Method of preparing 6-amino-2',3',5',6'-tetrahydro-spiro-/penam-2,4'-/4h/thio/py

专利摘要:
Amino-spiro[oxa(or thia)cycloalkane-penam]-carboxylic acid, a salt or an ester thereof, of the formula <IMAGE> (I) wherein Z is a hydrogen or an alkali metal atom, or a group protecting the carboxylic function, X is a sulfur or oxygen atom, n is 1 or 2, m is 1 or 2, and process of preparing the same.
公开号:SU786902A3
申请号:SU782566653
申请日:1978-01-18
公开日:1980-12-07
发明作者:Родригес Людовик；Леклерк Жак；Икман Пьер；Коссеман Эрик
申请人:Юцб С.А. (Фирма)；
IPC主号:

专利说明:

in a water-alcohol solution, in the presence of sodium acetate and at 50-75 ° C, they are reacted with c4-amino-4-mercapto-2, 3,5,6-tetrahydro-4H (thio) pyran-4-ycyclic acid of the formula
N $
OU
(W);
the resulting “b-isomer of tert-6utyl-4 .carboxy-A-thalimido-1,8-dithia (or 8-oxa-1-thia) -3-azaspiro 4, 5 decai-2-acetate of the formula
introduced into the reaction with a benzyl halide in a polar aprotic solvent in the presence of an acid acceptor, the resulting benzyl ester of the formula
wherein Bz is a benzyl group, is reacted at a low temperature with hydrazine dissolved in dimethyl (|) ormamide, the resulting product is acidified with hydrochloric acid, the resulting tert-butyl-o (. amino-4-benzyloxycarbonyl-1 , 8-dithia (or 8-oxa-1-thia) -3-aza-spiro 4, 5 decan-2-acetate of formula
HN
YOOVg, W)
i
hydrolyzed with gass-shaped hydrogen chloride in nitpomethane at a temperature not higher, in order to avoid epimerization, the semi-brined hydrochloride in α-amino-4-benzyloxycarbonyl-1, 8-dithia (or 8-oxa-1-thia) -3-aza-spiroCl4 , 5} decane-2-acetic acid of formula
I HN
(OOBz, (W) HE
are introduced into interaction with triphenylmethyl chloride in methylene chloride or chloroform, in the presence of an acid acceptor at a temperature of from -20 to 0 C, the resulting 4-benzyloxycarbonyl-o4-triLenylmethylamino-1-, 8-pitia (or 8-oxa- 1-tia) -3-aa-spiro 4, 5-decane-2-acetic acid 10 Formula
 (c.Hs)
CooBz, (w
IJJ in a solvent selected from methylene chloride, nitromethane and chlorofiopMa, at 20-40 sec, obtained benzyl b-triLenylmethylamino-23516-tetrahydro-spiropenam-2, 4-4n3 (yew) pyran-3-carboxylate of Lormula
(CgHsb (
COOBz, (k)
treated with p-toluensulfonate in acetone, the resulting benzyl p-toluenesulfonate benzyl-6-amino-2, 3,5, 6-tetrahydro-spiro (lieHaM-2, 4-4p (thio) py-ran-3-carboxylate of formula
/ 7-TS-H2I GH /
5 (OOBz, U)
in which p-TC is p-toluenesulphonic acid,
subjected to hydrogenolysis in an alcohol medium over a catalyst based on palladium 0 under a hydrogen pressure of 24 kg / cm and the resulting target product is isolated in the form of the free acid of formula (1) or its benzyl ester.
Example 1. Preparation of cc-amino-4-mercapto-2, 3,5,6-tetrahydro-4H (thio) pyran-4-acetic acids of the formula (lit).
1, cL-Amino-4-mercapto-2,3,5,6-tetrahydro-4H-pyran-4-acetic acid.
1 a) Ethyl-C | 1.-formamido-2, 3, 5, 6-tetrahydro-4H-pyran-acetate.
To a suspension of 12.5 g (0.5 mol) of sodium hydride in 500 ml of anhydrous
55 tetrahydrofuran are added under nitrogen and at ambient temperature a solution containing 50 g (0.5 mol) of tetrahydro-4H-pyran-4-one and 56.5 g (0.5 mol) of ethyl 2-isocyanoacetate per 300 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated under vacuum and 5 residue is taken up with a solution of 45 g of acetic acid in 500 ml of water. This solution is extracted with ether, then the organic phase is washed with three consecutive bicarbonate solution with three and water. After drying over sodium sulfate, the ether is evaporated to obtain a crude residue in an amount of 160 g, which after recrystallization from a mixture of ethyl acetate and hexane gives 58 g - {yield 55%) ethyl-oo-formamido-2, 3.5, 6- tetrahydro-4H-pyran-L-acetate, mp. Analysis for C NO. (mol. weight. 213). Calculated: C 56.33; H 7.04; N 6.57. Found,%: C 56.20; H 7.10; N 6.60. 16) Ethyl-8-oxa-1-thia-3-aza-spiro 14, 5j dec-2-en-4-carboxylate. 53 g (0.25 mol) Ethyl-o {.- formamido - 2, 3,5,6-tetrahydro-4H-pyran A j aueTaTa and 14.5 g of phosphorus pentasulfide (form P) are suspended in 300 ml of anhydrous benzene . After boiling under reflux with stirring for 4 hours, the benzene solution is decanted from the insoluble part, treated with active coal and filtered. After evaporation of the solvent, a brownish oil remains, which is distilled under a pressure of 0.5 mm Hg. at 130 135s. Thus receive 30 g. (yield 52%) ethyl-8-oxa-1-thia-3-aza-spiro 4.5 dec-2-ene-4-carboxylate, which is used for the next synthesis without further purification. 1c) C1-Amino-4-mercapto-2, 3.5, 6-tetraparido-4H-pyran-4-yccyclic acid (formula (1 m); X 0). 2g (0.0087 mol) of ethyl 8-oxa-1-thia-3-aza-spirr 4, 5j dec-2-ene-4-carboxyl is dissolved in 100 ml of 6N. hydrochloric acid. The mixture is heated under reflux for 3 hours and then concentrated under vacuum in a rotary evaporator. The resulting resinous residue is triturated three times with 50 ml of benzene, which is then evaporated under reduced pressure to remove residual traces of water and saline. The residue is dissolved in 100 ml of water, the solution is treated with active charcoal, then lyophilized. Rub the lyophilisate with anhydrous dye ester in 1.6 g of o1-amino-4-mercapto-2, 3,5,6-tetrahydro-4H-pyran-4-acetic acid hydrochloride (yield). The product gives only one spot during chromatography in a thin layer of silica (eluent: butanol, acetic acid, water 4: 1; 1), R 0,3 so pl. 196-157С (decomposition). 2. Amino-4-mercapto-2,3,5,6-tagtrahydro-4H-thiopyran-4-hydroxy acid. 2a) Ethyl-x-formamido-2, 3.5, 6-tetrahydrO74H-thiopyran-L-acetate. to suspension 29, g of sodium hydride (1.21 mol) in 1.4 l of anhydrous tetrahydrofuran is added with vigorous stirring and under nitrogen atmosphere — a mixture of 127.2 g (1.1 mol) of tetrahydro-4H-thiopyran-4-one and 124 g (1.1 mol) of ethyl-2-isocyanoacetate in 800 ml of anhydrous tetrahydro-Luran. Hydrogen is released, which is accompanied by a slight increase in temperature (about 3540 ° C). Continue to stir overnight, then the solvent is evaporated on a rotary evaporator under vacuum (at a temperature of about 25 ° C). The residue is then carefully treated (exothermic) with a solution of 99 g (1.65 mol) of acetic acid in 1.4 liters of water. The aqueous Laza is extracted with chloroform and the organic phase is washed in turn with 5% sodium bicarbonate solution and water. After drying over sodium sulfate, chloroform is removed under vacuum to obtain a crude residue weighing 210 g. After recrystallization from benzene and chromatography on silica-mother liquor, 173 g of ethyl-formamido-2, 3,5,6-tetrahydro-4H- are obtained. thiopyran-A4-acetate, melted at 112-113 ° C. Yield 67%. 2 b) Ztil-1,8-dithia-3-aza-cyclo 4, 53 dec-2-en-4-carboxylate. 57.2 g (0.25 mol) ethyl-Forgamido-2, 3,5,6-tetrahydro-4H-thiopyran-L L-adatate and 15 g (0.0675 mol) of phosphorus pentasulfide (form P 5) are suspended in 600 ml of anhydrous benzene. After boiling under reflux with stirring, the benzene solution was decane-tated from the insoluble part and evaporated to dryness-C to obtain a residue of 55 g. The residue was distilled under a pressure of 5-10 mm Hg. At 154-162 seconds, about 27.2 g of ethyl-1,8-dithia-3-aza-spiro | 4, 5 dec-2-ene.-4-carboxylate is distilled; the yield is 45%. The product is used in raw form for subsequent synthesis. 2 c) o1-Amino-4-mercapto-2,3,5,6-tetrahydro-4H-thiopyran-4-yccyclic acid (formula (lU): XS), 2742 g (0.11 mol) ethyl-1, 8-dithia-3-aza-spiro 4, 5} dec-2-en-4-carboxylate is dissolved in 865 ml of 6N. hydrochloric acid and refluxed for 5 hours. Then the solution is concentrated in vacuo in a rotary evaporator. The residue is treated several times with anhydrous benzene to remove residual traces of water, then triturated in ether and filtered. Thus, 27 g (or about 100%) of C1-amino-4-mercapto-2, 3,5,6-tetrahydro-4H-thiopyran-4-acetic acid hydrochloride are obtained. The product gives only QQ ONE-SPECK with thin-layer chromatography on silica (eluent: butanol, acetic acid, 4: 1: 1), RI 0.45, mp 193-197 ° C.
Example I. Preparation of tert-butyl-4-carboxy-o {.-Phthalimido-1,8-dithia (or 8-oxa-1-thia) -3-aa-spiro-p, Sj two-can-2-acetates of formula (IV ) and the corresponding benzene esters of formula (V).
1a) tert-Butyl-4-carboxy- "1-phthalimido-8-oxa-1-thia-3-aza-spiro 4, Sjdecan-2-acetate (formula (IV): X 0).
In a flask at room temperature, 28.9 g (0.1 mol) of tert-butyl 2-formyl-2-phthalimidoacetate, 22.75 g (0.1 mol) of oir-amino-4-mercapto-2,3 , 5, b-tetrahydro-4H-pyran-4-acetic acid, 12.3 g of sodium acetate, 430 ml of ethanol and 350 ml of water are stirred under a nitrogen atmosphere and gradually heated until a solution is formed (b5-70c). Maintain agitation for the entire time during which the reaction is. on the mixture gradually takes room temperature. The mixture is left to stand overnight, then a white precipitate is filtered off (44 g). This product contains a mixture of o (g, f) - and - diastereoisomers.
c -Isomer, solely compatible with the stereochemistry of natural penicillin, can be exacted by crystallization of the mixture in pyridine; Epimerization to thermodynamic equilibrium of mother solutions in pyridine
while enriching them with the o.-isomer, which can again be extracted by crystallization. The same process is repeated until the o1 isomer cannot be isolated by crystallization. Thus, 21.5 g of the t-butyl-4-carboxy-o-phthalimido-8-oxa-1-thia-3-aza-spiro 4, 5 decane-2-acetate is obtained from the α-isomer, the yield being 46 6% m.p. 199200 ° C (decomposition).
Analysis for 2 O at S / (mol. Wt. 462 Calculated,%: C 57.14; H 5.63;
N 6.06.
Found,%: C 57.10; H 5.70; N 6.10.
1 b) tert-Butyl-4-benzyloxycarbonyl-1-phthalimido-8-oxa-1-thia-3-aza-spiro t4, 5} decane-2-acetate (formula (): X O),
To a solution of 4.62 g (0.01 mol) of the oL-isomer of tert-butyl-4-carboxy-α-phthalimido-8-okra-1-thia-3-aza-spiro 4, 5 decane-2-acetate in 50 ml 3.3 g (0.019 mol) of benzyl bromide was immediately added to dimethylformamide, then 1.32 (0.013 mol) of triethylamine in 5 ml of dimethylformamide was added over 20 minutes. Maintain with mild agitation overnight at room temperature. The clear solution thus obtained is poured into a mixture of ice-water, which is extracted with benzene. After washing the organic phase with 5% sodium bicarbonate solution, then with water, it is evaporated to dryness. The residue obtained is recrystallized from ether to give 4.7 g (0.00085 mol) of tert-butyl-4-benzyloxycarbonyl-c-phthalimido-8-oxa-1-thia-3-aza-spiro 4, 5 decane-2-acetate (yield 85.2%) m.p. 168-169 seconds (Another experience with quantities, ten times higher than indicated, gives a yield of 93.6%).
Analysis dL (mol. Weight. 55
Calculated,%: C 63.04; H 5.79; N 5.07
Found,%: C 63.05; H 5.80; N 5.03.
2a) tert-Rutile-4-carboxy-c -Palimido-1, 8-dithia-3-aza-spiro 4, 5 decan-2-acetate (formula (W): X S}.
To a mixture of 178 g (0.616 mol) tert-butyl-2-Lormyl-2- (stalimidoacetate and 150 g (0.616 mol) of o-amino-4-mercapto-2,3,5,6-tetrahydro-4H-thiopyran-hydrochloride 4-acetic acid in 2.11 liters of ordinary ethanol is added immediately at room temperature a solution of 75.7 g (0.924 mol) of sodium acetate in 2.11 liters of water.
Heat at a temperature of about 55-60 seconds to complete the dissolution (for a time of about 5 minutes). Leave the mixture to stand at room temperature and stir overnight. The precipitate formed (185 g) was filtered off and the mother liquor was concentrated to complete evaporation of the ethanol, then the residue was extracted with chloroform. The extract is dried over sodium sulfate and then evaporated under vacuum to obtain a residue weighing 200 g. The precipitate and the residue, which contain a mixture of PG and 3 diastereoisomers, are combined and epimerized to form the isomer that is only compatible with the stereochemistry of natural penicillin. The method is the same as that described above in paragraph 1 a). Thus, 159.6 g of the isomer of tert-butyl-4-carboxy-o (gphthalmido-1, 8-dithia-3-aza-spiro 4.5 decan-2-acetaTa, mp. 210-212 0 are obtained .
Analysis for 52 (478)
Calculated,%: C e5,2; H 5.44; N 5.85.
Found,%: C 56.1; H 5.50; . N 5.80.
2 b) tert-Butyl-4-benzyloxycarb6-n- (-phthalimido-1,8-dithia-3-aza-spiro 4, 5 decan-2-acetate (formula (.): X S).
To a solution of 3.26 g (0.019 mol) of benzyl bromide and 4.8 g (0.01 mol) of the o6-isomer of tert-butyl-4-carboxy-β-phthalimido-1, 8-dithia-3-aza-spiro 4, 5 decan-2-acetate in 50 ml of dimethylformamide is added dropwise and under a temperature of about 25 ° C using an ice bath, 1.34 g (0.013 mol) of triethylamine is added. Stir overnight at room temperature. Thus, the resulting clear solution was poured into a mixture of ice-water and extracted with benzene. Genol Laza is separated, then washed successively with aqueous 5% sodium biconate solution and water. Dry, concentrate to dryness and recrystallize the crude product from a mixture of benzene and hexane. Thus, the resulting tert-butyl-4-benzyloxycarbonyl-in-phthalimido-1,8-dithia-3-aza-spiro 4, 5 decan-2-acetate (4.2 g or 74% mp. 197-198 ° C. Analysis for (mol. Weight. 568) Calculated: C 61.3; H 5.64; N 4.93 C 62.0; H 5.62; Found,% N 4.88. Example 1 ( 1. Preparation of tert-butyl-α-amino-4-benzyloxycarbonyl -1,8-dithia (or B-oxa-1-thia) -3-aza-spiro 4, 5 dskan-2-acetates of the formula ClV) and corresponding with {.-amino-4-benzyloxycarbonyl-1,8-dithia (or 8-oxa-1-thia) -3-aza-spiro 4, 5 decane-2-acetic acids r formula (1 (). 1 a) tert -Butyl-o6-amino-4-.benzyloxycarbonyl-8-oxa-1-thia-3-azaspiro 4, 5 decan-2-acetate (forms la (VI): X O). To a suspension of 4.4 g (0.008 mol) tert-butyl-4-benzyloxy-carbonyl-naphthalimido-8-oxa-1-thia-3-aza-spiro 4, 5 decane 2 ml of anhydrous dimethylformamide in 4 ml of anhydrous dimethyl lormamide solution containing 2 mol per 1 liter of hydrazine hydrate (or 0.0088 mol) is added dropwise and under nitrogen atmosphere. The temperature is allowed to rise gradually to room temperature (about 30 min). To the thus obtained clear yellow solution is added dropwise 7.7 gll 1.18 N. hydrochloric acid. The reaction mixture becomes cloudy, then crystallizes in bulk. After 1 hour, the precipitate was filtered, redissolved in chloroform, which contained a little methanol, filtered, dried and evaporated to dryness. The residue obtained is triturated with hexane and 3.3 g (0.0072 mol) of tert-butyl-o6-amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-aza-spiro 4, 5 decane are thus obtained. 2-acetate (yield 90%), mp. 1556157 C. 1 b) Amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-azaspiro p 5 decane-2-acetic acid (Formula (VII): X 0). Bleeding dry gaseous hydrogen chloride into suspension 6 by sparging. , 6 g (0.0144 mole) of tert-butyl-e-amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-aza-spiro 4, 5} decane-2-acetate hydrochloride in 150 ml: anhydrous nitromethane at 0 ° C. After 15 minutes, the product is mostly dissolved, and sparging of hydrogen chloride is continued for 1 hour. The insoluble part is filtered off and then the solution of nitromethane is degassed under a pressure of 20 mm Hg. in a rotary evaporator at room temperature to remove the maximum amount of gaseous hydrogen chloride. 700 ml of anhydrous ether are then added and cooled to -5 ° C over 4 hours. In this way, a precipitate is obtained which is. filtered, washed with ether and dried under vacuum to obtain finally 4.2 g (0.0104 mol) of c6-amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-aza-spiro 4, 5 decane hydrochloride 2-acetic acid (yield 72.5%), mp 152-153 ° C. 2 a) tert-Butyl-oC-amino-4-benzyloxycarbonyl-1, 8-dithia-3-aza-spiro 4, 51 decan-2-acetate (formula (VI): X S). To a suspension of 156.3 g (0.275 mol) of tert-butyl-4-benzyloxycarbonyl-c6-phthalimido-1, 8-dithia-3-aza-spiro 4, 5} decane-2-acetate in 170 ml of anhydrous dimethylformamide are added ( at) 151.5 ml of dimethylformamide solution containing 2 mol in 1 liter of hydrazine hydrate (or 0.3025 mol). The addition is carried out for 1.25 hours and is accompanied by complete dissolution of the product. The temperature is allowed to rise to room temperature over 1 hour and 309 ml of 1N are added dropwise at 20-25 ° C. hydrochloric acid. The phthalhydrazide precipitate formed is filtered off and the mother liquor is evaporated to dryness. Ost: OK dissolved in methanol and precipitated with ether. Thus, 119.1 g of tert-butyl-ci-amino-4-benzyloxycarbonyl-1, 8-dithia-3-aza-spiro 4,5 decane-2-acetate hydrochloride are obtained (yield 91.5%), mp. .178-181 ° C. Analysis for CH. N 0. E (mol. Weight .475). ° C 53.00; -N Calculated,%; N 5.90. S 52.98; H Found,%: N 5,85. 2 b) O1., - Amino-4-benzyloxycarbonyl-1, 8-dithia-3-aza-spiro (4, B decan-2-acetic acid (Formula (VII): XS). Dry hydrogen chloride gas is bubbled by sparging in suspension of 39.1 g (0.0824 mol) of tert-butyl-оС-amino-4-benzyl-xycarbonyl-1 hydrochloride, in-dithia-3-aza-spiro 4, 5 decan-2-acetate 1z 1, 3 l anhydrous nitromethane at temperatures from 0 to for 1 and 1, 5 hours. After filtration, 21.1 g of hydrochloride is obtained with l.-amino-4-benzyl oxycarbonyl, 8-dithia-3-aza-spiro 4, 5 decane -2-acetic acid (yield about 801), mp. 170-173 C (decomposition).
Example IV Getting benzyl - b-phenylmethyl fino-2, 3, 5 | b-tetrahydro-spiro-penam-2, 4HJ (yew-3 carboxylates of the formula (IV). 1) Benzyl-b-triphenylmethylamino-2, 3, 5 6-tetrahydro-spiro-pen 2, 4-4H pyran-3-carboxylate (formula (W: X - 0),.
In 750 ml of anhydrous methylene chloride, 43 g (0.107 mol) of o1-amino-4-benzyloxycarbonyl 8-oxa-1-thia-3-aza-spiro 4, 5 decan-2-acetic acid hydrochloride and 100 g (0, 36 mol) triphenylmethyl chloride. Cool to -20 ° C. 100 g (1 mol) of triethylamine in 200 ml of anhydrous methylene chloride are added over 1 and 0.5 hours. The reaction mixture was left to stand overnight at. It is then poured into a mixture of ice water, which is acidified to dilute phosphoric acid. The aqueous phase is extracted with chloroform, the extract is then washed with water. After drying. and evaporation gives 160 g of an amorphous product, which is redissolved in 800 ml of dry nitromethane. this new solution is added. 55P. (0.437 mol) of diisopropylcarbodiimide (DKI) in 100 ml of methylene chloride. A precipitate of N, N-diisopropyl urea gradually appears. Leave the reaction mixture to stand for overnight. The precipitate is filtered off and the solvent is evaporated in vacuo to yield 147 g of solid. First crystallisation from a mixture of benzene and hexane, followed by a mixture of ether and hexane, finally gives 46.5 g of benzyl-b-triphenylmethyl MINO-2, 3, 56 tetrahydro pyrpotpvnam-2, 4-4n pyran-3-carboxylate, yield 73.6 % m.p. 144-145p.
Ayalysis for CjjHjj NjO S. (mol. Weight 590 Calculated,%: C 73.22; H 5.76;
N 4.74. 1%,% C 71.30; H 6, 01;
N 4.80.
2) Benzyl-b-triphenylmethylamino-2, 3, 5, b tetryhydro-spiro fnenaM-2, 4-4n thiopyran-3-carboxylate (Formula (IK): X S).
To a suspension of 1.4 g (0.0033 mol) of hydrochloride (amino-4-benzyloxycarbonyl-1, 8-dithia-3-aza-spiro J4, 5j decane-2-acetic acid in 30 ml of anhydrous dichloromethane is added with 3.42 g (0.012 mol of triphenylmethyl chloride then
- add a solution of 3.25 g (0.0322 mol) of triethylamine in 30 ml of dichloromethane. After standing overnight in the refrigerator, the solution is poured into 100 ml of ice-water and acidified to phosphoric acid.
The organic phase is decantirucized, washed with water, dried over sodium sulfate and evaporated to give a crude residue weighing 4.7 g. This residue is dissolved in 30 ml of nitromethane and 1.68 g (0.0134 mol) DKI is added at room temperature. Stir during the night. After filtering off the insoluble part, the filtrate is evaporated to dryness and the residue is chromatographed on silica. 0.8 g of benzyl-6-triphenylmethylamino-2, 3, 5, 6-tetrahydro-spiro-pen-2,4-4H thiopyran-J-3-carboxylate is obtained, which after recrystallization from ether / hexane melts at 147-148 ° C . Analysis for C N m O 5 „(mol. Weight 606). Calculated,%: C 71.25; H 5.61; N 4.62.
Found,%: C 71.18; H 5.62; N 4.59.
Example V. Preparation of p-toluenesulfonates of benzyl-b-amino-2, 3/5, 6-tetrahydro-spiro | foams-2, 4- pHj (thio) pyran} -3-carboxylates of formula (K) -.
1) benzyl-b-amino 2, 31 5 6-tetrahydro-spiro fnam-2, 4-4n pyran-3-carboxylate p-toluenesulfonate
(formula (.Y): X 0).
To suspension 17, .7 g (0.03 mol) benzyl-6-triphenylmethyl-amino-2, 3, 5, -tetrahydro-spiro | to foams 2, 4- | 4n1pyranZ-3-carboxylate in 100 ml of acetone are added immediately (in one portion) with stirring and at room temperature 5.7 g (0.3 mol) of p-toluenesulfonic acid monohydrate. After the fast dissolution of triphenylmethyl compound The p-toluenesulfonate is gradually precipitated for 3 hours. Then 300 ml of anhydrous ether is added, stirred vigorously and filtered. After rinsing the precipitate with ether and drying, 13.6 g of benzyl-b-amino-2, 3, 5, b-tetrahydro-spiro | foam-2, 4-5n} pyran | -3-carboxylate p-toluenesulfonate are obtained.
(yield 87.2%), mp.1bZ-164 s. Analysis for Cx-, H., .1, Ox5-C, HsO, S
(mol. weight 520) .- - t b
Calculated,%: C 55.38; H 5.38;
N, 5.38; Found: C, 55.45; H 5.45;
N 5.36.
2) p-Toluensulfonate-benzyl-6-amino-2, 3,5,6-tetrahydro-spiro {prices-2, 4- | 4n thiopyran 3-3-carboxylate
(formula (E: X S).

权利要求:
Claims (1)
[1]
1. US patent No. 3159617, CL, 260-239.1, published 1964.

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SU1189351A3|1985-10-30|Method of producing 5&#39;-s-|-peptidergotalkaloid or its additive salts with acids

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Vida et al.1968|Investigation in the 3, 4-dihydrocoumarin melilotic acid series

同族专利:

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公开号 | 公开日

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YU8578A|1983-04-30|

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NO780110L|1978-07-19|

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PL204066A1|1979-04-09|

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FI780088A|1978-07-19|

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US4137236A|1979-01-30|

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AU512338B2|1980-10-02|

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PT67537A|1978-02-01|

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AU3249578A|1979-07-26|

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DD135284A5|1979-04-25|

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HU173788B|1979-08-28|

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LU78885A1|1978-09-18|

---

PT67537B|1979-06-15|

---

FR2377408B1|1980-04-18|

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BE862972A|1978-07-17|

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SE7800367L|1978-07-19|

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IL53825D0|1978-04-30|

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IT1103123B|1985-10-14|

---

FR2377408A1|1978-08-11|

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CH634324A5|1983-01-31|

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ES466053A1|1978-10-01|

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NL7800397A|1978-07-20|

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JPS5390290A|1978-08-08|

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CA1101411A|1981-05-19|

---

DK15678A|1978-07-19|

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ATA32078A|1979-08-15|

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IT7847658D0|1978-01-17|

---

IL53825A|1981-01-30|

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GB1567561A|1980-05-14|

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ZA78304B|1978-12-27|

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AT355721B|1980-03-25|

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DE2801849A1|1978-07-20|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US3047467A|1957-08-02|1962-07-31|Beecham Res Lab|Process for the preparation of penicillins|

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US3129217A|1959-08-19|1964-04-14|Beecham Group Ltd|Derivatives of 6- penicillanic acid|

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US3134767A|1960-04-20|1964-05-26|Beecham Group Ltd|Synthetic penicillin|

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US3210337A|1962-09-21|1965-10-05|Smith Kline French Lab|6-- and 6--penicillanic acid derivatives|GB2052497B|1979-06-25|1983-06-29|Ucb Sa|6 - amino - spiro -- 3 - carboxylic acid derivatives|

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GB2052496B|1979-06-25|1983-06-29|Ucb Sa|6 - amino - spiro -- 3 - carboxylic acid derivatives|

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ES2147162B1|1999-01-27|2001-03-16|Lacer Sa|"S-NITROSOTIOLS AS AGENTS FOR THE TREATMENT OF CIRCULATORY DYSFUNCTIONS".|

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EP1939179A1|2006-12-28|2008-07-02|Lacer, S.A.|Stable S-nitrosothiols, method of synthesis and use|

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EP2601940A1|2011-12-05|2013-06-12|Lacer, S.A.|-aminoacetic acid derivatives, pharmaceutical compositions and uses thereof|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB1905/77A|GB1567561A|1977-01-18|1977-01-18|Amino-spirocycloalkane-penam) - carboxylic acids|

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