JPS6238356B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a series of thienos [2.
3-d] pyrimidine compound, an antiallergic agent containing the compound as an active ingredient, and a method for producing the compound. The compounds of the invention can be prepared from intermediates having the following formula or alternatively from intermediates having the formula:

【formula】

【formula】

The compound having the above formula of the present invention (and its intermediate compound having the above formula or formula) is:
It is 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. 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. In summary, R ² is defined by the following formula (where R ³
has the meaning given 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] In the formula, R ³ is the same as above, R ⁵ and
R ⁶ is hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, nitro, amino, chlorine, bromine, iodo, and halo including fluorine, phenyl, 2 to Alkanoyl with 6 carbon atoms or R ⁵
and R ⁶ together with the thieno ring constitute a tetrahydrobenzothieno ring. In the formula ^, R ³ has the same meaning as above and A is a covalent bond connecting -CO ₂ R ³ to the ring _or a vinyl group, -
CH=CH−. Symbols L and B are R ⁵ and R ⁶
means some of the same groups defined for
Their definition is somewhat limited. L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having 2 to 6 carbon atoms, or B together with the thienyl group constitutes a tetrahydrobenzothienyl group. In the formula, the symbols R ³ , A, L and B have the same meaning as given for the formula. Compounds of formulas and inhibit granule reduction in sensitized mast cells. Immediate sensitivities such as asthma, hay fever, allergic rhinitis, measles, and food allergies are caused by immunoglobulin E (sometimes called reagin antibodies) reacting with antigens on the cell membrane of mast cells, resulting in the production of gradikinin and histamine. ,
It is thought to be mediated by initiating reactions within mast cells that release mediating agents such as serotonin or slow reactant substance A (SRS-A). 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. Suitable compounds are particularly distinguished by the fact that they are orally active, have extremely low toxicity, and are substantially 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 It has been shown in the prior art that the activity of test compounds in the case of passive cutaneous anaphylaxis (PCA) in rats correlates with the usefulness of the active compound in the treatment of immediate hypersensitivity conditions such as asthma. Using a male Sprague Dawley (Carworth Farms) or Wistar (Harlan) rat weighing 100-175 g, substantially
The lattreagin antiserum is prepared according to the method of Immunology 7 , 681-699 (1964). Rats are injected intramuscularly with a solution of egg albumin in saline at a dose of 10 mg per kg and intraperitoneally with 2×10 ¹⁰ Bordetella pertussis bacteria. Twelve days after injection, serum is collected and antibody titers are determined. Sera containing enough antibodies to produce a 10 mm spot on the dorsal skin of rats in the PCA test after 10-fold dilution are pooled. The highest dilution of antiserum that can cause PCA in rats 48-72 hours after injection is usually 50-80. In conducting this test, groups of 5 to 10 male Sprague-Dawleys (Carworth Farms) (each weighing 100 to 150 g) are used. Before exam 48
At time, animals are passively sensitized by intradermal injection of 0.1 ml of diluted antiserum at various locations on the dorsal depilated skin. Use a dilution of the antiserum to obtain spots 20-25 mm in diameter after challenge. A relatively high dilution of the antiserum is injected such that the activity of less potent compounds can be measured relatively sensitively at at least one location. There is usually an incubation period of 48 hours before challenging the animal. According to standard screening procedures, test drugs are administered by intraperitoneal injection, intraperitoneal injection, or oral ingestion 15 minutes before the challenge. The challenge is 25mg/saline solution.
It is carried out by intravenous injection of ovalbumin at a dose of Kg and Evans Blue dye at 25 mg/Kg. The dye simply acts as a marker. The response to the antigen challenge at the previously sensitized skin location causes an increase in capillary permeability at the sensitized location and leakage of blue pigment into the area surrounding the sensitized location. The PCA response is scored by measuring the mean spot diameter on the excised and reversed skin 20-30 minutes after the challenge. A group of non-drug control animals is used in each experiment. Percent inhibition of PCA is determined by measuring the mean diameter of the spots in the control and treated animals, calculating the difference in the square of the mean diameter of the control and treated animals, and expressing this difference as a percentage of the mean diameter of the control animal squared. Calculated by. Results are expressed as percent inhibition. Rats may be injected intradermally with 0.1 ml of a solution containing 1 mg/ml histamine 10 minutes before death. This allows it to be determined whether the test compound exhibits an antihistamine effect on the end organs in blocking PCA rather than interfering with mediator release from mast cells. When dose-response curves are to be constructed for quantitative comparisons of potency between active compounds, different doses of test compounds are used in parallel experiments. 50% of PCA
The dose ID ₅₀ at which inhibition occurs is determined by interpolation. In other variations, various intervals are used between drug treatment and challenge to ensure the durability of the drug's effect. A more complex test reflecting the usefulness of this substance in the treatment of immunologically induced tracheal constriction is the allergic respiratory model in rats, in which each body weight 225 ml as before for the preparation of the Reagen antiserum. ~275
G male Harlan rats were treated with ovalbumin and B. pertussis vaccine (2 x ¹⁰ bacteria per rat).
active sensitization. 13-15 days after sensitization, rats are prepared for intraduodenal administration of compounds by exposing the duodenum through a small intestinal incision, cannulating the cervix, cervix, and trachea. A cannula is used to administer egg albumin challenge, and blood pressure is measured from the cannula through the cannula. The tracheal cannula is connected to a glass T-tube,
One arm is open to the atmosphere, and the other arm is connected to a pressure transducer to measure inspiration and expiration pressures. Changes in inspiratory and expiratory pressures are monitored as a reflection of changes in airway resistance after challenge with egg albumin antigen. The drug was administered into the duodenum 15 minutes before the challenge with egg albumin injection.
Measure the change in airway resistance compared to control animals.
The challenge dose of antigen is approximately 36 cm above the inspiratory and expiratory pressures.
% reduction - which was found to be approximately the maximum the animal could survive. The effect of the drug on this reduction in expiratory and inspiratory pressures is then determined for various doses of the drug. The dose that produces a half-maximal response is determined by interpolation from the dose-response curve (ID _1/2 max). The data presented in the following table reflect the oral antiallergic effect of some of the substances of the invention in the above-mentioned tests.

Table: Cromolyn sodium is inactive upon oral administration in the above test. This substance is used clinically for the prophylactic treatment of asthmatic patients by oral inhalation, and its activity is reflected in the rat PCA study described above when administered by intravenous or intraperitoneal injection. When chronotropically administered cromolyn sodium simultaneously with antigen, it can show an ID ₅₀ of about 1 mg/Kg in rats in the PCA test. Similarly, the inherent activity of the substances of the invention, which show a reduced level of activity in the PCA test when administered orally, compared to the activity of the substances shown in the table above, is due to the intraperitoneal or intraperitoneal routes. can be demonstrated by administering it to test animals. The activity of the substances in interfering with the release of allergy mediating substances can be demonstrated in vitro by a test consisting of antagonizing antigen-induced histamine release from peritoneal mast cells of passively sensitized rats. The method used is described by Kussner et al., Journal of
Pharmacology and Experimental Therapeutics
184 , 41-46 (1973). This test consists of isolation of mast cells from rats by peritoneal lavage and isolation of cellular material from the lavage fluid. Cells are sensitized by shaking in antiserum from rats sensitized as described above for passive cutaneous anaphylaxis. The sensitized cells are then exposed to ovalbumin antigen,
Histamine release from cells is measured by automated fluorophotometry. Inhibition of histamine release by the presence of a test compound during challenge of sensitized cells is a measure of the test compound's activity. Create a dose-response curve using various concentrations of the test compound;
The concentration that inhibits 50% histamine release (IC ₅₀ ) is determined by interpolation. Cromolyn sodium was found to exhibit an IC ₅₀ of 1 μm in this test system. Compounds of the invention prepared by steps 2, 3 and 36 have an IC ₅₀ in the range of 0.3-0.8 μm.
It was substantially more potent than cromolyn sodium in terms of potency. Thus, the present invention provides a method for suppressing the allergic manifestations of immediate hypersensitivity in susceptible warm-blooded animals upon exposure to an allergen.
Mammals that undergo immediate hypersensitization include humans, mice, rats, hamsters, gerbils, dogs, cats, sheep, goats, horses, cows, and the like. The method comprises administering an effective amount of one of the compounds of the invention by oral, topical, parenteral, or inhalation routes. The effective dose range in rats is about 1-200 mg/kg body weight, with preferred compounds being effective orally in the range of about 1-15 mg/kg body weight. Estimated human doses for the material in Procedure 29 range from 1 to 500 mg orally. Suitable dosage unit forms for the above-mentioned applications of the substance, such as tablets, solutions or suspensions for injection or inhalation, as well as formulas, are determined according to conventional pharmaceutical practice in accordance with established practice in pharmaceutical technology. It can be produced using a carrier. The compounds of the present invention are 2-amino-thiophene-3-carboxyamides or 2-aminothiophene-3-carboxylic acids of the formula shown in the following scheme (wherein 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 new formula for use in preparing the compounds of the present invention can be prepared by obvious adaptation of the method of Gewald et al. Symbols L and B in the formula
is independently selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having 2 to 6 carbon atoms. mosquito,
Alternatively, L and B together with a thienyl group constitute a tetrahydrobenzothienyl group. 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, , and
is H, lower alkyl having 1 to 8 carbon atoms, or M, where M is a non-toxic pharmacologically usable metal cation. The acylating agent of the formula is oxalic acid or a 1,4-but-2-enedionic acid derivative. That is, A in the above formula is
A covalent bond directly connected to the group shown 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 intermediates of the formula when R ³ is lower alkyl, the 2-aminothiophene-3-carboxamide of the formula when Z is -NH ₂ can be reacted with pyridine or an acylation reaction 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 agent (which is preferably ethyloxalyl chloride). The acylating agent is carefully mixed with the solution of intermediate at room temperature by adding the acylating agent in portions to the carboxamide intermediate while cooling the reaction vessel, or vice versa. It is undesirable to pre-cool the reactants before starting the reaction. After the reaction has stopped,
The reaction is usually stirred for a period of time at room temperature to ensure completion of the reaction. The reaction mixture is then poured into an aprotic solvent such as isopropanol,
This intermediate is recovered by collecting the intermediate of formula precipitated by filtration. The thienyl intermediate of formula is not only a useful material for the preparation of compounds of formula of the present invention, but is itself a novel compound with anti-allergic activity. Thienyl compounds of the formula when R ³ is lower alkyl are converted to thienopyrimidines of the invention having the formula by heating in the melt at a temperature in the range of about 200-265°C, preferably the latter. be done. 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 can be estimated by determining the temperature at which vigorous evolution of water vapor occurs when the melt is heated in a test tube. The oxazines of the formula are not only useful materials in the preparation of the compounds of the formula of the present invention, but also themselves.
It is a novel compound with antiallergic activity.
Oxazines of the formula when R ³ is lower alkyl can be prepared using 2-aminothiophene-3- of the formula when Z is -OH under exactly the same conditions as described above for the preparation of intermediates of the formula. It is prepared by reacting a carboxylic acid with an acylating agent of the formula. 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 is further cyclized to give the oxazine of the formula by treatment with one molecular moiety of the acylating agent of the formula or other cyclodehydrating agent such as _SOCl2 . Obtainable. 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 (where 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 as by-products in the preparation of compounds of formula from 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 (when R ³ is H) can be prepared by selective hydrolysis of the corresponding acid halide, followed by neutralization to form the M salt. 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 nitro, amino, and halogen, or R ² is CH ₂ OH,

【formula】

Serves as an intermediate for [formula]. 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, when R ⁵ or R ⁶ is a nitro group, the compound of formula R ⁵ in trichloroacetic acid and acetic anhydride
or by nitration of the corresponding compounds in which each R ⁶ is a hydrogen atom by treatment with a solution of nitric acid in trichloroacetic acid. 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. The resulting compound of the formula in which one of R ⁵ and R ⁶ is a nitro group is then prepared using a conventional method 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 to the corresponding amino compound by hydrogenation method. 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. Diazonium fluoroborate salts can also be converted to the corresponding fluoro derivatives 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 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. 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 titro-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 fluoborate, which is then 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.
This 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. 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 is −OR
<Examples and Reference Examples> The present invention will be explained in more detail using the following operations 1 to 100. Steps 2, 3, 5, 13-19, 27
-58, 60, 62, 68, 78-82, 88-100 are examples of target compounds of the formula of the present invention. Operation 1, 6~
12, 77, and 83 are production examples up to intermediates of the formula,
Operations 4, 20-26, 59, 61, 84-87 are examples of producing intermediates of the formula. Residual operations 63~67, 69~
71, 73, 75, and 76 are reference examples for the production of formula-related compounds, and the remaining operations 72 and 74 are reference examples for the production of formula-related compounds. 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 at 4.70 ppm was 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 (b _s ), singlet (s),
Reported as multiplets (m), doublets (d), triplets (t), or quartets (q), and coupling constants (J values) are reported where appropriate. The composition 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. The infrared spectrum is
Measurements were made on potassium bromide pellets containing 0.5% of the experimental substance. Operation 1 N-[3-aminocarbonyl)-4, 5, 6, 7
-tetrahydrobenzo[b]thien-2-yl]
Ethyl oxamate - A suspension of 2.92 grams (0.41 moles) of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide in 200 ml of dry pyridine was dissolved in 50 ml of dry acetonitrile. Oxalylethyl chloride 55.25
25 °C during the addition (dropwise addition) of g (0.41 mol)
Stir at . 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. the reaction is complete,
After removing the ice bath, add acetonitrile to the reaction mixture.
Add 150 ml to facilitate stirring and continue to stir the mixture in one part. Then pour into isopropanol and collect the precipitated product on a filter. The product was air-dried to give 58.80 g (49%) of a yellow solid;
Obtain mp204.0~205.0℃. A sample of this is recrystallized from isopropanol and shows the same melting point. NMR (DMSO- _db ): 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-
Oxobenzothieno[2,3-d]pyrimidine-
2-Carboxylic acid ester - product of operation 1, 8.89
g (0.030 mol) are melted at 261° C. in a round bottom flask with a magnetic stirring bar immersed in an oil bath. 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 is collected and recrystallized from a mixture of dimethylformamide and methanol to yield 4.92 g (48%) of the desired product as yellow needles, mp 207.0-209.0°C. 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 1035 cm ^-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]pyrimidine-
2-Carboxylic acid disodium salt dihydrate
C ₁₁ H ₁₀ N ₂ O ₃・2Na・2H ₂ O - product of operation 2,
12.0g (0.043mol) and 4.0g (0.10mol) of caustic soda
mol) in a mixture of 440 ml of water and 160 ml of ethanol and heated on a steam bath until dissolved. 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. When this solution was stirred at room temperature for 6 hours,
During this time the desired disodium salt precipitates. This product was collected on a filter and air-dried to 10.4 g (73
%). This product, when heated in a capillary tube,
It did not melt at 355°C. NMR ( _DMSO4 - _d6 ): 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
-thieno[2,3-d][1,3]oxazine-
Ethyl 2-carboxylate - 2-amino-4-methyl-5- in 25 ml of dry pyridine (initially cooled to 0°C)
In a suspension of 6.88 g (0.025 mol) of (n-octyl)thiophene-3-carboxylic acid hydrate (1/4H ₂ O), 6.92 g (0.051 mol) of oxalylethyl chloride is added.
Add dropwise. The mixture is stirred for 1 hour at 25° C. after the addition is complete and then poured into 1 liter of cold water. The product precipitates and is recovered by extraction with octane;
Yield 6.4g (73%). Recrystallized from low-boiling petroleum ether, white crystals, mp66.0~69.0℃. NMR (CDCl ₃ ): 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 770cm
^-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-octylthiophene-3-carboxylic acid and carrying out the cyclization using 1 equivalent of oxalylethyl chloride. Operation 5 3,4-dihydro-5-methyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-
Ethyl 2-carboxylate - 5.54 g (0.016 mol) of the product of Step 4 in 50 ml of absolute ethanol, 1.10 g (0.0143 mol) ammonium acetate, and 0.385 g acetic acid.
(0.0064 mol) is 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, dried and 4.39
g (79%). This was obtained as off-white needles after recrystallization from isopropanol.
mp136.0~137.0℃. NMR (CDCl ₃ : 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, and 1033 cm ^-1 . Analysis Experimental values: C, 61.53; H, 7.37; N, 8.01. Steps 6-12 Supplementary Thienyloxamates - By using the method of Step 1 on an appropriately substituted 2-aminothiophene-3-carboxyamide, the following correspondingly substituted N-[3- Ethyl (aminocarbonyl)thien-2-yl]oxamate is produced. 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 Recrystallized from [3-(aminocarbonyl)-5-phenylthien-2-yl]-ethyl oxamate-ethanol-isopropanol, mp 198-200°C. Analysis Experimental value:
C, 56.70; H, 4.56; N, 8.87. 7 N-[3-(aminocarbonyl)-4-
Methyl-5-phenylthien-2-yl]ethyl oxamate-dimethylformamide-recrystallized from ethanol,
mp175-176℃. 8 N-[3-(aminocarbonyl)-5-
Hexyl-4-methylthien-2-yl]ethyl oxamate-isopropyl acetate-recrystallized from isopropyl ether, mp 147-149°C. Analysis Experimental value:
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, C ₁₄ H ₂₀ N ₂ O ₄ S.
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 value:
C, 46.86; H, 4.78; N, 10.76. 10 N-[3-(aminocarbonyl)-4-
Recrystallized from ethyl methyl-5-pentylthien-2-yl oxamate-isopropanol, mp 153-154°C. 11 N-[3-(aminocarbonyl)-4-
Recrystallized from ethyl methyl-5-(3-methyl-2-butenyl)thien-2-yl]oxamate-isopropanol, mp 199-200°C. 12 N-[3-(aminocarbonyl)-6-
Recrystallized from tertiary butyl-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]ethyl oxamate-chloroform-ethanol, mp228.5~
231.5℃. Analysis Experimental value:
C, 58.28; H, 7.03; N, 7.80. Steps 13-19 Supplementary Thienopyrimidine-2-Carboxylates by Cyclization of Thienyloxamates - These products of the invention are shown in the table and prepared in Step 2 above.
by heating the molten thienyl oxamate indicated in the table according to the method of
The number in brackets after the operation number in the table is the operation number for the preparation of the starting material used. Table Thienopyrimidine-2-carboxylate Operation number Name Name 13(6) 3,4-dihydro-4-oxo-6-
Recrystallized from ethyl phenylthieno[2,3-d]pyrimidine-2-carboxylate-acetonitrile, yellow crystalline solid, mp 228.0-232.0°C. 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 value:
C, 59.87; H, 4.03; N, 9.32. 14(7) 3,4-dihydro-5-methyl-4-
Oxo-6-phenylthieno [2,3
-d] Ethyl pyrimidine-2-carboxylate-dimethylformamide-recrystallized from ethanol, mp225.5-227.5
°C, yellow crystalline solid. NMR ( _CDCl3 ): 10.40 (bs, ),
7.39 (m, 5), 4.51 (q, 2, J=
7.1Hz), 2.65 (s, 3), 1.47 (t,
3, J=7.1). Infrared (KBr): 3160, 3090, 3020,
2980, 2930, 1727, 1665, 1565,
1480, 1368, 1300, 1175, 1030,
1005, 778, 760, 737, and 695cm
^-1 . Analysis Experimental value:
C, 61.02; H, 4.38; N, 8.87. 15(8) 3,4-dihydro-6-hexyl-5
-Methyl-4-oxothieno [2,3
-d] Recrystallization from ethyl pyrimidine-2-carboxylate-isopropanol,
Yellow needles, 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 1030 cm ^-1 . Analysis Experimental value:
C, 59.90; H, 6.92; N, 8.61. 16(9) 3,4-dihydro-5-methyl-4-
Oxothieno[2,3-d]pyrimidine-2-carboxylic acid ethyl-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 1010
cm ^-1 . Analysis Experimental value:
C, 50.24; H, 4.22; N, 11.72. 17(10) 3,4-dihydro-5-methyl-4-
Oxo-6-pentylthieno [2,3
-d] Recrystallization from ethyl pyrimidine-2-carboxylate-isopropanol,
Olive green crystal, mp152.5~153.5
℃. NMR ( _CDCl3 ): 9.80 (bs, 1),
4.52 (q, 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 1030
cm ^-1 . Analysis Experimental value:
C, 58.42; H, 6.65; N, 9.19. 18(11) 3,4-dihydro-3-methyl-6-
(3-Methyl-2-butenyl)-4-oxothieno[2.3-d][ethyl pyrimidine-2-carboxylate] chromatographed on silica gel, eluting with chloroform. Evaporation of the solvent gave an oil without crystallization. Nuclear magnetic resonance spectra show that this product is similar to the above compound and -6-(-
methyl-1-butyl) isomer. 19(12) 7-t-butyl-3, 4, 5, 6.
Ethyl 7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxylate-chromatographed on silica gel (hexane), eluting 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 1029
cm ^-1 . Analysis Experimental value:
C, 61.30; H, 6.60; N, 8.35. Steps 20-26 Thienooxazine-2-carboxylic acids-Step 4
2-aminothiophene-3- appropriately substituted in
The following thienoxazines are prepared by substitution of the carboxylic acid. These thienoxazines are
They are listed in the table along with physical properties and operational modifications if necessary. Table Thienooxazine-2-carboxylic acids Operation number Name 20 5, 6, 7, 8-tetrahydro-4-
Oxo-4H-benzothieno [2.3
-d] [1,3] Recrystallized as a hydrate from ethyl oxazine-2-carboxylate-isopropyl acetate (1/2H ₂ O), yellow solid, mp 148.5-180.5°C. 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 value:
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-1:1 using pyridine acetonitrile 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 =
7.1Hz), 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 value:
C, 54.27; H, 4.94; N, 5.13. 22 5-Methyl-6-(2-methylpropyl)-4-oxo-4H-thieno[2.
3-d] [1.3] Oxazine-2-
Recrystallized from ethyl carboxylate-hexane, mp 78.5-79.5°C. NMR (DMSO− _d6 ): 4.35(q,
2, J = 7.0Hz), 2.72 (d, 2, J =
6.8Hz), 2.38 (s, 3), 1.87 (m,
1), 1.32 (t, 3, J = 7.0 Hz), and 0.92 (d, 6, J = 6.5 Hz). Infrared (KBr): 2960, 2935, 2880,
1764, 1740, 1592, 1470, 1374,
1320, 1196, 1160, 1102, and 770
cm ^-1 . Analysis Experimental value:
C, 57.31; H, 5.77; N, 4.84. 23 Ethyl 6-ethyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate-13:1 acetonitrile-pyridine used as reaction medium; ethyl acetate-low boiling petroleum Recrystallized from 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 value:
C, 51.93; H, 4.26; N, 5.55. 24 6-acetyl-5-methyl-4-oxo-4H-thieno[2.3-d][1.
2] Using ethyl oxazine-2-carboxylate-3:8 pyridine-acetonitrile as reaction medium; chromatography on silica gel (CHCl ₃ ), recrystallized from chloroform-hexane, pale yellow platelets, mp 102.0-103.0 ℃. NMR ( _CDCl3 ): 4.50 (q, 2, J
=7.1Hz), 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 value:
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-2:1 using pyridine-acetonitrile as the reaction medium; ethanol recrystallization, dark brown crystals, mp129~
130℃. 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 value:
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 the reaction medium; recrystallized from low-boiling petroleum ether, light tan solid,
mp56.5~57.0℃. NMR ( _CDCl3 ): 4.63 (q, 2, J
= 7.0Hz), 2.92 (t, 2, J = 6.8
Hz), 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 value:
C, 59.44; H, 6.42; N, 4.26; S,
10.01. Operations 27 to 31 Supplementary thienopyrimidine-2-carboxylates from thieno-oxazine-2-carboxylate - Preparation of the compounds listed in the table by substitution of suitably substituted thienooxazine-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 fixation. The number in brackets following the operation number indicates the manufacturing operation of the starting material. Starting materials are listed in the table. Table Thienopyrimidine-2-carboxylate 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, mp148.5-173.5℃. NMR (CDCl ₃ ) 4.51 (q, 2, J=
7.1Hz), 2.85 (q, 2, J = 7.3Hz),
2.25 (s, 3), 1.46 (t, 3, J=
7.1Hz), and 1.30 (t, 3, J = 7.3
Hz). Infrared (KBr): 3180, 3100, 2600,
2930, 1730, 1680, 1555, 1488,
1460, 1368, 1300, 1186, and 1032
cm ^-1 . Analysis Experimental value:
C, 54.17; H, 5.50; N, 10.029. 28(22) 3,4-dihydro-5-methyl-6-
(2-Methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-
Recrystallized from ethyl carboxylate-isopropanol, grayish white crystals, mp175~
176℃. NMR (DMSO−d ₆ ): 12.40 (bs,
1), 4.36 (q, 2, J = 7.1Hz), 2.68
(d, 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 value: 29 (23) 6-ethyl-3,4-dihydro-4-
Oxothieno[2,3-d]pyrimidine-2-carboxylic acid ethyl- recrystallized from ethanol, pale yellow needle crystals,
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 770 cm ^-1 . Analysis Experimental value:
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-dimethylformamide-recrystallized from 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 1027
cm ^-1 . Analysis Experimental value:
C, 51.17; H, 4.15; N, 9.90. 31(25) 3,4-dihydro-5,6-dimethyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid ethyl-recrystallized from acetonitrile, brown crystalline solid, mp 211.5-212.5℃ . 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 value:
C, 52.14; H, 4.62; N, 10.89. Operation 32 3, 4, 5, 6, 7, 8-hexahydro-4-
Oxobenzothieno[2,3-d]pyrimidine-
2-Carboxylic acid hydrate - product of step 3, 5.0 g
was dissolved in warm water and the solution was clarified by filtration.
The filtrate was acidified with glacial acetic acid and the solution was frozen. The precipitate was collected, washed with water on a filter, and dried. Cream solid, mp254.5~256.5℃. NMR (DMSO- _d6 ): 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. Operations 33 to 45 Supplementary Thienopyrimidine-2-Carboxylic Acid Metal Salts - The method of Operation 3 was applied to various other thienopyrimidine-2-carboxylic acid esters to produce various salts. The materials obtained are listed in the table with reference to the starting material source indicated by the operation number shown in the box next to the operation number, as well as the analytical information for these products. 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 C ₁₆ H ₂₂ N ₂ O ₃ S・
Does not melt at 2Na・H ₂ O−300℃. NMR (DMSO-d ₆ ): 2.79 (t,
2, J = 6.9Hz), 2.45 (s, 3), 1.26
(m, 12), as well as 0.86 (m, 3). Infrared (KBr): 2980, 2945, 2876,
1660, 1630, 1580, 1553, 1493,
1445, 1392, 1360, 1060, and 814
cm ^-1 . Analysis Experimental value:
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・2Na・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 value:
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・
Does not melt at 2Na・H ₂ O−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 . Analysis Experimental value:
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・
Addition of 2Na·1/4H ₂ O-isopropanol induces 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 value:
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 by evaporation of the solvent and trituration of the residue with methanol. Recovery: Off-white powder, does not melt at 300°C. NMR (D ₂ O): 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, 620 cm ^-1 . Analysis Experimental value:
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, no decomposition at 350°C. 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
805 cm ^-1 . Analysis Experimental value:
C, 4446; 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/
Precipitated from the reaction after evaporation of the alcohol by addition of _2H2O -isopropanol; yellow solid, not melting at 350<0>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=6.5
Hz). Infrared (KBr): 3420, 2965, 2925,
1655, 1625, 1572, 1432, 1384,
1370, 1350, 1050, and 805cm ^-1 . Analysis Experimental value:
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 - for solubilization Addition of dimethylformamide to the reaction mixture; product precipitation with isopropanol; no melting 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,
1752, 1540, 1479, 1430, 1380,
1317, 1045, and 780 cm ^-1 . Analysis Experimental value:
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・
Product precipitated from the aqueous reaction mixture with 1-1/ _2H2O -isopropanol; gray solid, not melting at 350<0>C. NMR (CF ₃ COOH): 2.64 (s,
6). Infrared (KBr): 2920, 1650, 1620,
1578, 1550, 1484, 1430, 1384,
1380, 1350, 1280, 1200, 1050, and 870cm ^-1 . Analysis Experimental value:
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.2H2O -isopropanol was added to the reaction mixture to induce crystallization of the product; white solid, not melting at 360<0>C. NMR (D ₂ O): 2.95 (q, 2, J=
7.2Hz), 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 value:
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−
Product precipitates from reaction mixture upon addition of isopropanol; white solid, 350
No melting at ℃. 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 value:
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 _{C9H8N2O3S ・}2Na・_2H2O -Methanol used as _reaction solvent; white powder, melts at 360°C figure. 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 value:
C, 35.63; 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
_{C10H8N2O4S.2Na.1-1 / 2H2O} - Yellow solid, does not melt at 360 _{<0> C.} 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 value:
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 - of the reaction mixture Product precipitates upon treatment with isopropanol; tan 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 value:
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 ₉ H ₇ N ₃ O ₃・
2Na.1.5H ₂ O - methanol used as reaction medium; product precipitates with isopropanol; yellow powder, does not melt at 250<0>C. NMR (DMSO−d ₆ ): 2.84 (q,
2, J = 7.2Hz). 1.25(t, 3, J=
7.2Hz). Infrared (KBr): 3405, 2975, 1655,
1625, 1590, 1538, 1505, 1410,
1360, 1295, 1050, 809, and 765cm
^-1 . Analysis Experimental value:
C, 35.34; H, 3.35; N, 13.20. Operation 48 3,4-dihydro-5-methyl-6-nitro-
4-oxothieno[2,3-d]pyrimidine-2
- Ethyl carboxylate - 1.0 g of the product of step 16 was dissolved in trifluoroacetic acid and 5 ml of acetic anhydride was added to this 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, add 100 ml of water to the reaction mixture and 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-2
- Ethyl 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 product is recovered from the aqueous solution by extraction with chloroform, and the orange solid remaining upon evaporation of the solvent is triturated with isopropanol and recrystallized from methanol. Yellow needles, mp199.5
~215℃. NMR (DMSO- _d6 ): 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-2
- Ethyl carboxylate - 5 g of the product of Step 29 is converted to the desired product by the method of Step 48.
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- _d6 ): 13.40 (bs, 1), 4.45
(q, 2, J = 7.0Hz), 3.02 (q, 2, J = 7.2
Hz), 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-2
- Ethyl 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 was recrystallized from a mixture of methanol and isopropanol to give a yellow powder, mp 181.5-184.5
Get ℃. NMR (CDCl ₃ ): 10.50 (bs, 1), 4.60 (q,
2, J = 7.1Hz), 4.09 (bs, 2), 2.74 (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-2
- Ethyl carboxylate - 2.65 g of the product of step 29
(0.0105 mol) 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 is kept under stirring at room temperature for 3 days, then the reddish-black solid is collected on a filter and washed with ethanol to yield 2.70 g of a tan solid. 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-d]pyrimidin-4-(3H)-one-absolute ethanol 150
To a solution of 2.0 g (0.052 mole) of sodium borohydride in ml is added 2.0 g (0.0069 mole) of the product of step 28 in small portions. 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 the product as a white crystalline solid, mp 182-183°C. NMR ( _CDCl3 ): 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 can be operated as a starting material
Prepared by the method of Procedure 53 using the product of 17. Recrystallized from ethyl acetate, pale yellow crystalline solid, mp 158.5-159.5°C. NMR (CDCl ₃ ): 4.57 (s, 2), 2.78 (t,
2, J=70Hz), 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 Experimental values: C, 58.83; N, 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 in small portions. Gas evolution occurs and the mixture is stirred for 1-1/2 hours at room temperature and then refluxed for 20 minutes. Add this mixture to 300ml of water.
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- _d6 ): 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-For the production of this substance, procedure 15
Apply the method of Operation 53 to the product of; recrystallized from ethyl acetate; light tan powder, mp 136.0-140.0
℃. NMR (DMSO- _d6 ): 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,
770 cm ^-1 . Analysis Experimental values: C, 59.76; H, 6.98; N, 9.83. Operation 57 Acetic acid (3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidin-2-yl)methyl-acetic anhydride in 30 ml of acetonitrile containing 5 ml of acetic anhydride and 5 ml of pyridine. operation 55
0.68 (0.00288 mol) of the product is dissolved and heated at 100° C. for 30 minutes. Then pour this mixture into cold water.
Pour into 150 ml to obtain the desired product as a pale yellow solid and recrystallize from ethyl acetate; pale yellow needles,
mp202.0~204.0℃. 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. Operation 58 3.05 g of ethyl sodium 3-(3.4.5.6.7.8-hexahydro-4-oxobenzothieno[2.3-d]pyrimidin-2-yl)-2-propenoate and 100 ml of ethanol Prepare a solution of sodium ethoxylate in ethanol from Next, 24.5 g of the product from step 1 in 300 ml of ethanol.
(0.125 mol) and 21.6 g (0.125 mol) of diethyl fumarate to form 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 for 1.5 hours at room temperature and is collected by filtration; washed with water on a filter and dried. Yellow solid, mp285~
287℃. NMR (CF ₃ COOH): 7.78 (d, 1, J = 16.1
Hz), 7.42 (d, 1, J = 16.1Hz), 4.53 (q,
2, J=7.2Hz), 3.05 (m, 4), 2.02 (m,
4), 150 (t, 3, J = 7.2Hz). Infrared (KBr): 3100, 2952, 1727, 1668,
1560, 1471, 1374, 1302, 1255, 1221, 1194,
1168, 990, 970 cm ^-1 . Analysis Experimental values: C, 59.06; H, 5.25; N, 9.16. Operation 59 (E)-ethyl 3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]oxazin-2-yl)-2-propenoate-
0.985 g of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid in 10 ml of acetonitrile containing 1.2 ml of pyridine.
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. Stirring is continued overnight at room temperature, then the precipitated solid is collected by filtration and washed with ether and finally aqueous hydrochloric acid, aqueous potassium bicarbonate, and water. This is purified by recrystallization from isopropanol and washed on a filter with isopropyl ether and low boiling petroleum ether.
Yellow crystalline solid, mp147.5-148.5℃. NMR ( _CDCl3 ): 7.16 (d, 2, J = 15.5Hz),
6.89 (d, 1, J = 15.5Hz), 4.25 (q, 2, J =
7.1Hz). 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 yield the desired product. , 3:1 ethyl acetate:ethanol. mp201.5~202.5℃. NMR (DMSO- _d6 ): 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 = 7.1
Hz), 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 2967 cm ^-1 . Analysis Experimental values: C, 51.19; H, 4.69; N, 13.25. Step 61 Ethyl 6-hexyl-4-oxo-4H-thieno[2.3-d][1.3]oxazine-2-carboxylate - This product can be prepared by 2-
Amino-5-(n-hexyl)thiophene-3-
Obtained by applying to carboxylic acid. Oxalylethyl chloride is dissolved in acetonitrile prior to addition of the aminothiophene carboxylic acid dissolved in pyridine. The product is collected as a pale green solid and recrystallized from ethanol. mp80~81℃. NMR ( _CDCl3 ): 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 - Treat the product of Step 61 with ammonium acetate and acetic acid in ethanol as described in Step 5. to obtain this product, mp 114-115°C. 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
Dissolve in 20 ml of 10% aqueous fluoboric acid and cool to 0°C. A solution of 0.01 mol of sodium nitrite in 5 ml of water is added dropwise. The mixture was stirred at 0°C for 30 minutes and then bulked with 2-carbetoxy-3.4.
The precipitate of diazonium -dihydro-5-methyl-4-oxothieno[2.3-d]pyrimidin-6-ylfluoroborate is collected on a filter and air-dried. 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 salt has been added, the temperature is raised to 20°C, then the mixture is poured into ice water and the product is filtered to give the desired 6-chloro compound. Operation 64 Ethyl 6-ethyl-3,4-dihydro-5-hydroxy-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - From the amino compound obtained in Operation 51, prepare diazonium fluoroborate salt. 63 to obtain 0.03 mol of the required diazonium fluoborate. The latter was added at once to potassium trifluoroacetate in 13 ml of trifluoroacetic acid at 0°C.
Add to 0.03M solution. The mixture is stirred at 25° C. for 1 hour and then refluxed 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 6-ethyl-3,4-dihydro-5-methoxy-4-oxothie[2,3-d]pyrimidine-2
- Ethyl carboxylate - 0.01 mol of the product of step 64 is dissolved in 100 ml of ether containing a chemical equivalent of boron trifluoride etherate and the solution is cooled to 0 DEG C. with stirring. Then a solution of 0.011 mol of diazomethane in 50 ml of ether is added in portions,
The solution is stirred at 0° C. until the yellow color disappears. Evaporation of the solvent yields the desired 5-methoxypyrimidine compound. Step 66 5,6,7,8-Tetrahydro-2-(5-tetrazolyl)benzothieno[2,3-d]pyrimidin-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 material. The solution is kept at room temperature for 4 hours, during which time a pale yellow precipitate forms. Collecting the latter by passing,
Air-dried to give 3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxamide, pale yellow solid,
Obtain 0.80 g of mp278.0-281.0°C (decomposition). 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-oxobenzothie[2,3- d ]pyrimidine-4-
(3H)-one is obtained. the latter, sodium azide
Dissolve in 100 ml of dimethylformamide containing 1.5 g and 1.0 g of ammonium chloride. 105% of this mixture
Heat at ~110°C for 24 hours. Pour this mixture into ice water and precipitate 4-azido-2-(5-tetrazoyl)-5,6,7,8-tetrahydrobenzothieno[2,3- d ]pyrimidine-4-
Collect (3H)-on. Hydrolysis of the latter with two chemical equivalents of caustic soda dissolved in ethanol gives 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 , and treated 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. Next, 0.01 mole of 5-aminotetrazole was added to this mixture,
This is stirred at room temperature for 1 hour and then heated on a steam bath for 2 hours. 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-oxobenzothieno [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 (0.01 mol) of the product of step 20 in 50 ml of absolute ethanol and n
- A mixture of 0.73 g (0.01 mol) of butylamine is 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 using 1:1 ether-low boiling petroleum ether for development on silica gel to give 1.52 g of the desired product as ethyl ether. . The latter was saponified according to the method of Step 3 and the resulting sodium salt was recrystallized from isopropanol-ether to give 0.90 g (59%) of the desired product as an off-white powder, mp 265.0-285.0°C (decomposition). obtain. NMR (D ₂ O): 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 774 cm ^-1 . Analysis Experimental values: C, 5317; 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 - Applying the method of step 68 to the oxazine obtained in step 23,
The butylamine used in was replaced with methylamine to give the desired product. Operation 70 3,4-dihydro-6-fluoro-5-methyl-
4-oxothieno[2,3-d]pyrimidine-2
- Ethyl carboxylate - As described in Operation 63 2
-carbetoxy-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidine-
0.03 mol of diazonium 6-ylfluoroborate is produced. 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-
To a solution of 0.01 mol of the product of step 55 and 0.3 mol of dicyclohexylcarbodiimide in 100 ml of 2-carboxaldehyde-dimethylsulfoxide is added 0.01 mol of orthophosphoric anhydride. The mixture was stirred at room temperature for 4 hours, then added with 250 ml of ethyl acetate.
ml, then a solution of 25 g of oxalic acid in methanol is 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 - Procedure 4 is applied to the preparation of this product by using 2-amino-4,5-dihydrocyclopenta[b]thiophene-3-carboxylic acid as the starting material. Operation 73 Ethyl 3,4,5,6-tetrahydro-4-oxocyclopenta[b]thieno[2,3-d]pyrimidine-2-carboxylate - Oxazine obtained in Operation 72 by the method of Operation 5 into this product. Step 74 Ethyl 3,4,5,6-tetrahydro-4-oxocyclohepta[b]thieno[2,3-d]oxazine-2-carboxylate - The method of Step 4 was repeated using 2-amino-4 as the starting material. - 5,6,7-tetrahydrocyclohepta [ b ] applied to the preparation of this substance by substitution of thiophene-3-carboxylic acid. 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 - In a mixture of 30 ml of acetic anhydride and 15 ml of 100% formic acid at 0°C, operate 55
Dissolve 0.01 mole of product. The mixture is then warmed to room temperature over the course of 1 hour while stirring. then in the ice
Pour into 200ml to collect formate ester. Operation 77 N-[3-(aminocarbonyl)-4・5・6・
7-Tetrahydrobenzo[b]thien-2-yl]oxamic acid - 2 in 5 liters of absolute ethanol
-Amino-4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide 392g
(2.0 mol) and diethyl oxylate 321.2 g (2.2
2 mol) of absolute ethanol in a nitrogen stream
Add to a solution of sodium ethoxylate prepared from 50.6 g (2.2 moles) of sodium in a liter. 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. Carefully acidify the solution with 150 g (2.5 mol) of acetic acid dissolved in 350 ml of water and precipitate the resulting product, which is collected on a filter, washed with water, and air-dried to yield 194.6 g of the product of step 2.
(0.7 mol) is obtained. The solution was acidified to pH 2 with concentrated hydrochloric acid, and the resulting precipitate was collected on a filter, washed with water, and air-dried to yield 264.8 g (0.99 mol) of the desired product.
get. A portion of 25 g is recrystallized from 1.4 liters of dioxane to yield 18.2 g, mp 223.5 224.5°C (decomposed). NMR (DMSO- _d6 ): 7.45 (s, 2), 1.79
(s, 8). Infrared (KBr): 3520, 3360, 3190, 2950,
2860, 1730, 1640, 1565, 1530, 1460, 1410,
1360, as well as 1290cm ^-1 . Analysis Experimental values: C, 49.04; H, 4.47; N, 10.25. Operation 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 isotonic) enough sodium phosphate (to buffer) to pH 7.5 Fill the filtered solution into clean sterile ampoules, 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 gelatin-like 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 2880 cm ^-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. Systemic routes of administration may be used, including oral, rectal, parenteral and oral. This dipotassium salt (operation 97)
is described on page 79 in Rat
PCA test shows the following ID ₅₀ value: Oral, 2.7 mg/
Kg; Seizunai, 0.14mg/Kg. Publications describing work chemically related to this disclosure include Arya, VP, Indian Journal of
Chemistry, 10, 1141-1150 (1972), which opens the aforementioned materials to procedure 2. The following procedure describes additional compounds and compositions that fall within the scope of this invention. Operation 83 Ethyl N-[3-(aminocarbonyl)thien-2-yl]oxamate-2-aminothiophene-
Applying the procedure of Procedure 1 to the 3-carboxamide yields the desired product, which is recrystallized from acetonitrile. 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). IR (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]oxazine-2-carboxylic acid ethyl-2-amino-5-pentylthiophene-3-carboxylic acid in Operation 4 to obtain the desired product as a crystalline solid; recrystallization from di-isopropyl ether, mp 69.6-70.5
℃. Analysis Experimental values: C, 56.88; H, 5.62; N, 4.66. NMR ( _CDCl3 ): 0.90 (t, 3, 6.0Hz), 1.40
(m, 1), 1.47 (t, 3, 7.0Hz), 2.93 (t,
2, 7.0Hz), 4.58 (q, 2, 7.0Hz), and 7.31
(s, 1). IR (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][1,3-oxazine-2-carboxylic acid ethyl-2-amino-5-propylthiophene-3-carboxylic acid] Apply the method.
The product obtained is recrystallized from diisopylether. mp90.5~91.5℃. Analysis Experimental values: C, 53.61; H, 4.88; N, 5.22. NMR ( _CDCl3 ): 1.03 (t, 3, 7.0Hz), 1.50
(t, 3, 7.1Hz), 1.87 (m, 2), 2.92 (t,
2, 7.0Hz), 4.60 (q, 2, 7.1Hz), and 7.34
(s, 1). IR (KBr): 3120, 1800, 1750, 1375, 1330,
1170, 945, 840, and 765 cm ^-1 . Operation 86 6-isopropyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylic acid ethyl-2-amino-5-isopropylthiophene-3-carboxylic acid in Operation 4 The desired product is prepared by applying the method 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, 6.5
Hz), 4.57 (q, 2, 6.6Hz), and 7.31 (s,
1). IR (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] Apply the method of Operation 4 to ethyl-2-amino-5-( n -butyl)thiophene-3-carboxylic acid oxazine-2-carboxylate. 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 ( _CDCl3 ): 0.96 (t, 3, 6.6Hz), 1.50
(t, 3, 7.1Hz), 1.60 (m, 4), 2.92 (t,
2, 7.2Hz), 4.57 (q, 2, 7.1Hz), and 7.33
(s, 1). IR (KBr): 3100, 2980, 1770, 1590, 1430,
1370, 1320, 960, and 770 cm ^-1 . Operation 88 Ethyl 6-ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Dissolve 5.0 g (0.019 mol) of the product of Operation 29 in 20 ml of butanol and prepare P- toluenesulfonic acid
Add 0.5g to it. The mixture is refluxed for 3 hours, heated and 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 ( _CDCl3 ): 1.03 (t, 3, 6.3Hz), 1.42
(t, 3, 7.0Hz), 1.81 (m, 4), 3.02 (q,
2, 7.0Hz), 4.61 (t, 2, 6.0Hz), 7.50 (s,
1), and 11.6 (bs, 1). IR (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 operation
The product of 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 ( _CDCl3 ): 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). IR (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 is repeated except that the post-chromatography saponification step is omitted and 2 molecular equivalents of acetic acid are 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 ( _CDCl3 ): 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). IR (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 the 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 (q, 2, 7.0Hz), 7.26
(s, 1), as well as 13.0 (bs, 1). IR (KBr): 3280, 3000, 1750, 1710, 1480,
1310, 1285, 1180, 1025, 845, and 760 cm ^-1 . Operation 92 3,4-dihydro-6-(1-methylethyl)-
4-oxothieno[2,3-d]pyrimidine-2
- Ethyl 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). IR (KBr): 3100, 2960, 1740, 1690, 1570,
1480, 1300, 1185, 1050 and 765 cm ^-1 . Operation 93 3,4-dihydro-6-(1-methylethyl)-
4-oxothieno[2,3-d]pyrimidine-2
- Carboxylic acid disodium salt - Hydrolyze the product of Step 92 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
This corresponds to a hydrate containing 1.75 mol of water per mol of disodium salt. Analysis Experimental values: C, 38.23; 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. IR (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 an ethanolic solution containing acetic acid according to the method of Operation 5. Treat with ammonium acetate. The product is recrystallized from ethanol-isopropanol. mp144~145℃. Analysis Experimental values: C, 55.58; H, 6.02; N, 10.00. NMR ( _CDCl3 ): 0.98 (t, 3, 6.0Hz), 1.52
(t, 3, 7.0Hz), 1.53 (m, 4), 2.90 (t,
2, 7.0Hz), 4.70 (q, 2, 7.0Hz), 7.40 (s,
1), 11.3 (bs, 1). IR (KBr): 3110, 2960, 1740, 1670, 1490,
1300, 1180, 1030 and 770 cm ^-1 . Step 95 Ethyl 3,4-dihydro-4-oxo-6-propylthieno[2,3-d]pyrimidine-2-carboxylate - The product of Step 85 was prepared according to the method of Step 5 except that the acetic acid was omitted. The desired product is then converted to the desired product 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 ( _CDCl3 ) 1.03 (t, 3, 6.5Hz), 1.52
(t, 3, 7.0Hz), 1.88 (m, 2), 2.90 (t,
2, 6.7Hz), 4.60 (q, 2, 7.0Hz), 7.35 (s,
1), and 11.5 (bs, 1). IR (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 is treated with acetic acid according to the method of Operation 5. This product is converted by treatment with ethanolic ammonium acetate. Recrystallize the product from a mixture of ethanol and isopropanol mp124-125
℃. Analysis Experimental values: C, 57.22; H, 6.20; N, 9.52. NMR ( _CDCl3 ): 0.87 (t, 3, 6.0Hz), 1.40
(m, 6), 1.47 (t, 3, 7.0Hz), 2.88 (t,
2, 7.0Hz), 4.56 (q, 2, 7.0Hz), 7.32 (s,
1), and 11.7 (bs, 1). IR (KBr): 3100, 2960, 1760, 1740, 1690,
1490, 1300, 1190, 1040 and 770 cm ^-1 . Operation 97 3,4-dihydro-5-methyl-6-(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, 4.28; N, 7.20. NMR ( _D2O ): 0.88 (d, 6, 6.0Hz), 1.89
(m, 1), 2.40 (s, 3), 2.61 (d, 2, 6.5
Hz), as well as 4.80. IR (KBr): 2840, 1650, 1590, 1560, 1535,
1470, 1415, 1340, 1040, and 800cm ^-1 . Operation 98 3,4-dihydro-3,5-dimethyl-6-octyl-4-xothieno[2,3-d]pyrimidine-2-carboxylic acid sodium salt - 2.34 g (0.0064 mol) of the oxane obtained in Operation 4 , 4.47 g (0.0576 mol) of 40% aqueous methylamine, and glacial acetic acid.
5.00 g (0.0832 mol) of the mixture is heated in 40 ml of absolute ethanol on a steam bath for 40 minutes. This mixture is then processed substantially as described in Procedure 5 to yield the desired product, mp 310.0-315.5°C (dec). This is obtained as a hydrate containing 0.25 mol of water per mol of salt. Analysis Experimental values: C, 56.36; H, 6.55; N, 7.70. NMR (DMSO-b ₆ ): 0.84 (m, 3), 1.30
(m, 12), 2.41 (s, 3), 2.77 (m, 2), and 3.45 (s, 3). IR (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. do. The product is recrystallized from ethyl acetate. mp141~143℃. Analysis Experimental values: C, 58.84; H, 6.94; N, 10.13. NMR ( _CDCl3 ): 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). IR (KBr): 3270, 2930, 2860, 1665, 1610,
1600, 1470, 1300, 840 and 755 cm ^-1 . Operation 100 Nasal Solution A 1% solution of the product of Operation 97 is prepared by dissolving a 1% solution of the product of Operation 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 [In the formula, R ² is -CO ₂ R ³ , -CH=CHCO ₂ R ³ , -
selected from the group consisting of CH ₂ OH, [Formula] and [Formula], where R is lower alkyl having 1 to 8 carbon atoms, and R 3 is hydrogen, and R ³ is hydrogen, and and M, where M is a non-toxic, pharmacologically inert metal cation, and R ⁵ and R ⁶ are hydrogen, 1 to 8 independently selected from the group consisting of lower alkyl having 3 to 6 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, nitro, amino, halo, phenyl, and alkanoyl having 2 to 6 carbon atoms; , or R ⁵ and R ⁶ together with a thieno ring constitute a tetrahydrobenzothieno ring]. 2 R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
A compound according to claim 1 selected from the group consisting of. ^3. The compound according ^to claim 1, wherein ^R2 is _-CO2R3 or -CH= _CHCO2R3 . 4 3,4-dihydro-5-methyl-6-(2-
methylpropyl)-4-oxothieno[2,3-
d] The compound according to claim 1, which is ethyl pyrimidine-2-carboxylate. 5 3,4-dihydro-5-methyl-6-(2-
methylpropyl)-4-oxothieno[2,3-
d] The compound according to claim 1, which is pyrimidine-2-carboxylic acid disodium salt. 6 3,4-dihydro-5-methyl-6-(2-
methylpropyl)-4-oxothieno[2,3-
d] The compound according to claim 1, which is a dipotassium pyrimidine-2-carboxylic acid salt. 7 3,4-dihydro-6-ethyl-5-iodo-4-oxothieno[2,3-d]pyrimidine-
Claim 1 which is ethyl 2-carboxylate
Compounds described in Section. 8 6-ethyl-3,4-dihydro-5-nitro-4-oxothieno[2,3-d]pyrimidine-
Claim 1 which is ethyl 2-carboxylate
Compounds described in Section. 9 formula [In the formula, R ² is -CO ₂ R ³ , -CH=CHCO ₂ R ³ , -
selected from the group consisting of CH ₂ OH, [Formula] and [Formula] in which R is lower alkyl having 1 to 8 carbon atoms, and R ³ is hydrogen, lower alkyl having an atom selected from the group consisting of M, where M is a non-toxic pharmacologically inert metal cation, and R ⁵ and R ⁶ are hydrogen, 1-8 independently selected from the group consisting of lower alkyl having 3 to 6 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, nitro, amino, halo, phenyl, and alkanoyl having 2 to 6 carbon atoms. or, alternatively, R ⁵ and R ⁶ together with the thieno ring constitute a tetrahydrobenzothieno ring; provided that R ⁵ and
R ⁶ is lower alkenyl, nitro, amino, halo,
When phenyl or alkanoyl,
R ² is -CO ₂ R ³ or -CH ₂ OH] as an active ingredient. 10 formula [In the formula, R ² is -CO ₂ R ³ , -CH=CHCO ₂ R ³ , -
selected from the group consisting of CH ₂ OH, [Formula] and [Formula] in which R is lower alkyl having 1 to 8 carbon atoms, and R ³ is hydrogen, lower alkyl having an atom selected from the group consisting of M, where M is a non-toxic pharmacologically inert metal cation, and R ⁵ and R ⁶ are hydrogen, 1-8 independently selected from the group consisting of lower alkyl having 3 to 6 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to ⁶ carbon atoms; R ⁶ together with the thieno ring constitutes a tetrahydrobenzothieno ring. (wherein Z is _-NH2 and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms;
Alternatively, L and B together with the thienyl group constitute a tetrahydrobenzothienyl group). [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and the compound of formula in the molten state is heated to a temperature ranging from 200 to 265 °C for 5 to
A process characterized in that the compound is converted into a compound of formula by heating for 15 minutes. 11 formula [In the formula, R ² is -CO ₂ R ³ , -CH=CHCO ₂ R ³ , -
selected from the group consisting of CH ₂ OH, [Formula] and [Formula] in which R is lower alkyl having 1 to 8 carbon atoms, and R ³ is hydrogen, lower alkyl having an atom selected from the group consisting of M, where M is a non-toxic pharmacologically inert metal cation, and R ⁵ and R ⁶ are hydrogen, 1-8 independently selected from the group consisting of lower alkyl having 3 to 6 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to ⁶ carbon atoms; R ⁶ together with the thieno ring constitutes a tetrahydrobenzothieno ring. (wherein Z is -OH, and L and B are
independently selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms; , or L and B together with the thienyl group constitute a tetrahydrobenzothienyl group) with the formula [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and a compound of formula R ³ NH ₂ (wherein R ³ is as defined above) is obtained. amines or soluble ammonium salts of ) which are converted into compounds of formula by treatment at reflux temperature with a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium. A method characterized by: 12 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation. and R ⁵ and R ⁶ are nitro] [wherein Z is _-NH2 , and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms. [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then the compound of formula in molten state is heated to a temperature in the range of 200 to 265°C for 5 to 15
By heating for a minute, the compound can be converted to the formula wherein L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion to nitro to obtain a compound of the desired formula. 13 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation. and R ⁵ and R ⁶ are amino] [wherein Z is _-NH2 , and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms. [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then the compound of formula in molten state is heated to a temperature in the range of 200 to 265°C for 5 to 15
By heating for a minute, the compound can be converted to the formula wherein L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion to amino to obtain a compound of the desired formula. 14 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation. and R ⁵ and R ⁶ are halo] [wherein Z is _-NH2 , and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms. [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then the compound of formula in molten state is heated to a temperature in the range of 200 to 265°C for 5 to 15
By heating for a minute, the compound can be converted to the formula wherein L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion into a halo to obtain a compound of the desired formula. 15 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation. and R ⁵ and R ⁶ are nitro] [In the formula, Z is -OH, and L and B are
independently selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms] Formula the compound of [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then a compound of formula R ³ NH ₂ (wherein R ³ is as defined above) is obtained. by treatment at reflux temperature with a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium. in which L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion to nitro to obtain a compound of the desired formula. 16 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
[Formula] and [Formula] (wherein R is lower alkyl having 1 to 8 carbon atoms)
^R3 is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation. and R ⁵ and R ⁶ are amino] [In the formula, Z is -OH, and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms. [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then a compound of formula R ³ NH ₂ (wherein R ³ is as defined above) is obtained. by treatment with a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium at reflux temperature. wherein L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion to amino to obtain a compound of the desired formula. 17 formula [In the formula, R ² is -CH=CHCO ₂ R ³ , -CH ₂ OH,
selected from the group consisting of [Formula] and [Formula], where R is alkyl having 1 to 8 carbon atoms, and R ³ is hydrogen, lower alkyl having 1 to 8 carbon atoms. , and M in which M is a non-toxic pharmacologically inert metal cation, and R ⁵ and R ⁶ are halo. ,formula [In the formula, Z is -OH, and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms,
independently selected from the group consisting of lower alkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6 carbon atoms. [wherein, X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, and R is 1
lower alkyl having ~8 carbon atoms;
and A is a covalent bond or (-CH=CH-)] by reacting with a compound having the formula (wherein L, B, A and R ³ are as defined above) and then a compound of formula R ³ NH ₂ (wherein R ³ is as defined above) is obtained. by treatment with a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium at reflux temperature. wherein L, B, A and R ³ are as defined above, substituents L and B in a compound of formula A process characterized by conversion into a halo to obtain a compound of the desired formula.