的全合成研究", 《有机化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957621A (en) * | 2022-05-13 | 2022-08-30 | 嘉应学院 | Conjugated polymer containing dinitrogen benzoacenaphthenequinoneimide and preparation method and application thereof |
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