JPS6310155B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an ethynooxazine compound having the following general formula and a method for producing the same. Although the compounds of the present invention have antiallergic activity on their own, they are useful as intermediates in the synthesis of thieno[2,3d]pyrimidines, which are very useful antiallergic agents, having the formula: . The present invention also provides thienooxamates having the following formula (which, like the compounds of the present invention, have antiallergic activity by themselves;
It is also useful as an intermediate in the synthesis of compounds of the formula). These substances are useful in the treatment of allergic diseases characterized by episodes of acute attack induced by inhalation or ingestion of allergens, and in particular asthma, hay fever, as well as food allergies. These compounds have the advantage for long-term prophylactic use of virtually no other pharmacological effects and low toxicity. Preferred members are orally active. In the formula, the symbol R ² refers to a carboxylic acid substituent or a lower alkyl ester thereof or a non-toxic pharmacologically inert metal salt. It is also R ²
is a vinyl substituent of CH=CHCO ₂ R ³ (R ³ is hydrogen, lower alkyl having 1 to 8 carbon atoms, or a non-toxic pharmacologically inert metal cation) carboxylic acids, esters, and salts. The term "non-toxic pharmacologically inert cation" means that the cation has no adverse or noxious pharmacological effect on the host at the doses required for administration of one of the salts containing the cation. It means that. Preferred metal cations are the alkali metals sodium and potassium, but other non-toxic pharmacologically inert cations such as calcium, magnesium, aluminum, zinc, and barium are also suitable. R ² may also be a methylol group or a formate, or a lower alkyl ester thereof. R ² is also carboxaldehyde, 5-
Tetrazolyl, or N-(tetrazole-5-
yl)carbamyl group. In summary,
R ² is a group having one of the following formulas in which R ³ has the meaning indicated above and R is lower alkyl having 1 to 8 carbon atoms. −CO ₂ R ³ , −CH=CHCO ₂ R ³ , −CH ₂ OH,

【formula】 【formula】

【formula】

【formula】

[Formula] In the formula, R ³ is the same as above, R ⁵ and
R ⁶ is hydrogen, lower alkyl with 1 to 8 carbon atoms, lower alkenyl with 3 to 6 carbon atoms, lower alkoxy with 1 to 6 carbon atoms, hydroxy, nitro, amino, chlorine, bromine ,
Iodine and halo containing fluorine, phenyl, 2
Cycloalkene rings or 5 to 7 cyclic rings which may be alkanoyl having ~6 carbon atoms or fused to each other to form a thiophene ring and having a total of 5 to 7 cyclic carbon atoms R-substituted cycloalkene having a carbon atom (wherein R is
with the same meaning as above). In the formula, R ³ is lower alkyl having 1 to 8 carbon atoms and A is -
is a covalent bond linking CO ₂ R ³ to the ring, or −
It is a vinyl group, -CH=CH-, which connects CO ₂ R ³ to the ring. L is hydrogen or lower alkyl having 1 to 8 carbon atoms; B is hydrogen, lower alkyl having 1 to 8 carbon atoms, or alkanoyl having 2 to 6 carbon atoms. In the formula, the symbol R ³ has the same meaning as in the formula, A has the same meaning as in the formula, and L and B are hydrogen, 1 to
It may be lower alkyl having 8 carbon atoms, phenyl, alkanoyl having 3 to 6 carbon atoms, or cyclo fused to a thiophene ring and having 5 to 7 cyclic ring carbon atoms. It may form an alkene ring or an R-substituted cycloalkene having 5 to 7 cyclic ring carbon atoms, in which R has the same meaning as above. Compounds of formulas and inhibit granule reduction in sensitized mast cells. Immediate sensitivities such as asthma, hay fever, allergic rhinitis, urticaria, and food allergies are caused by immunoglobulin E (sometimes called reagin antibodies) reacting with antigens on the cell membrane of mast cells, ultimately leading to bradykinin and histamine. , serotonin, or slow reactant A (SRS-A)
It is thought to be mediated by initiating reactions within mast cells that release mediating agents such as Mediators cause changes in end organs such as the respiratory tract, blood vessels, skin, and mucous membranes, resulting in symptoms of allergic attack. This substance is believed to prevent the release of mediators and thereby prevent allergic attacks. However, they are useful in the prophylactic treatment of humans with hypersensitivity of the type mentioned above, preventing acute allergic attacks such as asthma attacks. Preferred compounds are orally active;
It is particularly distinguished by the fact that it has extremely low toxicity and is virtually devoid of other types of pharmacological action, including antihistamine action. Therefore, they are not primarily of value in the treatment of acute allergic reactions, but are used prophylactically by hypersensitive humans to prevent the development of allergic reactions when exposed to allergens for hypersensitive conditions. It is especially valuable to The compounds of the present invention are 2-amino-thiophene-3-carboxyamides or 2-amino-thiophene-3-carboxylic acids of the formula shown in the following scheme, where Z is -OH or _-NH2 . Manufactured from. The compound of formula was previously described by Gewald et al., Chem.
Berichte 98 , 3571 (1965), and the same magazine 99 , 94
(1966). Compounds of the novel formula for use in preparing the compounds of the present invention and thienooxamates of the formula can be prepared by the obvious application of the method of Gewald et al. In the formula, symbols L and B are hydrogen, 1 to
lower alkyl having 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, 2
independently selected from the group consisting of alkanoyl having ~6 carbon atoms, or cycloalkenes having a total of 5 to 7 cyclic ring carbon atoms;
R-substituted cycloalkenes having ~7 cyclic ring carbon atoms, where R is a lower alkyl group having 1 to 8 carbon atoms. The intermediate 2-aminothiophene-3-carboxyamide or 2-aminothiophene-3-carboxylic acid, when reacted with an acylating agent of the formula:
This yields a thiophene derivative of the formula or an oxazine derivative of the formula. R ³ in the formula is H, 1-8
lower alkyl having 4 carbon atoms, or M
where M is a non-toxic pharmacologically usable metal cation. The acylating agent of the formula is
Oxalic acid or 1,4-but-2-enedionic acid derivatives. That is, A in the above formula is either a covalent bond directly connected to the indicated group or a vinyl group (-CH
=CH−). X is chloro, bromo, or lower alkoxy having 1 to 8 carbon atoms, preferably an ethoxy group when working with the starting material of formula when Z is -OH, and When working on the starting material of the formula where Z is _-NH2 , it is chloro. In the case of the preparation of substances of the formula and when A is a vinyl group, starting materials of the formula when Z is -OH and 1,4 as acylating agent are used.
It is preferred to use lower alkyl diesters or lower alkyl monoesters of -but-2-enedionic acid. For the preparation of compounds of the formula when R ³ is lower alkyl, the 2-aminothiophene-3-carboxamide of the formula when Z is -NH ₂ is combined with pyridine or an acylating reagent of the formula The treatment is carried out in acetonitrile, benzene, or other aprotic solvents such as diisopropyl ether containing at least one molecule of pyridine per molecule of pyridine (which is preferably ethyloxalyl chloride). The acylating agent is carefully mixed with the solution of the intermediate at room temperature by adding the acylating agent in portions to the carboxyacid intermediate while the reaction vessel is cooled, or vice versa. It is undesirable to pre-cool the reactants before starting the reaction. After the reaction has stopped, the mixture is usually stirred at room temperature for a certain period of time to ensure completion of the reaction. The intermediate is then recovered by pouring the reaction mixture into an aprotic solvent such as isopropanol and collecting the intermediate of formula precipitated by filtration. The thienyl intermediate of formula is a novel compound with antiallergic activity. When R ³ is lower alkyl, thienyl compounds of the formula
By heating in the molten state at a temperature in the range of 265° C., preferably the latter, it is converted into the thienopyrimidines of the invention having the formula. The progress of this reaction can be estimated by the foaming caused by the evaporation of water, which is formed as a by-product during the process. In each particular case, the optimal temperature at which the pyrolysis is carried out is determined by looking at the melt when heated in a test tube.
It can be estimated by determining the temperature at which vigorous evolution of water vapor occurs. Oxazines of the formula are novel compounds with antiallergic activity and are the object compounds of the present invention. Oxazines of the formula can be prepared by combining the 2-aminothiophene-3-carboxylic acid of the formula with the acylating agent of the formula when Z is -OH under exactly the same conditions as described above for the preparation of the intermediates of the formula. Manufactured by reaction. In this case, it is preferable to use a bimolecular portion of the acylating agent. If a single molecule portion of the acylating agent is used, a mixture containing the intermediate 2-carbamylthiophene-3-carboxylic acid, which is structurally similar to thiophenecarboxamides, may be obtained. This 2-
Carbamylthiophene-3-carboxylic acid can be further cyclized to give the oxazine of the formula by treatment with one molecule of the acylating agent of the formula or other cyclodehydrating agent such as _SOCl2 . can. Although such stepwise operation is possible, there are no advantages. In the first case, it is preferred to use a bimolecular portion of the acylating agent to obtain the pure oxazine as the reaction product. Oxazines of the formula are converted to thienopyrimidines of the formula by reaction with an amine of the formula RNH ₂ where R is as defined above or an ammonium salt that is soluble in the reaction medium. As reaction medium a protic solvent is used, preferably a lower alkanol such as ethanol or isopropanol. The reaction is carried out at reflux temperature and upon cooling the product usually crystallizes out of the reaction mixture. Suitable ammonium salts are: ammonium fluoride, ammonium fluorosulfonate, ammonium fluorosilicate, ammonium acetate, ammonium iodide, ammonium nitrate, ammonium hypophosphite, and ammonium valerate. It is preferred to use ammonium acetate, optionally in the presence of about 1 chemical equivalent of acetic acid, to form a buffer system to minimize the formation of amide from the 2-carboxyester group. Compounds of formula and when R ³ is H or M are prepared by hydrolysis and neutralization of the corresponding ester (R ³ is lower alkyl) as exemplified by Steps 3 and 32. Compounds of formula (when R ³ is H or M) are sometimes obtained from compounds of formula as by-products in the preparation of compounds of formula. They can also be obtained by hydrolysis and neutralization of compounds of formula (when R ³ is lower alkyl). Compounds of formula include R ² is CO ₂ R ³ or CH=
CHCO ₂ R ³ constitutes a subgroup of compounds of formula where R ⁵ and R ⁶ of formula partially correspond to L and B of formula, respectively. They are compounds of other formulas (R ⁵ and R ⁶ are hydroxy, alkoxy, nitro, amino, or halogen;
or R ² is CH ₂ OH,

【formula】

[Formula] 5-tetrazolyl, N-(tetrazol-5-yl)carbamyl, or CHO
serves as an intermediate for Conventional aromatic substitution reactions that can be used for substituted thiophenes can be used for compounds of the formula when one of L and B is hydrogen to introduce the R ⁵ and R ⁶ groups. For example, treating a compound of the formula where R ⁵ or R ⁶ is a nitro group with a solution of nitric acid in trichloroacetic acid and the corresponding compound where R ⁵ or R ⁶ is a hydrogen atom, respectively, in trichloroacetic acid and acetic anhydride. It is produced by its nitration. The reaction is carried out by carefully adding the nitration solution to a solution of the reactants at a temperature of about -15°C. Any convenient temperature from about 0 to -20°C may be used. The nitrothiophene is recovered from the reaction mixture by quenching with water and filtering the resulting precipitate. Then R ⁵ and R ⁶
The resulting compound of the formula in which one of the is a nitro group is treated by conventional hydrogenation methods such as atmospheric pressure hydrogenation over charcoal-supported palladium using a solvent for contacting the hydrogen with the catalyst and reactants. It can be converted into an amino compound. Compounds of the formula when one of R ⁵ and R ⁶ is an amino group can be converted by diazotization and substitution of the diazonium group with a halogen according to known reaction conditions. For example, the amino compound can be dissolved in fluoboric acid and treated with sodium nitrite at ice temperature to yield the corresponding diazonium fluoborate. When the latter is treated with cuprous chloride, bromide or iodide, R ⁵ or R ⁶ becomes chloro,
Compounds of the corresponding formula which are bromo or iodo are obtained. It can be converted to the fluoroboric acid diazonium salt or the corresponding fluoro derivative in which one of R ⁵ and R ⁶ is a fluoro group by heating just above the melting point (standard Schaiman reaction conditions). These iodo compounds can also be prepared by mercurylation of compounds of the formula when L or B is hydrogen by reaction with mercuric acetate and treatment of this mercury compound with iodine and potassium iodide. Compounds of the formula when one of R ⁵ and R ⁶ is hydroxy are prepared by hydrolysis of the intermediate diazonium fluoborate salt, preferably with potassium trichloroacetate in trichloroacetic acid and then treatment of the reaction product with water. and then manufactured. The hydroxy compound is converted to an alkoxy compound under conventional alkylation conditions such as reaction with a diazoalkane, alkyl iodide, or dialkyl sulfate. Compounds of the formula when R ² is a hydroxymethyl group or an ester thereof can be prepared by reduction using a borohydride derivative such as lithium borohydride or sodium iodohydride when R ² is CO ₂ R ² It is produced from a compound of the formula. Again, conventional conditions consisting of contacting the reactants in a reaction-inert solvent are used. When R ² is carboxaldehyde, compounds of formula are prepared from the corresponding hydroxymethyl compound by oxidation, for example using manganese dioxide or dimethyl sulfoxide in dicyclohexylcarbodiimide under known conditions. In summary, compounds of formula are prepared using a process consisting of reacting a compound of formula with an acylating agent of formula to obtain a compound of formula or formula. The compound of formula is then converted to a compound of formula by heating in the molten state for 5 to 15 minutes at a temperature in the range of 200 to 265°C. A compound of formula can be treated in solution with an amine of formula R ³ NH ₂ or a soluble ammonium salt using a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium at reflux temperature. is converted to a compound of formula by The compounds of the formula thus prepared correspond to the subgroup defined by the above formula. If desired, compounds of the formula in which one of L or B is hydrogen can be prepared by nitration under conditions which can be used for the preparation of nitro-substituted thiophene compounds by direct nitration of the corresponding unsubstituted thiophene compounds. It can be converted to the corresponding nitro compound. The resulting compound of formula where R ⁵ or R ⁶ is nitro is then converted by catalytic hydrogenation of the nitro group to obtain a compound of formula where R ⁵ or R ⁶ is amino. The latter can then be diazotized to form the corresponding diazonium salt, such as fluoborates, which can then be reacted with cuprous halides such that R ⁵ or R ⁶ is Cl, Br, Alternatively, a compound of the formula can be obtained, or a diazonium salt can be hydrolyzed to obtain a compound of the formula in which one of R ⁵ or R ⁶ is hydroxyl.
The fluoroboric acid diazonium salt can also be heated to its decomposition point to obtain compounds of formula where R ⁵ or R ⁶ is fluoro. Hydroxy derivatives are
Etherification under conditions customary for the formation of aromatic ethers can give compounds of the formula in which R ⁵ or R ⁶ is a lower alkoxy group having 1 to 6 carbon atoms. Furthermore, compounds of the formula when R ⁵ or R ⁶ are hydrogen can be converted into mercuric acetate derivatives by known methods and thus by treatment of this mercuric acetate derivative with I ₂ and KI to form R ⁵ or It can be converted to the corresponding compound where R ⁶ is iodo. This is illustrated in the following flowchart.

[Table] ↓
formula
R ⁵ or R ⁶ -OR
Any compound of the above formula in which A ^is a covalent bond linking the CO ₂ R group to the ^ring can be prepared by R It can be converted to compounds of formula where ² is 5-tetrazoyl or N-(tetrazol-5-yl)carbamoyl. EXAMPLES AND REFERENCE EXAMPLES The present invention and related matters will be explained in more detail by the following operations 1 to 100. Steps 4, 20-26, 59, 61, 72, 74, and 84-
Example 87 shows the preparation of the target compound of the formula of the present invention. Steps 2, 3, 5, 13~19, 27~58, 60, 62~
71, 73, 75, 76, 78-82, and 88-100 are reference examples showing the production and use of the final compounds of the formula,
The remaining operations are illustrative examples illustrating the preparation of compounds of formula (which are relevant to the present invention in that they are intermediates of compounds of formula). The nuclear magnetic resonance spectral characteristics reported in these operations are chemical shifts (δ) expressed as parts per million (ppm) relative to tetramethylsilane as a reference standard (D ₂ O is shown as the solvent). , except when HDO lines at 4.70 ppm were used). The relative areas reported for the various shifts correspond to the number of hydrogen atoms in the substituents involved, and the nature of the shifts with respect to multiplicity is broad singlet (bs), singlet (s), and multiplet. (m), doublet (d), triplet (t), or quartet (q), and the coupling constant (J
values) are reported where appropriate. The configuration is
NMR (solvent): δ (multiple precision, relative area, J value). Abbreviations for solvents are:
CDCl ₃ (deuterochloroform), DMSO−d ₆
(deuterodimethyl sulfoxide), CF ₃ CO ₂ H
(trifluoroacetic acid), and D ₂ O (deuterium oxide). Infrared spectrum data displays the wavelength of maximum absorption (in cm ^-1 units). This indicates the properties of the functional group. Infrared spectra were measured on calicum bromide pellets containing 0.5% of the experimental substance. Operation 1 N-[(3-aminocarbonyl)-4,5,6,
Ethyl 7-tetrahydrobenzo[b]thien-2-yl]oxamate 2-amino-4,5,6, in 200 ml of dry pyridine
7-tetrahydrobenzo[b]thiophene-3-
A suspension of 72.92 grams (0.41 mol) of carboxamide is stirred at 25° C. during the addition (dropwise) of 55.25 grams (0.41 mol) of oxalylethyl chloride dissolved in 50 ml of dry acetonitrile. Cool the reaction vessel by immersing it in ice and place the flask in the ice bath for 30 minutes after the addition is complete. The reaction vessel should not be pre-cooled before beginning the addition of oxalylethyl chloride. After the reaction is complete and the ice bath is removed,
Add 150 ml of acetonitrile to the reaction mixture to facilitate stirring and keep the mixture stirring overnight.
Then pour into isopropanol and collect the precipitated product on a filter. Air dry the product to obtain 58.80 g (49%) of a yellow solid, mp 204.0-205.0°C. A sample of this is recrystallized from isopropanol and shows the same melting point. NMR (DMSO-d ₆ ): 12.88 (s, 1), 7.30 (s,
2), 4.37 (q, 2), 2.70 (m, 4), 1.75 (m,
4), 1.37 (t, 3). Infrared (KBr): 1635, 1680, and 1720 cm ^-1 . Analysis - Experimental values: C, 52.68; H, 5.34; N, 9.42. Operation 2 3,4,5,6,7,8-hexahydro-4-
Ethyl oxobenzothieno[2,3-d]pyrimidine-2-carboxylate 8.89 g (0.030 mol) of the product from Step 1 was added to 261
Melt in a round bottom flask with a magnetic stirring bar immersed in an oil bath at .degree. The melt is heated with stirring until the evolution of water, indicated by foaming of the reaction mixture, is no longer evident. Approximately 5-15 minutes is sufficient. The melt is then dissolved in dimethylformamide and the hot solution is poured into a larger volume of methanol than the reaction mixture. The precipitate was collected and recrystallized from a mixture of dimethylformamide and methanol to give 4.92 g of the desired product as yellow needles, mp 207.0-209.0°C.
(48%). NMR ( _CDCl3 ): 10.35 (bs, 1), 4.50 (q, 2, J
=7.0Hz), 2.90 (m, 4), 1.88 (m, 4), 1.47
(t, 3). Infrared (KBr): 3110, 3030, 2940, 1740, 1670,
1570, 1490, 1465, 1370, 1365, 1300, 1187,
and 1035cm ^-1 . Ultraviolet absorption maximum: (0.1 N -HCl) 255, 348 mμ; (0.1
N-NaOH) 275 and 311 mμ. Analysis - Experimental values: C, 55.92; H, 5.53; N, 10.04. Operation 3 3,4,5,6,7,8-hexahydro-4-
Oxobenzothieno[2,3-d]pyridine-
2-Carboxylic acid disodium salt dihydrate
C ₁₁ H ₁₀ N ₂ O ₃ S・2Na・2H ₂ O Dissolve 12.0 g (0.043 mol) of the product from Step 2 and 4.0 g (0.10 mol) of caustic soda in a mixture of 440 ml of water and 160 ml of ethanol. Heat on a steam bath until warm. After dissolution of the starting material, the monosodium salt of the product precipitates temporarily. This redissolves as heating continues until a clear solution is finally obtained. The solution is stirred at room temperature for 6 hours, during which time the desired disodium salt precipitates. Collect this product on a filter,
Air dry to obtain 10.4 g (73%). This product is
When heated in a capillary tube, it did not melt at 355°C. NMR (DMSO ₄ −d ₆ ): 2.81 (m, 4), 1.78 (m,
4). Infrared (KBr): 2940, 1630, 1580, 1550, 1490,
1435, 1390, 1350, 1320, 1275, 1050, 810,
and 768 cm ^-1 . Analysis - Experimental values: C, 40.27; H, 3.63; N, 8.40. Operation 4 5-Methyl-6-octyl-4-oxo-4H
-ethyl thieno[2,3-d][1,3]oxazine-2-carboxylate 2-amino-4-methyl-5-(n-octyl)thiophene-3 in 25 ml dry pyridine (initially cooled to 0°C) -Carboxylic acid hydrate (1/4H ₂ O), 6.88g
(0.025 mol) of oxalylethyl chloride.
Add 6.92 g (0.051 mol) dropwise. The mixture was stirred for 1 hour at 25°C after the addition was complete, then 1 hour of cold water was added.
Pour into a liter. The product precipitates and is recovered by extraction with octane; yield 6.4 g (73%), recrystallized from low boiling petroleum ether, white crystals, mp 6.0 ~
69.0℃. NMR ( _CDCl3 ): 4.48 (q, 2, J = 7.1Hz), 2.81
(t, 2, J=6.8Hz), 2.45 (s, 3), 1.44 (t,
3, J = 7.1Hz), 1.28 (m, 12), and 0.88
(m, 3). Infrared (KBr): 2960, 2930, 2860, 1765, 1742,
1588, 1468, 1448, 1368, 1310, 1198, 1150,
1100, 1020, and 770 cm ^-1 . Analysis - Experimental values: C, 61.48; H, 7.21: N, 3.89. Step 4 uses 2-[[(ethoxycarbonyl)carbonyl]amino]-4-methyl- as the starting material.
It can be modified by using 5-octylthiophoene-3-carboxylic acid and carrying out the cyclization using 1 equivalent of oxalylethyl chloride. Operation 5 Ethyl 3,4-dihydro-5-methyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate 5.54 g of the product of step 4 in 50 ml of absolute ethanol
(0.016 mol), 1.10 g (0.0143 mol) of ammonium acetate, and 0.385 g (0.0064 mol) of acetic acid are heated on a steam bath for 40 minutes. On cooling, the desired product crystallizes in the form of needles, which are collected on a filter and dried to yield 4.39 g (79%). This was obtained as off-white needles after recrystallization from isopropanol. mp136.0~137.0℃. NMR ( _CDCl3 ): 4.51 (q, 2, J = 7.1Hz), 2.80
(t, 2, J=6.8Hz), 2.53 (s, 3), 1.46 (t,
3, J=7.1Hz), 1.30 (m, 12), 0.89 (m, 3). Infrared (KBr): 1180, 3100, 3040, 2925, 2850,
1740, 1680, 1570, 1492, 1470, 1370, 1305,
1193, as well as 1033cm ^-1 . Analysis - Experimental values: C, 61.53; H, 7.37; N, 8.01. Procedure 6-12 Supplementary Thienyloxamates Appropriately substituted 2-aminothiophene-3-
By using the method of Procedure 1 with the carboxamide, the following correspondingly substituted ethyl N-[3-(aminocarbonyl)thien-2-yl]oxamate is prepared. In the table, the physical properties and recrystallization solvent are added after the name of each of these substances. Table Thienoxamates Operation number Name Name 6 Ethyl [3-(aminocarbonyl)-5-phenylthien-2-yl]oxamate... Recrystallized from ethanol-isopropanol, mp 198-200°C. Analysis - Experimental values: C, 56.70; H, 4.56; N, 8.87. 7 N-[3-(aminocarbonyl)-4-
Methyl-5-phenylthien-2-yl]ethyl oxamate... Recrystallized from dimethylformamide-ethanol,
mp175-176℃. 8 N-[3-(aminocarbonyl)-5-
Hexyl-4-methylthien-2-yl]ethyl oxamate... Recrystallized from isopropyl acetate-isopropyl ether, mp 147-149°C. Analysis - Experimental values: C, 56.31; H, 7.24; N, 8.25. Hydrolysis of this substance results in N-[3
-aminocarbonyl)-5-hexyl-4-methylthien _- 2 _- yl]oxamic acid sodium salt, _{C14H20N2O4 ・}
Na salt, mp>350℃ is obtained. 9 N-[3-(aminocarbonyl)-4
-Methylthien-2-yl]ethyl oxamate...dimethylformamide-
Recrystallized from absolute ethanol, mp196~
198℃. Analysis - Experimental values: C, 46.86; H, 4.78; N, 10.76. 10 Ethyl N-[3-(aminocarbonyl)-4-methyl-5-pentylthien-2-yl]oxamate...Recrystallized from isopropanol, mp 153-154°C. 11 Ethyl N-[3-(aminocarbonyl)-4-methyl-5-(3-methyl-2-butenyl)thien-2-yl]oxamate... Recrystallized from isopropanol, mp 199-200°C. 12 N-[3-(aminocarbonyl)-6-tert-butyl-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]
Ethyl oxamate...Chloroform-
Recrystallized from ethanol, mp228.5~
231.5℃. Analysis - Experimental values: C, 58.28; H, 7.03; N, 7.80. Procedures 13 to 19 Supplementary Thienopyrimidine-2-Carboxylates by Cyclization of Thienyloxamates These products of the invention are prepared in the form of molten thienopyrimidine-2-carboxylates shown in the table and according to the method of Step 2 above. Produced by heating oxamate. The number in brackets after the operation number in the table is the operation number for the starting material used. Table Thienopyrimidine-2-carboxylates Operation number Name 13(6) Ethyl 3,4-dihydro-4-oxo-6-phenylthieno[2,3-d]pyrimidine-2-carboxylate...Recrystallized from acetonitrile , yellow crystalline solid, mp228.0~232.0℃. NMR ( _CDCl3 ): 10.80 (bs, 1), 7.71
(s, 1), 7.45 (m, 5), 4.52 (q,
2, J=7.0Hz), and 1.48(t,
3, J = 7.0Hz). Infrared (KBr): 3440, 3090, 3050,
1720, 1667, 1560, 1468, 1440,
1365, 1178, 1030, 840, 750, and 684 cm ^-1 . Analysis - Experimental values: C59.87; H, 4.03; N, 9.32. 14(7) 3,4-dihydro-5-methyl-4-oxo-6-phenylthieno[2,3-
d] Ethyl pyridine-2-carboxylate... Recrystallized from dimethylformamide-ethanol, mp 225.5-227.5°C, yellow crystalline solid. NMR ( _CDCl3 ): 10.40 (bs, 1), 7.39
(m, 5), 4.51 (q, 2, J=7.1
Hz), 2.65 (s, 3), 1.47 (t, 3,
J = 7.1Hz). Infrared (KBr): 3160, 3090, 3020,
2980, 2930, 1727, 1665, 1565,
1480, 1368, 1300, 1175, 1030,
1005, 778, 760, 737, and 695cm
^-1 . Analysis - Experimental values: C, 61.02; H, 4.38; N, 8.87. 15(8) 3,4-dihydro-6-hexyl-5-
Methyl-4-oxothieno[2,3-
d] Ethyl pyrimidine-2-carboxylate... recrystallized from isopropanol,
Yellow needle crystal, mp134.0~135.0℃. NMR ( _CDCl3 ): 10.33 (bs, 1), 4.49
(q, 2, J = 7.1Hz), 2.79 (t,
2, J=7.0Hz), 2.50(s, 3),
1.43 (t, 3, J = 7.1Hz), 1.36 (m,
8), 0.88 (m, 3). Infrared (KBr): 3100, 2020, 2840,
1734, 1672, 1565, 1488, 1460,
1365, 1300, 1185, and 1030cm
^-1 . Analysis - Experimental values: C59.90; H, 6.92; N, 8.61. 16(9) Ethyl 3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate... Recrystallized from ethanol, pale yellow crystals, mp151.5
~162.0℃. NMR (DMSO-d ₆ ): 12.50 (bs, 1),
7.33 (q, 1, J = 1.1Hz), 4.37 (q,
2, J = 7.1Hz), 2.50 (d, J, J
= 1.1Hz), and 1.35(t, 3, J =
7.1Hz). Infrared (KBr): 3180, 3080, 1732,
1672, 1570, 1490, 1370, 1300,
1285, 1180, 1155, 1035, and
1010cm ^-1 . Analysis - Experimental values: C, 50.24; H, 4.22; N, 11.72. 17(10) 3,4-dihydro-5-methyl-4-oxo-6-pentylthieno[2,3-
d] Ethyl pyrimidine-2-carboxylate... recrystallized from isopropanol,
Olive green crystal, mp152.5~153.5
℃. NMR ( _CDCl3 ): 9.80 (bs, 1), 4.52
(p, 2, J = 7.2Hz), 2.81 (t,
2, J=6.5Hz), 2.52(s, 3),
1.46 (t, 3, J = 7.2Hz), 1.38 (m,
6), and 0.91 (m, 3). Infrared (KBr): 3080, 3020, 2950,
2920, 2842, 1738, 1675, 1568,
1490, 1365, 1300, 1090, and
1030cm ^-1 . Analysis - Experimental values: C, 58.42; H, 6.65; N, 9.19. 18(11) 3,4-dihydro-3-methyl-6-
Ethyl (3-methyl-2-butenyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylate...Chromatographed on silica gel, eluted with chloroform. Evaporation of the solvent gave an oil without crystallization. Nuclear magnetic resonance spectroscopy showed that the product was a mixture of the above compound and the -6-(methyl-1-butyl) isomer. 19(12) 7-t-butyl-3,4,5,6,7,
8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2
-Ethyl carboxylate...Chromatographed on silica gel (hexane), eluted with ether. Recrystallized from isopropanol, pale yellow powder, mp180.0~183.0
℃. NMR ( _CDCl3 ): 10.30 (bs, 1), 4.50
(q, 2, J = 7.1Hz), 2.80 (m,
4), 2.03 (m, 3), 1.45 (t, 3,
J = 7.1Hz), and 0.95 (s, 9). Infrared (KBr): 2930, 1730, 1662,
1362, 1300, 1281, 1180, and
1029cm ^-1 . Analysis - Experimental values: C, 61.30; H, 6.60; N, 8.35. Procedures 20-26 Thienooxazine-2-carboxylic acids The following thienooxazines are prepared by substitution of appropriately substituted 2-aminothiophene-3-carboxylic acids in Procedure 4. These thienoxazines are listed in the table, along with physical properties and modifications of operation if necessary. Table Thienoxazine-2-carboxylic acids Operation number Name 20 5,6,7,8-tetrahydro-4-oxo-4H-benzothieno[2,3,-
d] [1,3] Ethyl oxazine-2-carboxylate... Recrystallized as a hydrate from isopropyl acetate (1/2H ₂ O),
Yellow solid, mp148.5~180.5℃. NMR (DMSO-d ₆ ): 4.32 (q, 2, J
=7.1Hz), 2.79 (m, 4), 1.79 (m,
4), and 1.33 (t, 3, J = 7.1
Hz). Infrared (KBr): 2990, 2950, 2880,
1767, 1740, 1640, 1582, 1560,
1460, 1372, 1350, 1300, 1185,
1150, 1090, 1020, and 768 cm ^-1 . Analysis - Experimental values C, 55.23; H, 5.06; N, 4.96. 21 6-ethyl-5-methyl-4-oxo-
4H-thieno [2,3-d] [1,3]
Ethyl oxazine-2-carboxylate...
...using 1:1 pyridineacetonitrile as reaction medium; chromatography on silica gel ( _CHCl3 ): recrystallized from isopropyl ether, pale yellow needles, mp 97.5-99.5°C. NMR (DMSO-d ₆ ): 4.36 (q, 2, J
= 7.1Hz), 2.88 (q, 2, J = 7.1
Hz), 2.38 (s, 3), 1.32 (t, 3,
J=7.1Hz), and 1.22(t, 3,
J = 7.2Hz). Infrared (KBr): 2980, 1778, 1760,
1590, 1544, 1470, 1450, 1390,
1320, 1275, 1210, 1170, 1110,
1025, 954, 924, 915, and 771cm
^-1 . Analysis - Experimental values: C, 54.27; H, 5.94; N, 5.13. 22 5-methyl-6-(2methylpropyl)-
4-oxo-4H-thieno[2,3-
d] [1,3] Ethyl oxazine-2-carboxylate... Recrystallized from hexane, pm 78.5-79.5°C. NMR (DMSO-d ₆ ): 4.35 (q, 2, J
= 7.0Hz), 2.72 (d, 2, J = 6.8
Hz), 2.38 (s, 3), 1.87 (m, 1),
1.32 (t, 3, J = 7.0Hz), and
0.92 (d, 6, J = 6.5Hz). Infrared (KBr): 2960, 2935, 2880,
1764, 1740, 1592, 1470, 1374,
1320, 1196, 1160, 1102, and
770 cm ^-1 . Analysis - Experimental values: C, 57.31; H, 5.77; N, 4.84. 23 6-ethyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-
Ethyl 2-carboxylate...13:1 acetonitrile-pyridine was used as the reaction medium; ethyl acetate-recrystallized from low-boiling petroleum ether, pale yellow needles,
mp109.0~111.0℃. NMR ( _CDCl3 ): 7.18 (m, 1), 4.48
(q, 2, J = 7.1Hz), 2.92 (m,
2), 1.43 (t, 3, J = 7.1 Hz), and 1.36 (t, 3, J = 7.2 Hz). Infrared (KBr): 3110, 3000, 1982,
1773, 1752, 1590, 1540, 1375,
1331, 1314, 1215, 1172, 1090,
844, and 769 cm ^-1 . Analysis - Experimental values: C, 51.93; H, 4.26; N, 5.55. 24 6-acetyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,
2] Ethyl oxazine-2-carboxylate...3:8 pyridine-acetonitrile is used as reaction medium; chromatograph on silica gel (CHCl ₃ ), recrystallized from chloroform-hexane, pale yellow platelets, mp102.0 ~103.0℃. NMR (CDCl ₃ ): 4.50 (q, 2, J = 7.1
Hz), 2.89 (s, 3), 2.62 (s, 3),
1.46 (t, 3, J = 7.1Hz). Infrared (KBr): 2992, 1770, 1752,
1671, 1594, 1510, 1312, 1274,
1238, 1188, 1131, 929, 770, and 574 cm ^-1 . Analysis - Experimental values: C, 51.03; H, 3.92; N, 4.86. 25 3,4-dihydro-5,6-dimethyl-
4-oxothieno[2,3-d][1,
2] Ethyl oxazine-2-carboxylate...using 2:1 pyridine-acetonitrile as reaction medium; ethanol recrystallization, dark brown crystals, mp 129-130°C. NMR ( _CDCl3 ): 4.409 (q, 2, J=
7.2Hz), 2.44 (s, 6), 1.44 (t,
3, J = 7.2Hz). Infrared (KBr): 3002, 2980, 1774,
1748, 1590, 1554, 1460, 1372,
1322, 1294, 1208, 1170, 1110,
1030, 958, 872, and 775 cm ^-1 . Analysis - Experimental values: C, 51.95; H, 4.49; N, 5.30. 26 6-hexyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,
3] Ethyl oxazine-2-carboxylate 5:1 acetonitrile-pyridine was used as reaction medium; recrystallized from low-boiling petroleum ether, light tan solid, mp 56.5-57.0°C. NMR ( _CDCl3 ): 4.63 (p, 2, J = 7.0
Hz), 2.92 (t, 2, J = 6.8Hz),
2.47 (s, 3), 1.46 (t, 3, J=
7.0Hz), 1.36 (m, 8), and 0.90
(m, 3). Infrared (KBr): 2950, 2920, 2850,
1750, 1580, 1465, 1440, 1370,
1318, 1278, 1205, 1160, 1096,
1016, 920, 906, and 765 cm ^-1 . Analysis - Experimental values: C, 59.44; H, 6.42; N, 4.26; S, 10.01. Procedures 27-31 Thienopyrimidine-2-carboxylates added from thieno-oxazine-2-carboxylate Preparation of the compounds listed in the table by substitution of appropriately substituted thieno-oxazine-2-carboxylate as starting material , apply the method in step 5. The products obtained are shown in the table together with information regarding purification and identification. The number in brackets next to the operation number indicates the manufacturing operation number of the starting material. Starting materials are listed in the table. Table Thienopyrimidine-2-carboxylates Operation number Name Name 27 (21) 6-ethyl-3,4-dihydro-5-methyl-4-oxothieno[2,3-
d] Pyrimidine-carboxylate...
...Recrystallized from absolute ethanol, white flaky crystals, mp 148.5-173.5℃. NMR ( _CDCl3 ): 4.51 (q, 2, J=7
Hz), 2.85 (q, 2, J = 7.3Hz),
2.25 (s, 3), 1.46 (t, 3, J=
7.1Hz), and 1.30 (t, 3, J=
7.3Hz). Infrared (KBr): 3180, 3100, 2600,
2930, 1730, 1680, 1555, 1488,
1460, 1368, 1300, 1186, and
1032cm ^-1 . Analysis - Experimental values: C, 54.17; H, 5.50; N, 10.029. 28(22)3.4-dihydro-5-methyl-6-(2-
Ethyl (methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylate... Recrystallized from isopropanol, grayish-white crystals, mp175-176
℃. NMR (DMSO-d ₆ ): 12.40 (bs, 1),
4.36 (q, 2, J = 7Hz), 2.68 (b,
2, J=7.1Hz), and 0.92(d,
6, J = 6.5Hz). Infrared (KBr): 3090, 2960, 2930,
2870, 1740, 1675, 1570, 1490,
1467, 1383, 1369, 1305, 1194,
1034, and 768 cm ^-1 . Analysis - Experimental values: 29 (23) Ethyl 6-ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate... Recrystallized from ethanol, pale yellow needles,
mp163.0~168.0℃. NMR ( _CDCl3 ): 10.30 (bs, 1), 7.26
(t, 1, J = 1.1Hz), 4.55 (q,
2, J = 7.0Hz), 2.92 (m, 2),
1.48 (t, 3, J = 7.0Hz) and 1.38
(t, 3, J=7.2Hz) Infrared (KBr): 3180, 3120, 3045,
2980, 2945, 2890, 1749, 1694,
1579, 1949, 1376, 1315, 1194,
1046, 852, and 700 cm ^-1 . Analysis - Experimental values: C, 52.48; H, 4.84; N, 11.21. 30(24)6-acetyl-3,4-dihydro-5-
Methyl-4-oxothieno[2,3-
d] Ethyl pyrimidine-2-carboxylate... Recrystallized from dimethylformamide-ethanol, grayish-white needle-like crystals,
mp236.0~242.0℃. NMR (DMSO-d ₆ ): 12.30 (bs, 1),
4.38 (q, 2, J = 7.0Hz), 2.84 (s,
3), 2.58 (s, 3) and 1.35 (t,
3, J = 7.0Hz). Infrared (KBr): 3100, 2980, 1732,
1698, 1665, 1572, 1512, 1430,
1368, 1310, 1233, 1185, and
1027cm ^-1 . Analysis - Experimental values: C, 51.17; H, 4.15; N, 9.90. 31(25)3,4-dihydro-5,6-dimethyl-
Ethyl 4-oxothieno[2,3-d]pyrimidine-2-carboxylate... Recrystallized from acetonitrile, brown crystalline solid, mp 211.5-212.5°C. NMR ( _CDCl3 ): 10.60 (bs, 1), 4.60
(q, 2, J=7.2Hz), 2.54(s,
3), 2.45 (s, 3), and 1.47
(t, 3, J = 7.2Hz). Infrared (KBr): 3170, 3100, 2992,
2920, 1736, 1680, 1562, 1490,
1362, 1298, 1188, 1162, 1035,
1019, and 775cm ^-1 . Analysis - Experimental values: C, 52.14; H, 4.62; N, 10.89. Operation 32 3,4,5,6,7,8-hexahydro-4-
Oxobenzothieno[2,3-d]perimidine-2-carboxylic acid-hydrate 5.0 g of the product from Step 3 was dissolved in warm water and the solution was clarified by filtration. The filtrate was acidified with glacial acetic acid and frozen overnight. The precipitate was collected, washed with water on a filter, and dried. Cream solid, mp254.5~
256.5℃. NMR (DMMSO-d ₆ ): 2.84 (m, 4), 1.79 (m,
4). Infrared (KBr): 3470, 3100, 3020, 2940, 1695,
1660, 1490, 1440, 1300, 1197, 1145, 1033,
960, and 720 cm ^-1 . Analysis - Experimental values: C, 49.39; H, 4.20; N, 10.33. Operation 33-45 Supplementary Thienopyrimidine-2-Carboxylic Acid Metal Salts The method of Operation 3 can be applied to various other thienopyrimidine-2-carboxylic acid salts.
The method was applied to 2-carboxylic acid esters to produce various salts. the source of the starting material indicated by the operation number shown in the box next to the operation number;
and the analytical information of these products are listed in the table with reference. Table Salts Operation Number Name Name 33(5) 3,4-dihydro-5-methyl-6-octyl-4-oxothieno[2,3-
_d ) Pyrimidine-2-carboxylic acid disodium salt _{hydrate C16H22N2O3S ・}
2Na・H ₂ O...Does not melt at 300℃. NMR (DMSO-d ₆ ): 2.79 (t, 2, J
= 6.9Hz), 2.45 (s, 3), 1.26 (m,
12), and 0.86 (m, 3). Infrared (KBr): 2980, 2945, 2876,
1660, 1630, 1580, 1553, 1493,
1445, 1392, 1360, 1060, and
814 cm ^-1 . Analysis - Experimental values: C, 49.81; H, 5.75; N, 7.05. 34(13) 3,4-dihydro-4-oxo-6-phenylthieno[2,3-d]pyrimidine-2-carboxylic acid sodium salt hemihydrate C ₁₃ H ₈ N ₂ O ₃ S・Na・1 /2H ₂ O…
...Dissolve the crude disodium salt prepared as in step 3 in warm water and carefully acidify with acetic acid until a precipitate forms; white powder, mp 292.0-294.0°C (decomposed) NMR (DMSO-d ₆ ): 7.80 (s, 2),
7.71 (m, 2) and 7.38 (m, 3). Infrared (KBr): 3430, 3230, 1660,
1465, 1440, 1360, 1290, 1180,
1040, 810, 750, 700, and 685cm
^-1 . Analysis - Experimental values: C, 51.61; H, 3.33; N, 9.08. 35(14) 3,4-dihydro-5-methyl-4-oxo-6-phenylthieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt hydrate C ₁₄ H ₁₀ N ₂ O ₃ S・
2Na・H ₂ O...Does not melt at 350℃. NMR (CF ₃ COOH): 7.46 (s, 5),
2.71 (s, 3). Infrared (KBr): 3450, 2970, 2930,
1620, 1570, 1490, 1440, 1385,
1365, 1296, 1070, 1050, 810,
765, 750, and 700 cm ^-1 . Analytical-experimental values: C, 48.14; H, 2.83; N, 8.07. 36(15)6-hexyl-3,4-dihydro-5-
Methyl-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt hydrate C ₁₄ H ₁₈ N ₂ O ₃ S・
2Na・1/4H ₂ O... Addition of isopropanol to induce precipitation; recrystallization from hot water; pale yellow solid, does not melt at 360°C. NMR (CF ₃ COOH): 3.02 (t, 2, J
= 6.5Hz), 2.63 (s, 3), 1.46 (m,
8), and 0.94 (m, 3). Infrared (KBr): 2960, 2930, 2860,
1650, 1565, 1480, 1379, 1045 and
785 cm ^-1 . Analysis - Experimental values: C, 49.31; H, 5.30; N, 8.18. 37(16) 3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt hydrate C ₈ H ₆ N ₂ O ₃ S・2Na・2H ₂ O ...Product recovered by evaporation of the solvent and trituration of the residue with methanol; off-white powder, does not melt at 300°C. NMR ( _D2O ): 6.84 (m, 1), 2.49
(m, 3). Infrared (KBr): 2940, 1660, 1630,
1582, 1539, 1510, 1490, 1439,
1380, 1350, 1290, 1076, 1055,
814, 801, and 620 cm ^-1 . Analysis - Experimental values: C, 33.40; H, 2.13; N, 9.44. 38(17) 3,4-dihydro-5-methyl-4-oxo-6-pentylthieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt sesquihydrate
C ₁₃ H ₁₆ N ₂ O ₃ S・2Na・1−1/2H ₂ O…
...Pale yellow solid, does not decompose at 350℃. NMR: 3.00 (t, 2, J = 6.5Hz),
2.62 (s, 3), 1.50 (m, 6) and
0.96 (m, 3). Infrared (KBr): 2960, 2924, 2878,
2860, 1654, 1620, 1571, 1482,
1438, 1384, 1370, 1350, 1050, and 805mm ^-1 . Analysis - Experimental values: C, 44.46; H, 4.85; N, 7.90. 39(18)3,4-dihydro-5-methyl-6-(3
-Methyl-2-butenyl)-4-oxothieno[2,3-d]pyrimidine-
2-Carboxylic acid disodium salt sesquihydrate C ₁₃ H ₁₄ N ₂ O ₃ S・2Na・1-1/2
_H2O precipitates from the reaction after evaporation of the alcohol by addition of isopropanol; yellow solid, does not melt at 350°C. NMR (CF ₃ COOH): 6.70 (s, 2),
5.55 (m, 1), 3.72 (m, 3), 2.71
(s, 6), 1.85 (m, 6), and
1.22 (d, 6, J = 6.5Hz). Infrared (KBr): 3420, 2965, 2925,
1655, 1625, 1572, 1432, 1384,
1370, 1350, 1050, and 805cm ^-1 . Analysis - Experimental values: C, 44.37; H, 3.94; N, 7.88. 40 (19) 7-t-butyl-3,4,5,6,7,
8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2
-Carboxylic acid disodium salt dihydrate
C ₁₅ H ₁₆ N ₂ O ₃ S・2Na・2H ₂ O...Dimethylformamide was added to the reaction mixture for solubilization; product was precipitated with isopropanol; did not melt at 300°C. NMR (CF ₃ COOH): 2.98 (m, 4),
2.18 (m, 2), 1.67 (m, 1), and 1.02 (m, 9). Infrared (KBr): 2960, 1650, 1600,
1572, 1540, 1479, 1430, 1380,
1317, 1045, and 780 cm ^-1 . Analysis - Experimental values: C, 46.76; H, 4.92; N, 7.01. 41(25)3,4-dihydro-5,6-dimethyl-
4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate C ₉ H ₈ N ₂ O ₃ S・2Na・
1-1/ _2H2O ...Product precipitation from the aqueous reaction mixture with isopropanol;
Gray solid, does not melt at 350°C. NMR ( _CF3COOH ): 2.64 (s, 6). Infrared (KBr): 2920, 1650, 1620,
1578, 1550, 1484, 1430, 1384,
1380, 1350, 1280, 1200, 1050, and 807 cm ^-1 . Analysis - Experimental values: C, 36.65; H, 2.90; N, 9.36. 42(27) 6-ethyl-3,4-dihydro-5-methyl-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt dihydrate C ₁₀ H ₁₀ N ₂ O ₃ S・
2Na.2H ₂ O...Isopropanol was added to the reaction mixture to induce crystallization of the product; white solid, not melting at 360°C. NMR (D ₂ O): 2.95 (q, 2, J = 7.2
Hz), 2.49 (s, 3), 1.30 (t, 3,
J = 7.2Hz). Infrared (KBr): 2975, 2940, 1650,
1620, 1570, 1540, 1484, 1435,
1386, 1355, 1320, 1278 ^{, 808cm -1} . Analysis - Experimental values: C, 37.73; H, 3.41; N, 8.46. 43(28)3,4-dihydro-5-methyl-6-(2-
Methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate
C ₁₂ H ₁₄ N ₂ O ₃ S・2Na・1−1/2H ₂ O…
…The product precipitates from the reaction mixture upon addition of isopropanol; white solid,
No melting at 350℃. NMR (CF ₃ COOH): 2.89 (d, 2, J
=7.0Hz), 2.63 (s, 3), 1.95 (m,
2), 1.41 (m, 1), 1.05 (d, 6,
J = 6.5Hz). Infrared (KBr): 2950, 2922, 2865,
1650, 1620, 1565, 1530, 1465,
1380, 1355, 1200, 1045, and
802 cm ^-1 . Analysis - Experimental values: C, 42.81; H, 4.62; N, 8.35. 44(29) 6-Ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt dihydrate C ₉ H ₈ N ₂ O ₃ S・2Na・2H ₂ O...Methanol was used as the reaction solvent; white powder, did not melt at 360℃. NMR ( _D2O ): 6.89 (s, 1), 2.68
(q, 2, J = 7.2Hz), 1.12 (b,
3, J = 7.2Hz). Infrared (KBr): 3440, 2980, 2942,
1660, 1580, 1540, 1498, 1428,
1350, 1050, 854, and 758 cm ^-1 . Analysis - Experimental values: C, 65.63; H, 3.07; N, 9.12. 45(30)6-acetyl-3,4-dihydro-5-
Methyl-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt sesquihydrate
C ₁₀ H ₈ N ₂ O ₄ S・2Na・1−1/2H ₂ O…
...Yellow solid, does not melt at 360℃. NMR (CF ₃ COOH): 3.10 (s, 3),
2.83 (s, 3). Infrared (KBr): 3460, 1665, 1633,
1580, 1484, 1438, 1370, 1350,
1305, 1259, 1060, and 812 cm ^-1 . Analysis - Experimental values: C, 37.20; H, 2.65; N, 8.36. 46(58)E-3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidin-2-yl)
-2-propenoic acid disodium hydrate
C ₁₃ H ₁₀ N ₂ O ₃ S・2Na・3.5H ₂ O...Product precipitation by treatment of the reaction mixture with isopropanol; yellow-brown solid,
Does not melt at 300℃. NMR (DMSO- _d6 ): 6.98 (s, 2),
2.80 (m, 4), 1.75 (m, 4). Infrared (KBr): 3400, 2930, 2850,
1652, 1565, 1540, 1395, 1290,
1150, 968, and 806 cm ^-1 . Analysis - Experimental values: C, 40.50; H, 4.10; N, 7.12. 47(51) 5-amino-6-ethyl-3,4-dihydro-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid disodium salt sesquihydrate C ₄ H ₇ N ₃ O ₃・
2Na・1.5H ₂ O...methanol used as reaction medium; product precipitated with isopropanol; yellow powder, not melted at 250°C. NMR (DMSO-d ₆ ); 2.84 (q, 2, J
= 7.2Hz), 1.25 (t, 3, J = 7.2
Hz). Infrared (KBr): 3405, 2975, 1655,
1625, 1590, 1538, 1505, 1410,
1360, 1295, 1050, 809, and 765
cm ^-1 . Analysis - Experimental values: C, 35.34; H, 3.35; N, 13.20. Operation 48 3,4-dihydro-5-methyl-6-nitro-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate 1.0 g of the product of step 16 was dissolved in trifluoroacetic acid and 5 ml of acetic anhydride was added to the mixture while cooling to -15°C. A solution of 1.2 ml of concentrated nitric acid in 4 ml of trifluoroacetic acid was then added dropwise to this solution under stirring at a temperature of -12 to -15°C. After the formation of a fine yellow precipitate, 100 ml of water was added to the reaction mixture;
Collect the precipitate on the filter. This is the desired product and is recrystallized from ethanol. mp229
~229.5℃. Analysis - Experimental values: C, 42.23; H, 3,32; N,
14.84. Operation 49 6-amino-3,4-dihydro-5-methyl-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate 2.10 g of the product of step 48 are dissolved in 100 ml of dry dimethylformamide and hydrogenated at atmospheric pressure over 1 g of a 10% suspension on palladium on charcoal. It takes about 5 minutes for the reaction solution to absorb the calculated amount of hydrogen. Remove the catalyst by filtration and pour the liquid into 1 liter of cold water. The aqueous product is recovered by extraction with chloroform, and the orange solid remaining upon evaporation of the solvent is triturated with isopanol and recrystallized from methanol. Yellow needles, mp199.5-215℃. NMR (DMSO-d ₆ ): 11.40 (bs, 1), 6.20 (bs,
2), 4.30 (q, 2, J = 7.0Hz), 2.25 (s, 3),
and 1.30 (t, 3, J = 7.0Hz). Infrared (KBr): 3422, 3315, 3190, 2996, 1728,
1645, 1622, 1552, 1450, 1365, 1335, 1280,
1180, 1032, 1010, and 770cm ^-1 . Analysis - Experimental values: C, 47.38; H, 4.33; N, 16.60. Operation 50 6-ethyl-3,4-dihydro-5-nitro-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate By the method of Step 48, the product of Step 29, 5 g
into the desired product. The product is a pale yellow solid and is recrystallized from a mixture of chloroform and ethanol. White crystal, mp200.0~212.0℃. NMR (DMSO-d ₆ ): 13.40 (bs, 1), 4.45 (q,
2, J = 7.0Hz), 3.02 (q, 2, J = 7.2Hz),
1.39 (t, 3, J = 7.0Hz), 1.31 (t, 3, J =
7.2Hz). Infrared (KBr): 3190, 3115, 3060, 2950, 2900,
1755, 1665, 1550, 1525, 1492, 1373, 1315,
1298, 1192, and 795 cm ^-1 . Analysis - Experimental values: C, 43.89; H, 3.67; N, 14.08. Operation 51 5-amino-6-ethyl-3,4-dihydro-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate Hydrogenate the product of Step 50 by the method of Step 49. It takes approximately 3 hours for the calculated amount of hydrogen to be absorbed. The catalyst is removed by filtration, and the product is recovered by concentrating the liquid to dryness. The residue is recrystallized from a mixture of methanol and isopropanol to give a yellow powder, mp 181.5-184.5°C. NMR (CDCl ₃ ): 10.50 (bs, 1), 4.60 (q, 2, J
= 7.1Hz), 4.09 (bs, 2), 2.34 (q, 2, J =
7.2Hz), 1.48 (t, 3, J = 7.1Hz), 1.33 (t,
3, J = 7.2Hz). Infrared (KBr): 3390, 3240, 2965, 2920, 1720,
1700, 1612, 1562, 1491, 1470, 1370, 1305,
1180, 795, and 785 cm ^-1 . Analysis - Experimental values: C, 49.04; H, 4.88; N, 15.56. Operation 52 3,4-dihydro-6-ethyl-5-iodo-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate 2.65 g (0.0105 mol) of the product from step 29 and 10.60 g (0.034 mol) of mercuric acetate are dissolved in 35 ml of glacial acetic acid and heated on a steam bath for 1 hour. This mixture is then poured into 400 ml of saturated saline to precipitate the 5-chloromercury intermediate, mp 237°C (decomposed). 4.10 g of this intermediate are then added to a solution of 4 g of iodine and 10 g of potassium iodide in 150 ml of water. The mixture was kept under stirring at room temperature for 3 days, then the red-black solid was collected on a filter and washed with ethanol to give a tan solid.
get g. It did not melt at 240°C. Analysis - Experimental values: C, 35.15; H, 3.10; N, 7.36. Operation 53 2-(hydroxymethyl)-5-methyl-6-
(2-methylpropyl)thieno[2,3-b]
Pyrimidine-4-(3H)-one Sodium borohydride in 150 ml of absolute ethanol
2.0 g of the product of step 28 in a solution of 2.0 g (0.052 mol)
(0.0069 mol) is added little by little. Foaming occurs during the addition and the solution turns yellow in color. The mixture is kept at room temperature for 2 hours under stirring. It is then poured into ice water with stirring and the mixture is acidified with glacial acetic acid. This acidic solution is then extracted with chloroform and the solvent is evaporated from the extract to yield a yellow solid. Recrystallization from ethyl acetate gives white crystalline solid, mp182-183
The product is obtained as ℃. NMR (CDCl ₃ ): 4.69 (s, 2), 2.56 (t, 2, J
= 6.5Hz), 2.47 (s, 3), 1.80 (m, 1), 0.95
(d, 6, J = 6.4Hz). Infrared (KBr): 3320, 3100, 2960, 2875, 1670,
1592, 1381, 1315, 1210, 1090, and 1037cm
^-1 . Analysis - Experimental values: C, 57.31; H, 6.45; N, 11.08. Operation 54 2-(Hydroxymethyl)-5-methyl-6-pentylthieno[2,3-d]pyrimidine-4-
(3H)-one This material was prepared by the method of Procedure 53 using the product of Procedure 17 as the starting material. Recrystallized from ethyl acetate, pale yellow crystalline solid, mp158.5~
159.5℃. NMR (CDCl ₃ ): 4.57 (s, 2), 2.78 (t, 2, J
=7.0H), 2.50 (s, 3), 1.46 (m, 6), 0.93
(m, 3). Infrared (KBr): 3350, 2962, 2930, 2860, 1672,
1606, 1442, 1316, 1215, 1120, 1038 and 782
cm ^-1 . Analysis - Found: C, 58.83; H, 6.83; N, 20.46. Operation 55 5,6,7,8-tetrahydro-2-hydroxymethyl)-benzothieno[2,3-d]-4-
(3H)-Pyrimidinone 1.0 g of the product from Step 2 is suspended in 50 ml of absolute ethanol, and 2.0 g of lithium borohydride is added little by little to this. Gas evolution occurs and the mixture is stirred for 1-1/2 hours at room temperature and then refluxed for 20 minutes. The mixture is poured into 300 ml of water and the aqueous mixture is then acidified with glacial acetic acid. The desired product precipitates out and is collected on a filter as slightly yellow needles and recrystallized from a mixture of dimethylformamide and ethanol. mp262.5~268.5℃. NMR (DMSO-d ₆ ): 5.36 (bs, 1), 4.35 (s,
2), 2.76 (m, 4), 1.77 (m, 4). Infrared (KBr): 3120, 2940, 2860, 1670, 1590,
1450, 1350, 1300, 1200, 1153, 1080, 1040,
970, 905, and 795 cm ^-1 . Analysis - Experimental values: C, 56.02; H, 5.09; N, 11.88. Operation 56 6-hexyl-2-(hydroxymethyl)-5-
Methylthieno[2,3-d]pyrimidine-4-
(3H)-one To prepare this material, apply the method of Operation 53 to the product of Operation 15; recrystallize from ethyl acetate;
Pale yellowish brown powder, mp136.0~140.0℃. NMR (DMSO-d ₆ ): 11.30 (bs, 1), 5.22 (bs,
1), 4.33 (s, 2), 2.71 (t, 2, J = 6.6Hz),
2.38 (s, 3), 1.31 (m, 8), 0.85 (m, 3). Infrared (KBr): 3180, 1950, 2920, 2844, 1670,
1595, 1460, 1309, 1208, 1115, 1020, 770cm
^-1 . Analysis - Experimental values: C, 59.76; H, 6.98; N, 9.83. Procedure 57 (3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidin-2-yl)methyl acetic acid Proceed to 30 ml of acetonitrile containing 5 ml of acetic anhydride and 5 ml of pyridine. 55 product 0.68g
(0.00288 mol) and heated at 100°C for 30 minutes. This mixture is then poured into 150 ml of cold water to give the desired product as a pale yellow solid, which is recrystallized from ethyl acetate; pale yellow needles, mp 202.0-204.0
℃. NMR ( _CDCl3 ): 11.20 (bs, 2), 5.08 (s, 2),
2.90 (m, 4), 2.20 (s, 3), 1.86 (m, 4). Infrared (KBr): 3125, 3020, 2950, 2900, 1760,
1673, 1612, 1281, 1260, 1239, ^{1050cm -1} . Analysis - Experimental values: C, 55.93; H, 5.12; N, 10.25. Procedure 58 Ethyl 3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidin-2-yl)-2-propenoate 3.05 g of sodium and 100 ml of ethanol Prepare a solution of sodium ethoxylate in ethanol from Next, 24.5% of the product from step 1 in 300ml of ethanol.
g (0.125 mol) and diethyl fumarate 21.6 g
(0.125 mol) of the mixture produces a red solution, which is stirred overnight at reflux temperature. The mixture is then allowed to cool to room temperature and poured into 1 liter of water containing 9 g of acetic acid. A yellow precipitate forms during stirring at room temperature for 1.5 hours, which is collected by filtration;
Rinse with water on a filter and dry. yellow solid,
mp285~287℃. NMR (CF ₃ COOH): 7.78 (d, 1, J = 16.1Hz),
7.42 (d, 1, J = 16.1Hz), 4.53 (q, 2, J =
7.2Hz), 3.05 (m, 4), 2.02 (m, 4), 1.50
(t, 3, J = 7.2Hz). Infrared (KBr): 3100, 2952, 1727, 1668, 1560,
1471, 1374, 1302, 1255, 1221, 1194, 1168,
990, 970cm ^-1 . Analysis - Experimental values: C, 59.06; H, 5.25; N, 9.16. Operation 59 (E)-3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d)
10 ml of acetenitrile containing 1.2 ml of ethyl pyridine (oxazin-2-yl)-2-propenoate
Medium 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid 0.985g
1.63 g (0.010 mol) of fumarylethyl chloride is added to a suspension of (0.005 mol) (cooled to 0° C.) with stirring. Upon completion of the fumarylethyl chloride addition a clear solution forms and the reaction mixture is stirred for an additional 1.5 hours at ice bath temperature. Continue stirring at room temperature overnight;
Next, the solid precipitated by filtration was collected, and ether was added.
Finally, wash with aqueous hydrochloric acid, aqueous potassium bicarbonate, and water. This is purified by recrystallization from isopropanol and washed on the filter with isopropyl ether and low boiling petroleum ether; yellow crystalline solid, mp 147.5-148.5°C. NMR ( _CDCl3 ): 7.16 (d, 2, J = 15.5Hz), 6.89
(d, 1, J = 15.5Hz), 4.25 (q, 2, J = 7.1
Hz), 2.84 (m, 4), 1.85 (m, 4), 1.31 (t,
3, J = 7.1Hz). Infrared (KBr): 2945, 2930, 2862, 1770, 1715,
1650, 1550, 1464, 1430, 1292, 1255, 1172,
974, and 768 cm ^-1 . Analysis - Experimental values: C, 58.78; H, 4.97; N, 4.59. Operation 60 6-Ethyl-2-(hydroxymethyl)thieno[2,3-d]pyrimidin-4-(3H)-one Applying the method of Operation 53 to the product of Operation 29 to obtain the desired product, Recrystallize from 3:1 ethyl acetate:ethanol. mp201.5~202.5℃. NMR (DMSO-d ₆ ): 12.00 (bs, 1), 7.12 (s,
1), 5.64 (t, 1, J = 5.2Hz), 4.47 (d, 2,
J = 5.2Hz), 2.90 (q, 2, J = 7.1Hz), 1.30
(t, 3, J = 7.1Hz). Infrared (KBr): 1083, 1140, 1153, 1200, 1279,
1300, 1366, 1428, 1461, 1485, 1535, 1567,
1584, 1640, 1675, 2829, 2844, 2871, 1938,
and 2967cm ^-1 . Analysis - Experimental values: C, 51.19; H, 4.69; N, 13.25. Operation 61 6-hexyl-4-oxo-4H-thieno[2,
3d] [1,3] Ethyl oxazine-2-carboxylate This product is obtained by using the method of Step 4 to obtain 2-amino-5
-(n-hexyl)thiophene-3-carboxylic acid. Before addition of aminothiophenecarboxylic acid dissolved in pyridine,
Dissolve oxalylethyl chloride in acetonitrile. The product is collected as a pale green solid and recrystallized from ethanol. mp80~81℃. NMR (CDCl ₃ ): 7.30 (s, 1), 4.58 (q, 2, J
= 7.0Hz), 2.93 (t, 2, J = 7.1Hz), 1.48 (t,
3, J=7.0Hz), 1.40 (m, 8), 0.92 (m, 3). Infrared (KBr): 1285, 1308, 1366, 1388, 1436,
1462, 1478, 1541, 1586, 1715, 2829, 2861,
and 2879cm ^-1 . Analysis - Experimental values: C, 58.52; H, 6.16; N, 4.48. Step 62 Ethyl 3,4-dihydro-6-hexyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate The product of Step 61 was treated with ammonium acetate and acetic acid in ethanol as described in Step 5. A lever product, mp 114-115°C is obtained. NMR ( _CDCl3 ): 11.00 (bs, 1), 7.34 (s, 1),
4.62 (q, 2, J = 7.0Hz), 2.94 (t, 2, J =
7.2Hz), 1.50 (t, 3, J = 7.0Hz), 1.41 (m,
8), 0.92 (m, 3). Infrared (KBr): 1035, 1104, 1149, 1195, 1221,
1241, 1313, 1373, 1401, 1415, 1481, 1569,
1689, 1741, 2834, 2865, and 2880cm ^-1 . Analysis - Experimental values: C, 58.49; H, 6.60; N, 9.29. Operation 63 6-chloro-3.4-dihydro-5-methyl-4
-oxothieno[2,3-d]pyrimidine-2
- Ethyl carboxylate 0.01 mol of the product of step 49 is dissolved in 20 ml of 10% aqueous fluoboric acid and cooled to 0°C. A solution of 0.01 mol of sodium nitrite in 5 ml of water is added dropwise. The mixture was stirred for 30 minutes at 0°C and then the bulky diazonium 2-carbetoxy-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-ylfluoroborate was precipitated. Collect on a filter and air dry. The latter is then added in portions to a solution containing a stoichiometric excess of cuprous chloride in concentrated hydrochloric acid at 0.degree. When all the diazonium salts have been added, increase the temperature to 20°C;
The mixture is then poured into ice water and the product is filtered to obtain the desired 6-chloro compound. Operation 64 Ethyl 6-ethyl-3,4-dihydro-5-hydroxy-6-oxothieno[2,3-d]pyrimidine-2-carboxylate From the amino compound obtained in Operation 51, fluoroboric acid diazonium salt was prepared in Operation 63. to obtain 0.03 mol of the required diazonium fluoborate. The latter was added at once to trifluoroacetic acid at 0 °C.
Add to a solution of 0.03 mol of potassium trifluoroacetate in 13 ml. The mixture was stirred at 25°C for 1 hour,
Then reflux overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product. Operation 65 Ethyl 6-ethyl-3,4-dihydroxy-5-methoxy-4-oxothieno[2,3-d]pyrimidine-2-carboxylate 0.01 mole of the product of Operation 64 and its chemical equivalent of boron trifluoride Ether containing etherified products
Dissolve in 100 ml and cool the solution to 0° C. while stirring. A solution of 0.011 mol of diazomethane in 50 ml of ether is then added in portions and the solution is stirred at 0° C. until the yellow color disappears. Evaporation of the solvent yields the desired 5-methoxypyrimidine compound. Procedure 66 5,6,7,8-tetrahydro-2-(5-tetrazolyl)benzothieno[2,3-d]pyrimidi-4-(3H)-one Add 1.0 g of the product of Step 2 to 30 ml of concentrated aqueous ammonia.
(0.0036 mol) is added. Enough ethanol is then added to form a clear solution and the mixture is cleared by filtering out a small amount of insoluble matter. The solution is kept at room temperature for 4 hours, during which time a pale yellow precipitate forms.
Collect the latter by filtration and air dry it.
6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxamide, pale yellow solid, mp278.0-281.0°C (decomposition)
Obtain 0.80g. NMR ( _CDCl3 ): 12.48 (s, 1), 8.30 (s, 1),
7.90 (s, 1), 2.75 (m, 4), 1.75 (m, 4). Infrared (KBr): 1690cm ^-1 . Analysis - Experimental values: C, 53.12; H, 4.45; N, 16.93. 0.01 mol of the latter is then added to a mixture of 5 g of phosphorus pentachloride in 10 ml of phosphorus oxychloride. After the initial exothermic reaction had stopped, the mixture was heated to 120°C for 1 hour,
Then pour into ice water and collect the insoluble matter on a filter. The collected material was air-dried to give 4-chloro-2-
Cyano-5,6,7,8-tetrahydro-4-oxobenzothieno[2,3-d]pyrimidine-4
-(3H)-one is obtained. The latter is dissolved in 100 ml of dimethylformamide containing 1.5 g of sodium azide and 1.0 g of ammonium chloride. this mixture
Heat at 105-110°C for 24 hours. Pour this mixture onto ice water and precipitate 4-azido-2-(5-
Tetrazole)-5,6,7,8-tetrahydrobenzothieno[2,3- d ]pyrimidine-4-
Collect (3H)-on. The latter is hydrolyzed with 2 chemical equivalents of caustic soda dissolved in ethanol to give the desired product as the sodium salt. Operation 67 5,6,7,8-Tetrahydro-2-N-(tetrazol-5-yl)carbamylbenzothieno[2,3-d]pyrimidin-4-(3H)-one The product of Operation 32 is Treat with 20 ml of thionyl chloride at room temperature until gas evolution ceases. The excess thionyl chloride is then evaporated in vacuo and the remaining acid chloride is dissolved in 25 ml of dry dimethylformamide. 0.01 mole of 5-aminotetrazole was then added to this mixture, which was stirred for 1 hour at room temperature and then placed on a steam bath for 2 hours.
Heat for an hour. This mixture is then poured into water and filtered to obtain the desired product. Operation 68 3-Butyl-3,4,5,6,7,8-hexahydro-4-oxonzothieno[2,3-d]
Pyrimidine-2-carboxylic acid sodium salt hemihydrate C ₁₅ H ₁₈ N ₂ O ₃ S・Na・1/2H ₂ O 2.79 g of the product of step 20 in 50 ml of absolute ethanol
(0.01 mol) and 0.73 g (0.01 mol) of n-butylamine are heated to reflux temperature over a steam bath for 4 hours. This mixture is then poured into 500 ml of cold water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo to give 2.83 g of a brown oil, which crystallized. The crystal mass was triturated with 1:1 ether-low boiling petroleum ether and the crystalline material was removed by filtration. The mother liquor was then concentrated in vacuo to give a brown oil, which was chromatographed on silica gel using 1:1 ether-low boiling petroleum ether to give the desired product as ethyl ether.
get g. The latter was saponified according to the method in Step 3, and the resulting sodium salt was dissolved in isopropanol.
Recrystallized from ether, grayish white powder, mp265.0~
0.90g (59%) of desired product as 285.0 (decomposition)
get. NMR ( _D2O ): 4.04 (m, 2), 2.58 (m, 4), 1.62
(m, 8), 0.92 (m, 3). Infrared (KBr): 2930, 2860, 2680, 2635, 1530,
1450, 1390, 1370, 1190, 1150, 1135, 905,
821, 780 and 744 cm ^-1 . Analysis - Experimental values: C, 53.17; H, 5.31; N, 8.01. Operation 69 6-ethyl-3,4-dihydro-3-methyl-
4-oxothieno[2,3-d]pyrimidine-
2-Carboxylic Acid Sodium Salt The method of Operation 68 was applied to the oxazine obtained by Operation 23, replacing the butylamine used during Operation 68 with methylamine to yield the desired product. Operation 70 3,4-dihydro-6-fluoro-5-methyl-
4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate 2-carbetoxy- as described in Operation 63
0.03 mol of diazonium 3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimididin-6-ylfluoroborate is prepared. The latter is then heated in an oil bath with appropriate aeration to carry off the boron trifluoride liberated by this treatment. A temperature of about 150°C is sufficient and heating is continued until no gas evolution is evident. The residue is cooled, triturated with water and filtered to obtain the desired compound. Operation 71 3,4,5,6,7,8-hexahydro-4-
Oxobenzothieno[2,3-d]pyrimidine-2-carboxaldehyde Product of step 55 in 100 ml of dimethyl sulfoxide
0.01 mol and dicyclohexylcarbodiimide
Add 0.01 mol of orthophosphoric anhydride to the 0.3 mol solution. The mixture is stirred at room temperature for 4 hours, then 250 ml of ethyl acetate and then a solution of 25 g of oxalic acid in methanol are added. Insoluble by-product dicyclohexylurea is removed by filtration. The liquid is washed with dilute aqueous sodium bicarbonate solution, the organic layer is separated and dried over magnesium sulfate. The solvent is evaporated in vacuo to yield the desired product. Operation 72 5,6-dihydro-4-oxo-4H-cyclopenta[b]thienyl[2,3-d][1,3]
Ethyl oxazine-2-carboxylate This product was prepared by procedure 4 by using 2-amino-4,5-dihydrocyclopenta[b]thiophene-3-carboxylic acid as the starting material.
apply. Step 73 Ethyl 3,4,5,6-tetrahydro-4-oxocyclopenta[b]thieno[2,3-d]pyrimidine-2-carboxylate The oxazine obtained in Step 72 by the method of Step 5 Convert to this product. Procedure 74 Ethyl 3,4,5,6-tetrahydro-4-oxocyclohepta[b]thieno[2,3-d]oxazine-2-carboxylate Using the method of Procedure 4 as a starting material, 2-amino-
The substitution of 4,5,6,7-tetrahydrocyclohepta[b]thiophene-3-carboxylic acid applies to the preparation of this material. Operation 75 3,4,5,6,7,8-hexahydro-4-
Oxocyclohepta[b]thieno[2,3-
d] Ethyl pyrimidine-2-carboxylate Convert the product of Step 74 to this material by the method of Step 5. Operation 76 (3,4,5,6,7,8-hexahydro-4
-Oxobenzothieno[2,3-d]pyrimidin-2-yl)methylformate 0.01 mol of the product of step 55 is dissolved in a mixture of 30 ml of acetic anhydride and 15 ml of 100% formic acid at 0°C.
The mixture is then warmed to room temperature over the course of 1 hour while stirring. Then pour into 200 ml of ice to collect the formate ester. Operation 77 N-[3-(aminocarbonyl)-4,5,6,
7-tetrahydrobenzo[b]-thien-2-
yl]oxamic acid 2-amino-4, in 5 liters of absolute ethanol
A suspension of 392 g (2.0 mol) of 5,3,7-tetrahydrobenzo[b]thiophene-3-carboxamide and 321.2 g (2.2 mol) of diethyl oxylate was added to 50.6 g of sodium in 2 liters of absolute ethanol under a stream of nitrogen. Add to the solution of sodium ethoxylate prepared from (2.2 l). The mixture is stirred under heating at reflux temperature for 6 hours and then refrigerated overnight. A fine precipitate forms and is removed by filtration. 150 g (2.5 moles) of acetic acid dissolved in 350 ml of water
The filtration is carefully acidified and the resulting precipitated product is collected on a filter, washed with water, and air dried to yield 194.6 g (0.7 mol) of the product of step 2. The filtrate is acidified to pH 2 with concentrated hydrochloric acid, and the resulting precipitate is collected on a filter, washed with water, and air-dried to obtain the desired product.
Obtain 264.8 g (0.99 mol). A portion of 25g was recrystallized from 1.4 liters of dioxane to yield 18.2g.
Obtain mp223.5-224.5℃ (decomposition). NMR (DMSO-d ₆ ): 7.45 (s, 2), 1.79 (s,
8). Infrared (KBr): 3520, 3360, 3190, 2950, 2860,
1730, 1640, 1565, 1530, 1460, 1410, 1360,
and 1290cm ^-1 . Analysis - Experimental values: C, 49.04; H, 4.47; N, 10.25. Procedure 78 Tablets for Oral Ingestion Blend the following ingredients dry in a twin shell blender and compress on a tablet press using an 11/32 inch die and concave punch. Product of Operation 29 50.0 g Pregranulated sucrose for direct compression 210.0 g Corn starch 6.0 g Microcrystalline cellulose 40.0 g Magnesium stearate 1.0 g This batch size is for 1000 tablets;
This yields tablets weighing 307 mg providing 50 mg of active ingredient per tablet. By using the same ingredients but adjusting the weight and tablet size accordingly, tablets containing 25-200 mg can be made. Procedure 79 Solution for Injection Dissolve the following ingredients in 1 liter of water for injection and pass the solution through a membrane filter with a pore size of 0.45 μm. Product of step 44 0.250g common salt (to make it isotonic) Sufficient amount of sodium phosphate (to buffer) to pH 7.5 Fill the filtered solution into a clean sterile ampoule, seal with flame, and then sterilize in an autoclave. Procedure 80 Powder for Inhalation The following ingredients are mixed aseptically and packed into hard gelatin capsules, each containing 50 mg of the mixture to provide 25 mg of active ingredient. Product of step 36, micronized 25.0g Lactose powder 25.0g The above is for 1000 capsules. These capsules are suitable for dispensing the powder into the inhaled air stream using a breath-propelling device. The composition can be suitably adjusted to obtain capsules containing 0.5 to 40 mg of active ingredient. Operation 81 3,4-dihydro-6-hexyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt hydrate C ₁₃ H ₁₄ N ₂ O ₃ S・
2Na.2-1/2H ₂ O Apply the method of Step 3 to the product of Step 62. At the end of the reaction period, the product is precipitated by adding isopropanol to the reaction mixture. A white gelatinous precipitate forms, which is collected on a filter and dried. NMR (CF ₃ COOH): 7.52 (s, 1), 3.10 (t, 2,
J = 7.1Hz), 1.52 (m, 8), 0.93 (m, 3). Infrared (KBr): 1265, 1346, 1375, 1429, 1471,
1495, 1579, 1605, 1660, 2828, 2861, and
2880cm ^-1 . Analysis - Experimental values: C, 42.34; H, 4.70; N, 7.42. Operation 82 2-(Hydroxymethyl)-6-hexylthieno[2,3-d]-pyrimidin-4-(3H)-one The product of Operation 62 is converted to the title compound by the method of Operation 53. The product is a tan solid. NMR ( _CDCl3 ): 11.60 (bs, 1), 7.14 (s, 1),
4.79 (s, 2), 2.82 (t, 2), 1.40 (m, 8),
0.91 (m, 3). Infrared (KBr): 1300, 1467, 1590, 1610, 1660,
2822, 2860, and 2878 cm ^-1 . The compounds of Step 28, as well as the corresponding disodium salts of the carboxylic acids described in Step 43, are of the preferred class as inhibitors of immediate hypersensitivity reactions.
The corresponding dipotassium salt is described in Operation 97 below and is particularly suitable for preventing immediate hypersensitivity reactions in mammals when allergic rhinitis is an episode. Due to its potency and water solubility, the latter is suitable for use as a nasal solution for application as drops, spray or aerosol to the nasal mucosa. A powder composition for deposition on the nasal mucosa after insufflation can be used, similar to the composition of step 80, except for micronization. For deposition on the nasal mucosa, approx.
A relatively large particle size of 100μ is preferred. oral,
Systemic routes of administration may also be used, including rectal, buccal and parenteral. This dipotassium salt (operation 97) is
In rats, the PCA test described on page 79 shows the following ID ₅₀ values: oral, 2.7 mg/Kg;
0.14mg/Kg. Publications describing work chemically related to this disclosure include Arya, VP, Indian Journal of
Chemistry, 10 , 1141-1150 (1972), which discloses the materials described above in Procedure 2. The following procedure describes additional compounds and compositions that fall within the scope of this invention. Procedure 83 Applying the method of Procedure 1 to ethyl N-[3-(aminocarbonyl)thien-2-yl]oxamate 2-aminothiophene-3-carboxyamide affords the desired product, which is purified from acetonitrile. recrystallize. mp186.0~
187.0℃. Analysis - Experimental values: C, 44.52; H, 4.16; N, 11.56. NMR (DMSO- _d6 ): 1.34 (t, 3, 7.0Hz), 4.48
(q, 2, 7.0Hz), 7.26 (d, 1, 6.0Hz), 7.65
(d, 1, 6.0Hz), 7.80 (bs, 1), 8.19 (bs,
1), and 13.6 (bs, 1). Infrared (KBr): 3415, 3390, 3180, 1730, 1685,
1650, 1590, 1550, and 1280cm ^-1 . This substance has an oral ED ₅₀ =4.5 mg/
Indicates weight in Kg. Operation 84 4-oxo-6-pentyl-4H-thieno[2,
3-d] [1,3] Ethyl oxazine-2-carboxylate Applying the method of Operation 4 to 2-amino-5-pentylthiophene-3-carboxylic acid yields the desired product as a crystalline solid; Recrystallized from di-isopropyl ether, mp 69.6-70.5°C. Analysis - Experimental values: C, 56.88; H, 5.62; N, 4.66. NMR (CDCl ₃ ): 0.90 (t, 3, 6.0Hz), 1.40 (m,
1), 1.47 (t, 3, 7.0Hz), 2.93 (t, 2, 7.0
Hz), 4.58 (q, 2, 7.0Hz), and 7.31 (s,
1). Infrared (KBr): 3100, 2960, 1770, 1590, 1470,
1430, 1320, 1130, 960, and 770 cm ^-1 . Operation 85 4-oxo-6-propyl-4H-thieno[2,
3-d] Ethyl [1,3]-oxazine-2-carboxylate Apply the method of Operation 4 to 2-amino-5-propylthiophene-3-carboxylic acid. The product obtained is recrystallized from diisopropyl ether.
mp90.5~91.5℃. Analysis - Experimental values: C, 53.61; H, 4.88; N, 5.22. NMR (CDCl ₃ ): 1.03 (t, 3, 7.0Hz), 1.50 (t,
3, 7.1Hz), 1.87 (m, 2), 2.92 (t, 2, 7.0
Hz), 4.60 (q, 2, 7.1Hz), and 7.34 (s,
1). Infrared (KBr): 3120, 1800, 1750, 1375, 1330,
1170, 945, 840, and 765 ^-1 . Operation 86 Ethyl 6-isopropyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate 2-amino-5-isopropylthiophene-3
The desired product is prepared by applying the method of Procedure 4 to the -carboxylic acid and recrystallized from di-isopropyl ether. mp87.5~88.5℃. Analysis - Experimental values: C, 53.76; H, 4.79; N, 5.15. NMR ( _CDCl3 ): 1.42 (d, 6, 6.5Hz), 1.48 (t,
3, 6.6Hz), 3,27 (Septet, 1, 6.5Hz),
4.57 (q, 2, 6.6Hz), and 7.32 (s, 1). Infrared (KBr): 2980, 1780, 1740, 1585, 1475,
1430, 1315, 1205, 1160, and 760 cm ^-1 . Operation 87 6-Butyl-4-oxo-4H-thieno[2,
3-d] [1,3] Ethyl oxazine-2-carboxylate 2-amino-5-(n-butyl)thiophene-
Apply the method of Step 4 to 3-carboxylic acid. The product obtained is recrystallized from di-isopropyl ether. mp76.0~77.5℃. Analysis - Experimental values: C, 55.42; H, 5.24; N, 4.93. NMR (CDCl ₃ ): 0.96 (t, 3, 6.6Hz), 1.50 (t,
3, 7.1Hz), 1.60 (m, 4), 2.92 (t, 2, 7.2
Hz), 4.57 (q, 2, 7.1Hz), and 7.33 (s,
1). Infrared (KBr): 3100, 2980, 1770, 1590, 1430,
1370, 1320, 1130, 960, and 770 cm ^-1 . Operation 88 Ethyl 6-ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate 5.0 g (0.019 mol) of the product from Operation 29 was dissolved in 20 ml of butanol, and p-toluene Sulfonic acid 0.5g
add to it. This mixture was refluxed for 3 hours,
After heating, the product (which crystallizes on cooling) is collected and recrystallized from butanol. mp116.0~
118.0℃. Analysis - Experimental values: C, 56.06; H, 5.73; N, 10.14. NMR (CDCl ₃ ): 1.03 (t, 3, 6.3Hz), 1.42 (t,
3, 7.0Hz), 1.81 (m, 4), 3.02 (q, 2, 7.0
Hz), 4.61 (t, 2, 6.0Hz), 7.50 (s, 1), and 11.6 (bs, 1). Infrared (KBr): 3100, 2970, 1745, 1680, 1660,
1480, 1290, 1185, 840 and 770 cm ^-1 . Operation 89 3,4-dihydro-4-oxothieno[2,3
-d] Ethyl pyrimidine-2-carboxylate The product of Step 83 is converted to this material by application of the method of Step 2. The product is purified by chromatography on silica gel using chloroform for elution and recrystallized from isopropanol. mp191.0~192.0℃. Analysis - Experimental values: C, 47.78; H, 3,80; N,
12.19. NMR (CDCl ₃ ): 1.50 (t, 3, 7.0Hz), 4.66 (q,
2, 7.0Hz), 7.60 (d, 1, 6.0Hz), 7.76 (d, 1,
6.0Hz), and 10.8 (bs, 1). Infrared (KBr): 3080, 1745, 1680, 1580, 1480,
1460, 1380, 1310, 1190 and 1040 cm ^-1 . Operation 90 6-ethyl-3,4-dihydro-3-methyl-
4-oxothieno[2,3-d]pyrimidine-
2-Carboxylate The method of Step 69 was repeated except that the post-chromatography saponification step was removed and 2 molecular equivalents of acetic acid were added to the reaction system relative to the oxazine starting material obtained in Step 23. Repeat. The desired product is obtained as a dark oil. Analysis - Experimental values: C, 53.86; H, 5.65; N, 9.58. NMR (CDCl ₃ ): 1.36 (t, 3, 7.0Hz), 1.49 (t,
3, 7.0Hz), 2.91 (q, 2, 7.0Hz), 3.72 (s,
3), 4.56 (q, 2, 7.0Hz), and 7.31 (s,
1). Infrared (KBr): 2970, 1735, 1690, 1560, 1535,
1370, 1290, 1240, 1105 and 1020 cm ^-1 . Procedure 91 Ethyl 3,4-dihydro-6-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate Using ethyl acetate as a solvent, 6-methyl-4
-Oxo-4H-thieno [2,3- d ] [1,3]
Apply the method of Step 5 to ethyl oxazine-2-carboxylate. The product is recovered as a crystalline solid, which can be recrystallized from 95% ethanol. mp204.0~208.0℃. Analysis - Experimental values: C, 50.13; H, 4.13; N,
11.69. NMR (DMSO- _d6 ): 1.36 (t, 3, 7.0Hz), 2.55
(s, 3), 4.36 (p, 2, 7.0Hz), 7.26 (s,
1), and 13.0 (bs, 1). Infrared (KBr): 3280, 3000, 1750, 1710, 1480,
1310, 1285, 1180, 1025, 845, and 760cm
^-1 . Operation 92 3,4-dihydro-6-(1-methylethyl)-
4-oxothieno[2,6-d]pyrimidine-
Ethyl 2-Carboxylate The product of Operation 86 is converted to the desired product by refluxing with ethanolic ammonium acetate and acetic acid according to the method of Operation 5. This product is recrystallized from ethanol. mp182
~183℃. Analysis - Experimental values: C, 54.01; H, 5.19; N, 10.42. NMR ( _CDCl3 ): 1.40 (d, 6, 6.5Hz), 1.51 (t,
3, 7.0Hz), 3.21 (Septet, 1, 6.5Hz),
4.52 (q, 2, 7.0Hz), 7.33 (s, 1), and
10.6 (bs, 1). Infrared (KBr): 3100, 2960, 1740, 1690, 1570,
1480, 1300, 1185, 1050, and 765cm ^-1 . Operation 93 3,4-dihydro-6-(1-methylethyl)-
4-oxothieno[2,3-d]pyrimidine-
2-Carboxylic Acid Disodium Salt The product of Step 92 is hydrolyzed with ethanolic caustic soda according to the method of Step 3. Dilute the cooled reaction mixture with isopropanol and collect the product on a filter. Air dry and grind in mortar. Does not melt when heated to 350°C in a capillary tube. Elemental analysis is based on water per mole of disodium salt.
Corresponds to a hydrate containing 175 mol. Analysis - Experimental values: C, 38.28; H, 3,74; N,
8.56. NMR ( _D2O ): 1.15 (d, 6, 6.5Hz), 2.90 (m,
1), 7.20 (s, 1), and 4.80 Infrared (KBr): 2860, 1650, 1570, 1425, 1365,
1340, 1060, 840 and 790 cm ^-1 . Operation 94 Ethyl 6-butyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate The product of Operation 87 was dissolved in ethanolic acetic acid containing acetic acid according to the method of Operation 5. Treat with ammonium. The product is recrystallized from ethanol-isopropanol. pm144-145℃. Analysis - Experimental values: C, 55.58: H, 6.02; N, 10.00. NMR (CDCl ₃ ): 0.98 (t, 3, 6.0Hz), 1.52 (t,
3, 7.0Hz), 1.53 (m, 4), 2.90 (t, 2, 7.0
Hz), 4.70 (q, 2, 7.0Hz), 7.40 (s, 1),
11.3 (bs, 1). Infrared (KBr): 3110, 2960, 1740, 1670, 1490,
1300, 1180, 1030 and 770 cm ^-1 . Operation 95 Ethyl 3,4-dihydro-4-oxo-6-propylthieno[2,3-d]pyrimidine-2-carboxylate The product of Operation 85 was prepared according to the method of Operation 5 except that the acetic acid was omitted. Conversion to the desired product is achieved by treatment with ethanolic ammonium acetate. The product is recrystallized from ethanol. mp169
~170℃. Analysis - Experimental values: C, 54.49; H, 5.29; N, 10.53. NMR (CDCl ₃ ): 1.03 (t, 3, 6.5Hz), 1.52 (t,
3, 7.0Hz), 1.88 (m, 2), 2.09 (t, 2, 6.7
Hz), 4.60 (q, 2, 7.0Hz), 7.35 (s, 1), sequence 11.5 (bs, 1). Infrared (KBr): 3100, 2960, 1735, 1690, 1570,
1480, 1305, 1185, 1035, and 765 cm ^-1 . Operation 96 Ethyl 3,4-dihydro-4-oxo-6-pentylthieno[2,3-d]pyrimidine-2-carboxylate The oxazine obtained in Operation 84 was dissolved in ethanol containing acetic acid according to the method of Operation 5. This product is converted to this product by treatment with ammonium acetate. The product is recrystallized from a mixture of ethanol and isopropanol. mp124~125℃. Analysis - Experimental values: C, 57.22; H, 6.20; N, 952. NMR (CDCl ₃ ): 0.87 (t, 3, 6.0Hz), 1.40 (m,
6), 1.47 (t, 3, 7.0Hz), 2.88 (t, 2, 7.0
Hz), 4.56 (q, 2, 7.0Hz), 7.32 (s, 1) and
11.7 (bs, 1). Infrared (KBr): 3100, 2960, 1760, 1740, 1690,
1490, 1300, 1190, 1040 and 770 cm ^-1 . Procedure 97 3,4-dihydro-5-methyl-5-(2-methylpropyl)-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid dipotassium salt The product of step 28 is hydrolyzed by treating 1.91 g thereof with 0.86 g caustic potash dissolved in 150 ml isopropanol. The mixture is heated under reflux for 4 hours while stirring. It is then allowed to cool and the product is collected on a filter. Grind in mortar and air dry. It did not melt when heated to 350°C in a capillary tube. Elemental analysis shows that the product contains water per mole of salt.
It was shown that it could be obtained as a hydrate containing 1.75 mol. Analysis - Experimental values: C, 38.66; H, 4.25; N, 7.20. NMR ( _D2O ): 0.88 (d, 6, 6.0Hz), 1.89 (m,
1), 2.40 (s, 3), 2.61 (d, 2, 6.5Hz), and 4.80. Infrared (KBr): 2840, 1650, 1590, 1560, 1535,
1470, 1415, 1340, 1040, and 800cm ^-1 . Operation 98 3,4-dihydro-3,5-dimethyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid sodium salt 2.34 g (0.0064 mol) of oxazine obtained in Operation 4, A mixture of 4.47 g (0.0576 mol) of 40% aqueous methylamine and 5.00 g (0.0832 mol) of glacial acetic acid is heated on a steam bath for 40 minutes in 40 ml of absolute ethanol. This mixture is then processed substantially as described in Step 5 to yield the desired product, mp310.0-315.5.
°C (decomposition). This is water per mole of salt.
Obtained as a hydrate containing 0.25 mol. Analysis - Experimental values: C, 56.36; H, 6.55; N, 7.70. NMR (DMSO-d ₆ ): 0.84 (m, 3), 1.30 (m,
12), 2.41 (s, 3), 2.77 (m, 2), and 3.45
(s, 3). Infrared (KBr): 3480, 2940, 2870, 1665, 1650,
1550, 1380, 1330, 1130, 795 and 755 cm ^-1 . Operation 99 6-hexyl-2-(hydroxymethyl)thieno[2,3-d]pyrimidin-4-(3H)-one Reduce the product of Operation 61 with sodium borohydride according to the method of Operation 53. . The product is recrystallized from ethyl acetate. mp141~143℃. Analysis - Experimental values: C, 58.84; H, 6.94; N, 10.13. NMR (CDCl ₃ ): 0.90 (t, 3, 6.0Hz), 1.35 (m,
9), 2.81 (t, 2, 7.0Hz)), 4.80 (s, 2),
7.12 (s, 1), and 11.6 (bs, 1). Infrared (KBr): 3270, 2930, 2860, 1665, 1610,
1600, 1470, 1300, 840 and 755 cm ^-1 . Procedure 100 Nasal Solution A 1% solution of the product of Procedure 97 is prepared by dissolving a 1% solution of the product of Procedure 97 in a suitable amount of water with a pharmaceutically acceptable microbial inhibitor and enough common salt to produce an isotonic solution. Adjust the pH to 9.0 with hydrochloric acid and bottle with nasal drop or spray attachment.

Claims (1)

[Claims] 1 formula [wherein R ³ is lower alkyl having 1 to 8 carbon atoms, and A is a covalent bond or -CH=CH-, and L is hydrogen or 1 to 8 carbon atoms and B is hydrogen, lower alkyl having 1 to 8 carbon atoms or alkanoyl having 2 to 6 carbon atoms. 2 formulas [wherein R ³ is lower alkyl having 1 to 8 carbon atoms, and A is a covalent bond or -CH=CH-, and L is hydrogen or 1 to 8 carbon atoms] B is hydrogen, lower alkyl having 1 to 8 carbon atoms or alkanoyl having 2 to 6 carbon atoms. (wherein Z is -OH, and L and B are as defined above), a compound of the formula [wherein X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, R is lower alkyl having 1 to 8 carbon atoms, and A is a covalent bond or -CH= A method characterized in that a compound having the above formula is obtained by reacting with a compound having the above formula.