JP5983714B2 - Crystal form of fluorine-containing amino acid prodrug and process for producing the same - Google Patents

Description

The present invention relates to (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- The present invention relates to a crystalline polymorph of 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid or a pharmaceutically acceptable salt thereof and a method for producing the same. More specifically, for example, neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, and drug addiction, cognitive disorders, Alzheimer's disease, Huntington's choreography Diseases associated with group 2 metabotropic glutamate receptors, such as neurological diseases such as Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, and head disorders (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane- is a metabotropic glutamate receptor agonist expected to be useful as a therapeutic and prophylactic agent The present invention relates to a polymorph of a prodrug of 2,6-dicarboxylic acid (hereinafter sometimes referred to as a parent compound or compound 2) and a method for producing the same.
Further, the present invention provides a prodrug having a parent compound which acts on a metabotropic glutamate receptor, which has increased mucosal absorbability such as oral absorption and increased in vivo exposure of the parent compound. The present invention relates to a crystal polymorph and a method for producing the same.

In recent years, the glutamate receptor gene has been cloned one after another, and it has become clear that there are many subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: “ion channel type in which the receptor has an ion channel type structure” and “metabolic type in which the receptor is coupled to G-protein”. Furthermore, ion channel glutamate receptors are classified into three types, NMDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainate (Non-patent Document 1). Metabotropic glutamate Receptors are classified into 8 types, mGluR1 to mGluR8 (Non-patent Documents 2 and 3). Group 2 metabotropic glutamate receptors are present in the presynapse of the glutamate nervous system and function as self-receptors, so that excessive release of glutamate is suppressed (Non-Patent Documents 4 and 5). Since the glutamate nervous system is involved in various neuropsychiatric functions, compounds that act on group 2 metabotropic glutamate receptors should be effective in the treatment or prevention of acute and chronic neuropsychiatric and neurological disorders .
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid is disclosed as an agonist of group 2 metabotropic glutamate receptors. (Patent Document 1). The ED ₅₀ value of the agonist activity, are each 29.4 nm (mGluR2) and 45.4nM (mGluR3), the effect of suppressing also recognized the phencyclidine hyperkinetic rat schizophrenia model, the ED ₅₀ The value is reported to be 5.1 mg / kg. Furthermore, an effect of suppressing phencyclidine-induced swinging behavior and condition avoidance reaction, which is a schizophrenia model, has been recognized (Non-patent Documents 6 and 7).
However, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid has poor oral absorbability in monkeys. Therefore, there is a possibility that oral absorption is also poor for humans.
There are roughly two approaches for improving mucosal absorbability such as oral absorbability of compounds. One is a method for changing the chemical structure of the compound itself, and the other is a method for devising a formulation without changing the chemical structure. Among the former is prodrug formation in which a small modifying group such as an alkyl group or an acyl group is bonded to a reactive substituent such as a hydroxyl group or amino group of a compound.
The prodrug is stable as a prodrug before absorption, and the absorption is improved by prodrug formation, and in the small intestine, liver, and / or plasma during or after absorption, chemically or enzymatically A compound that is rapidly converted to the parent compound is desired.
However, it is difficult to develop an ideal prodrug that satisfies all the above conditions. For example, since a prodrug derivative having an ester bond may be susceptible to hydrolysis reaction, it may greatly affect the chemical stability before absorption. Prodrug derivatives having an amide bond may greatly affect mucosal absorbability such as oral absorbability due to large changes in the physical properties of the compound. In addition, since the amide bond is difficult to be hydrolyzed, it may greatly affect the conversion of the compound into the parent compound in vivo and the plasma concentration. In addition, enzymes that control biotransformation of prodrugs to parent compounds have substrate specificity, and in particular, the prodrug's body such as the enzyme cannot react due to steric hindrance of the substituent inserted to form a prodrug. It is difficult to predict dynamics. For these reasons, it is not easy to increase the plasma concentration of the parent compound by estimating the mucosal absorption such as oral absorption of the prodrug compound and the conversion to the parent compound.
In fact, Patent Document 1 generally describes a prodrug of (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid. However, there is no specific disclosure at all, and there has been no successful example of prodrug formation until 1999 after the filing of this document.
In addition, pharmaceutical products are desired to have physical characteristics that are industrially easy to handle on a scale and excellent in storage stability of products.

JP 11-279129 A

Science, 258, 597-603, 1992. J. et al. Neurosci. , 13, 1373-1378, 1993. Neuropharmacol. , 34, 1-26, 1995. Neuropharmacol. , 40, 20-27, 2001. Eur. J. et al. Pharmacol. 356, 149-157, 1998. J. et al. Med. Chem. 43, 4893-4909, 2000. Life Science, 73, 1721-1728, 2003.

  The object of the present invention is to treat and prevent neuropsychiatric diseases such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, etc., and drug dependence, cognitive disorders Group 2 metabotropic glutamate receptors, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, brain failure, spinal cord injury, and head injury As a therapeutic or prophylactic agent for diseases that are said to be present, the storage stability of prodrugs that increase mucosal absorbability such as oral absorption of parent compound acting on group 2 metabotropic glutamate receptors and increase in vivo exposure Another object is to provide a crystal form preferable for use in pharmaceuticals and pharmaceutical raw materials in terms of ease of handling and the like, and a method for producing the same.

  We have (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid acting on group 2 metabotropic glutamate receptors. As a result of intensive studies on a prodrug having an acid (hereinafter sometimes referred to as compound 2) as a parent compound, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((( S) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ((1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) Oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1. 0] hexane-2-carboxylic acid (hereinafter sometimes referred to as Compound 1) as a prodrug, has been found to increase mucosal absorbability such as oral absorbability and increase the amount of parent compound exposed in vivo; It has been found that crystalline polymorphs and hydrates exist in the compound or a pharmaceutically acceptable salt thereof.

In addition to free A and B crystals, the compounds include benzene sulfonate A, B crystals, ethane sulfonate A, B crystals, paratoluene sulfonate, and camphor sulfonic acid. In the environment where pharmaceuticals are used, ethanesulfonate is a room temperature stable form of ethanesulfonate, and benzenesulfonate is a crystal form that has solid stability and good hygroscopicity for both A and B crystals. I found out.

That is, one aspect of the present invention is as follows:
(I) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (c) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate ( Hereinafter, it may be referred to as compound 1-1 in this specification) (crystal A).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.4 degrees, 17.1 degrees, 22.7 degrees and 25.7 degrees;
(B) Melting point is 173 to 178 ° C .; and (c) In infrared absorption spectrum, characteristic absorption bands are 1763 cm ⁻¹ , 1446 cm ⁻¹ , 1257 cm ⁻¹ , 1157 cm ⁻¹ , 1072 cm ⁻¹ , 1040 cm ⁻¹ , 961 cm ⁻¹ and 733 cm ⁻¹ .
Another aspect of the present invention is as follows:
(II) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine ] -3'-ium-8-weid (hereinafter sometimes referred to as compound 1-1-3) or (1S, 2S, 3S, 5R, 6S)-in ethyl acetate and acetone 2-Amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] Hexa After suspending the 2-carboxylic acid (Compound 1), benzenesulfonic acid was added, a method for producing a resulting crystals, characterized in that drying (I) according crystals.

One aspect of the present invention is as follows:
(III) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (c) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate ( This is a crystal of compound 1-1) (B-form crystal).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.6 degrees, 9.2 degrees, 10.9 degrees and 17.8 degrees;
(B) the melting point is 177-182 ° C.; and in (c) an infrared absorption spectrum, characteristic absorption band ^{1763cm -1, 1445 cm -1, 1261cm} -1, 1071cm -1, to 961cm ^-1 and 730 cm ^-1 is there.
Another aspect of the present invention is as follows:
(IV) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl -5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form A crystals of benzenesulfonate (compound 1-1) were suspended, The method for producing a crystal according to (III), wherein the obtained crystal is dried.

One aspect of the present invention is as follows:
(V) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (c) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate ( This is a crystal of compound 1-1) (2-propanol solvate).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.9 degrees, 16.0 degrees, 17.8 degrees, and 20.2 degrees; and (b) 127 by thermal mass measurement. There is a 9-10% weight loss around 0 ° C; and (c) in the suggested thermal analysis, the endothermic peaks are 120-130 ° C and 173-178 ° C.
Another aspect of the present invention is as follows:
(VI) 2-propanol to (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form A crystals of benzenesulfonate (compound 1-1) are suspended. The method for producing a crystal according to (V), wherein the obtained crystal is dried.

One aspect of the present invention is as follows:
(VII) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (b) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate ( Hereinafter, it may be referred to as compound 1-2).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.0 °, 12.0 °, 17.8 ° and 21.2 °; and (b) a melting point of 193 to 198 ° C. It is.
Another aspect of the present invention is as follows:
(VIII) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine ] After dissolving 3′-ium-8-weide (compound 1-1-3), or (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro in ethyl acetate and acetone -6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] Hexane-2-carboxylic acid Was suspended, ethanesulfonic acid was added, a method for producing a resulting crystals, characterized in that drying (VII) according crystals.

One aspect of the present invention is as follows:
(IX) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (b) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate ( This is a B-form crystal of the compound 1-2).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 11.9 °, 14.6 °, 16.8 ° and 23.4 °; and (b) a melting point of 160 to 165 ° C. It is.
Another aspect of the present invention is as follows:
(X) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine ] After dissolving 3′-ium-8-weide (compound 1-1-3), or (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro in ethyl acetate and acetone -6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] Suspend hexane-2-carboxylic acid After, ethanesulfonic acid was added, a method for producing a resulting crystals, characterized in that drying (IX) according crystals.

One aspect of the present invention is as follows:
(XI) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (b) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonic acid A crystal of a salt (hereinafter sometimes referred to as compound 1-3).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 8.2 degrees, 13.1 degrees, 21.3 degrees and 24.6 degrees; and (b) melting point is 172 to 177 ° C. It is.
Another aspect of the present invention is as follows:
(XII) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine ] After dissolving 3′-ium-8-wid (compound 1-1-3), or (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro in ethyl acetate and acetone -6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] Hexane-2-carboxylic acid ( After compound 1) was suspended, p- toluenesulfonic acid was added, a method for producing a resulting crystals, characterized in that drying (XI) according crystals.

One aspect of the present invention is as follows:
(XIII) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (b) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-camphor It is a crystal of a sulfonate (hereinafter sometimes referred to as compound 1-4).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.0 degrees, 17.6 degrees, 20.2 degrees, and 29.1 degrees; and (b) melting point of 171 to 176 ° C. It is.
Another aspect of the present invention is as follows:
(XIV) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine ] After dissolving 3′-ium-8-wid (compound 1-1-3), or (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro in ethyl acetate and acetone -6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] Hexane-2-carboxylic acid ( After compound 1) was suspended, (-) - camphorsulfonic acid was added, a method for producing a resulting crystals, characterized in that drying (XIII) according crystals.

One aspect of the present invention is as follows:
(XV) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (b) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1) It is an A-form crystal.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 10.0 degrees, 13.7 degrees, 16.6 degrees and 19.9 degrees; and (b) melting point of 173 to 178 ° C. It is.
Another aspect of the present invention is as follows:
(XVI) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R ) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form A crystals of benzenesulfonate (compound 1-1) The method for producing a crystal according to (XV), wherein the crystal obtained by suspending is dried.
One aspect of the present invention is as follows:
(XVII) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-) having at least one of the following physical properties (a) to (c) ((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1) It is a B-form crystal.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.2 °, 11.3 °, 17.9 ° and 20.4 °; and (b) melting point of 186 ° -191 ° C. And (c) in the infrared absorption spectrum, the characteristic absorption bands are at 1751 cm ⁻¹ , 1452 cm ⁻¹ , 1262 cm ⁻¹ , 1081 cm ⁻¹ , 960 cm ⁻¹ , and 602 cm ⁻¹ .
Another aspect of the present invention is as follows:
(XVIII) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl -5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form A crystals of benzenesulfonate (compound 1-1) were suspended, The method for producing a crystal according to (XVII), wherein the obtained crystal is dried.

Compound 1-1 is a crystalline form of an anhydride that is stable at a temperature close to room temperature, and is also easy to handle and useful because it does not undergo crystal form transition even during formulation operations such as grinding and compression. It was confirmed that it could be a raw material.
It also makes it possible to obtain crystalline polymorphs and hydrates of compound 1 or a pharmaceutically acceptable salt thereof.

The powder X-ray-diffraction pattern of the A form crystal | crystallization of compound 1-1, a B form crystal | crystallization, and 2-propanol solvate is shown. 2 shows a differential thermal analysis / thermal mass measurement curve of Compound 1-1 type A crystal. The infrared absorption spectrum (ATR method) of the A-form crystal of compound 1-1 is shown. The differential thermal analysis / thermal mass measurement curve of the B-form crystal of compound 1-1 is shown. The infrared absorption spectrum (ATR method) of the B type crystal of compound 1-1 is shown. 2 shows a differential thermal analysis / thermal mass measurement curve of a crystal of 2-propanol solvate of Compound 1-1. The powder X-ray-diffraction pattern of the A form crystal | crystallization of a compound 1-2 and a B form crystal | crystallization is shown. 2 shows a differential thermal analysis / thermal mass measurement curve of Compound A type A crystal. The differential thermal analysis / thermal mass measurement curve of the B type crystal of compound 1-2 is shown. 1 shows a powder X-ray diffraction pattern of Compound 1-3. The differential thermal analysis / thermal mass measurement curve of compound 1-3 is shown. 1 shows a powder X-ray diffraction pattern of Compound 1-4. The differential thermal analysis / thermal mass measurement curve of compound 1-4 is shown. The powder X-ray-diffraction pattern of the A form crystal | crystallization of compound 1 and a B form crystal | crystallization is shown. 2 shows a differential thermal analysis / thermal mass measurement curve of Compound A Form A crystal. 2 shows a differential thermal analysis / thermal mass measurement curve of Compound 1 Form B crystal. The infrared absorption spectrum (ATR method) of the B type crystal of Compound 1 is shown.

  The powder X-ray diffraction pattern of the Form A crystal of Compound 1-1 is as shown in FIG. Form A crystals are characterized by having peaks at diffraction angles (2θ) around 4.4 degrees, 17.1 degrees, 22.7 degrees and 25.7 degrees in the powder X-ray diffraction pattern.

  The differential thermal analysis / thermomass measurement curve of the Form 1-1 crystal of Compound 1-1 is as shown in FIG. The A-type crystal has a feature that an endothermic peak of differential thermal analysis derived from melting is around 173 to 178 ° C.

  The infrared absorption spectrum of the Form A crystal of Compound 1-1 is as shown in FIG. The A-type crystal has characteristic absorption bands in the infrared absorption spectrum near 1763 cm-1, 1446 cm-1, 1257 cm-1, 1157 cm-1, 1072 cm-1, 1040 cm-1, 961 cm-1 and 733 cm-1. It is characterized by.

  As can be seen from FIG. 1 to FIG. 3, the following physical property data derived from impurities such as a significant amount of B-form crystals, solvates, and free forms have not been detected from each physical property data.

  For example, as physical property data of the B-form crystal, (a) powder X-ray diffraction (Cu-Kα) has peaks at 2θ = 4.6 degrees, 9.2 degrees, 10.9 degrees, and 17.8 degrees. And (b) a physical property that the melting point is 177 to 182 ° C.

  For example, as physical property data of crystals of 2-propanol solvate, (a) powder X-ray diffraction (Cu-Kα), 2θ = 9.9 degrees, 16.0 degrees, 17.8 degrees and 20.2 degrees. And (b) there is a 9-10% weight loss near 127 ° C. by thermal mass measurement; and (c) endothermic peaks are 120-130 ° C. and 173-178 ° C. in differential thermal analysis. The physical property is.

  The powder X-ray diffraction pattern of the Form A crystal of Compound 1-2 is as shown in FIG. Form A crystals are characterized by having peaks at diffraction angles (2θ) around 9.0 degrees, 12.0 degrees, 17.8 degrees and 21.2 degrees in the powder X-ray diffraction pattern.

  The differential thermal analysis / thermal mass measurement curve of Compound A type A crystals is as shown in FIG. A-type crystals have a feature that the endothermic peak of differential thermal analysis derived from melting is around 193 to 198 ° C.

  As the physical property data of the B-form crystal, (a) it has peaks at 2θ = 11.9 degrees, 14.6 degrees, 16.8 degrees and 23.4 degrees in powder X-ray diffraction (Cu-Kα); and (B) The physical property that melting | fusing point is 160-165 degreeC is mentioned.

  The powder X-ray diffraction pattern of the crystals of compound 1-3 is as shown in FIG. Form A crystals are characterized by having peaks at diffraction angles (2θ) in the vicinity of 8.2 degrees, 13.1, 21.3 degrees, and 24.6 degrees in the powder X-ray diffraction pattern.

  The differential thermal analysis / thermal mass measurement curve of the compound 1-3 crystal is as shown in FIG. The crystal has a feature that an endothermic peak of differential thermal analysis derived from melting is around 172 to 177 ° C.

  The powder X-ray diffraction pattern of the crystals of compound 1-4 is as shown in FIG. The crystal is characterized by having peaks at diffraction angles (2θ) around 9.0 degrees, 17.6 degrees, 20.2 degrees, and 29.1 degrees in the powder X-ray diffraction pattern.

  The differential thermal analysis / thermal mass measurement curve of the compound 1-4 crystal is as shown in FIG. The crystal has a feature that an endothermic peak of differential thermal analysis derived from melting is around 171 to 176 ° C.

  The powder X-ray diffraction pattern of the Form A crystal of Compound 1 is as shown in FIG. Form A crystals are characterized by having peaks at diffraction angles (2θ) in the vicinity of 10.0 degrees, 13.7 degrees, 16.6 degrees, and 19.9 degrees in the powder X-ray diffraction pattern.

  The differential thermal analysis / thermal mass measurement curve of Compound A Form A crystals is as shown in FIG. The A-type crystal has a feature that an endothermic peak of differential thermal analysis derived from melting is around 173 to 178 ° C.

  The physical property data of the B-form crystal of Compound 1 are as follows: (a) In powder X-ray diffraction (Cu-Kα), peaks at 2θ = 4.2 degrees, 11.3 degrees, 17.9 degrees and 20.4 degrees. And (b) a physical property that the melting point is 186 to 191 ° C.

  The infrared absorption spectrum of the B-form crystal of Compound 1 is as shown in FIG. The B-type crystal is characterized by having characteristic absorption bands in the vicinity of 1751 cm-1, 1452 cm-1, 1262 cm-1, 1081 cm-1, 960 cm-1, and 602 cm-1 in the infrared absorption spectrum.

  As mentioned above, it turns out that the A-type crystal | crystallization of the compound 1-1 manufactured by the manufacturing method of this invention is a crystal | crystallization with high purity fundamentally. It is desirable that the purity of the A-form crystal is high, and it is preferably one that is substantially free of other crystal forms.

  As shown in the test examples described later, since the Form A crystal of Compound 1-1 produced by the production method of the present invention is a stable crystal particularly in an environment where it is used as a pharmaceutical product, it is preferably used as a pharmaceutical material. it can. That is, according to the present invention, it is also possible to provide use of Form A crystals for producing a pharmaceutical composition or a pharmaceutical product.

Crystals of the compounds of the present invention may be combined with one or more pharmaceutically acceptable carriers, excipients and diluents into a pharmaceutical formulation. Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, and cellulose. And various oils such as water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.
The crystal of the compound of the present invention is mixed with these carriers, excipients or diluents, and additives such as extenders, binders, disintegrants, pH adjusters and solubilizers that are generally used as necessary. In addition, tablets or pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches, etc. It is prepared as a prodrug of a group 2 metabotropic glutamate receptor agonist.
The crystal of the compound of the present invention can be administered to an adult patient in an amount of 0.01 to 500 mg orally or parenterally once or several times a day. From the viewpoint of oral administration, oral administration is preferred. This dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

  Next, the manufacturing method of the A form crystal | crystallization of the compound 1-1 of this invention is demonstrated. The A-form crystal of the compound 1-1 of the present invention is basically (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3- 3, which is compound 1 or an intermediate in a predetermined solvent. Fluoro-6-((((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [ Bicyclo [3.1.0] hexane-2,4′-oxazaborolidine] -3′-ium-8-weide (Compound 1-1-3) is dissolved or suspended, and then benzenesulfonic acid is added. In addition, crystals can be obtained by drying and can also be obtained by recrystallization, although recrystallization may be repeated not only once but twice or more. Recrystallizes only once.

  Examples of the raw material compound 1-1 before recrystallization include crystal forms other than A-form crystals such as B-form crystals, solvates, and amorphous powders.

  As a solvate, the presence of 2-propanol solvate has been confirmed. As an amorphous powder, an amorphous thing is mentioned, for example.

  Examples of the predetermined solvent for dissolving or suspending the raw material compound 1 before crystallization include an organic solvent or a mixed solution of organic solvents. The raw material compound 1 before crystallization is dissolved or suspended in these solvents, and then benzenesulfonic acid is added and stirred for crystallization.

  Examples of the organic solvent include ethyl acetate, acetone, toluene, 2-butanone, acetonitrile, THF, DMF, diethyl ether, isopropyl ether, hexane, methanol, ethanol, 1-propanol, 2-propanol and the like.

  Examples of the predetermined solvent for dissolving or suspending the intermediate compound 1-1-3 include an organic solvent or a mixed solution of organic solvents. After dissolving or suspending the intermediate compound 1-1-3 in these solvents, benzenesulfonic acid is added and crystallized by stirring.

  Examples of the organic solvent include ethyl acetate, acetone, toluene, 2-butanone, acetonitrile, THF, DMF, diethyl ether, isopropyl ether, hexane, methanol, ethanol, 1-propanol, 2-propanol and the like.

  Crystallization of the A-form crystal is usually suspended at around room temperature, and then benzenesulfonic acid is added to precipitate the crystal. The precipitated A-form crystals are dried from the solution after being separated from the solvent by filtration, centrifugation or the like.

  The A-form crystal of the compound 1-1 of the present invention can also be obtained by crystal transition when the A-form crystal is added as a seed crystal to a liquid in which the compound 1-1 is suspended in an organic solvent.

  Examples of the raw material compound 1 before the crystal transition include crystal forms other than the A form crystal such as B form crystals, solvates, and amorphous powders.

The A-form crystal of the compound 1-1 of the present invention is prepared by dissolving or suspending the intermediate compound 1-1-3 in an organic solvent and then adding benzenesulfonic acid to the A-form crystal. It can also be obtained by crystal transition when is added as a seed crystal.

  As a solvate, the presence of 2-propanol solvate has been confirmed. As an amorphous powder, an amorphous thing is mentioned, for example.

  Examples of the organic solvent include ethyl acetate, acetone, toluene, 2-butanone, acetonitrile, THF, DMF, diethyl ether, isopropyl ether, hexane, methanol, ethanol, 1-propanol, 2-propanol and the like. Preferred are ethyl acetate and acetone.

  The suspension temperature is usually 40 ° C. or lower, preferably 5 to 30 ° C.

  The suspension time is not necessarily constant depending on the type of solvent, the temperature, the crystal form of the raw material used, and other conditions, but the end point of the transition is that a part of the crystal is filtered from the suspension, and powder X-ray diffraction of this crystal It can be confirmed by measuring a pattern or an infrared absorption spectrum.

  The A-form crystals obtained as described above are dried from the suspension after being separated from the solvent by filtration, centrifugation or the like.

  As the crystalline polymorph of compound 1-1, an anhydrous B crystal and a 2-propanol hydrate were found in addition to the anhydrous A crystal.

The Form B crystal of Compound 1-1 has at least one of the following physical properties (a) to (b).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.6 degrees, 9.2 degrees, 10.9 degrees and 17.8 degrees; and (b) melting point is 177 to 182 ° C. It is.

  The powder X-ray diffraction pattern of the B-form crystal of compound 1-1 is as shown in FIG. 1, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG.

  The B-form crystal of compound 1-1 is obtained by suspending the A-form crystal in ethanol and causing crystal transition.

The 2-propanol solvate of Compound 1-1 has at least one of the following physical properties (a) to (c).
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.9 degrees, 16.0 degrees, 17.8 degrees and 20.2 degrees;
(B) There is a 9-10% weight loss near 127 ° C. by thermal mass measurement; and (c) in the differential thermal analysis, endothermic peaks are at 120-130 ° C. and 173-178 ° C.

  The powder X-ray diffraction pattern of 2-propanol solvate of Compound 1-1 is as shown in FIG. 1, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG.

  9-10% weight loss around 127 ° C. observed in thermal mass measurement, and 120-130 ° C. endothermic peak observed in differential thermal analysis show transition to Form A by desolvation, 173-178 ° C. The endothermic peak suggests melting of Form A crystals.

  The 2-propanol solvate of compound 1-1 is obtained by suspending A-form crystals in 2-propanol and crystallizing them.

  Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.

In Reference Examples and Examples, Biotage (registered trademark) SNAPPartridge KP-Sil and HP-Sil manufactured by Biotage were used as the “silica gel cartridge” when purified using column chromatography. YMC-Actus Trial C18, 5.0 μm, φ30 × 50 mm was used for “reverse phase column chromatography when purified using reverse phase column chromatography”. Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using TLC.
Each instrument data described in the examples was measured with the following measuring instruments.
LCMS spectrum: Shimadzu LCMS-IT-TOF, Shimadzu LCMS-2010EV, micromass Platform LC, micromass GCT, Agilent 6150, Agilent 1290 Infinity and Agilent 1100
NMR spectrum: [ ¹ H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL)
X-ray structural analysis: RINT2200 Ultimate III (Rigaku)
Melting point: differential thermal balance (TG-DTA): Thermo plus EVO TG8120 (Rigaku)
Infrared spectrum: IRAffinity-1 (Shimadzu Corporation)
The compound names in the examples were named by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).
Abbreviations in the nuclear magnetic resonance (NMR) spectra used in the examples are shown below.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet double, doublet Doublet (double doublet), ddt: double double triplet, ddd: double double doublet, mul: doublet, m: doublet Constant, Hz: Hertz, DMSO-d6: deuterated dimethyl sulfoxide Indicated by pm value.

Reference Example 1: (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium Synthesis of -8-Wide (Compound 1-1-3)

(1) (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′- Oxazaborolidine] -3′-ium-8-weide (Compound 1-1-1)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (2) (70.0 g) was added with 1 mol / L triethylborane. -Tetrahydrofuran solution (362 mL) was added dropwise over 20 minutes under ice-cooling and stirred for 4 hours under water-cooling. The reaction solution was added dropwise to heptane (4200 mL) over 1 hour and stirred at room temperature for 30 minutes. The obtained solid was collected by filtration, washed with heptane (140 mL), and (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [ 3.1.0] Hexane-2,4′-oxazaborolidine] -3′-ium-8-wide (Compound 1-1-1, 89.68 g) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.89-6.80 (m, 1H), 6.15-6.04 (m, 1H), 4.95-4.81 (m, 1H) , 3.33 (s, 1H), 2.53-2.37 (m, 1H), 2.25-2.15 (m, 1H), 2.06-2.02 (m, 1H), 2 0.00-1.93 (m, 1H), 1.82-1.76 (m, 1H), 0.77-0.69 (m, 6H), 0.35-0.22 (m, 4H) .
MS m / z; 272 ([M + H] ⁺ )

(2) (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (compound 1-1-2-1), and (R) -1-chloroethyl (( 1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (compound 1-1-2-2)

1-Chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) Carbonate (146 g) in heptane (146 mL) was stirred at −25 ° C. for 1.5 hours. The obtained solid was collected by filtration to give a colorless solid containing (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate. A solution of the resulting colorless solid (46.8 g) containing (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate in heptane (94 mL) at −40 ° C. Stir for 1.5 hours. The obtained solid was collected by filtration, and (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (compound 1-1-2-1, 37.87 g) was obtained. Obtained as a colorless solid. Alternatively, 1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (300 mg) was separated by chiral column chromatography (CHIRALCEL OD, hexane), and (S) -1-chloroethyl was used. ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) Carbonate (Compound 1-1-2-1, 117 mg) as a colorless solid, (R) -1-chloroethyl ((1R, 2S, 5R ) -2-Isopropyl-5-methylcyclohexyl) carbonate (compound 1-1-2-2, 129 mg) was obtained as a colorless oil. The absolute configuration of the obtained compound 1-1-2-1 was determined by X-ray structural analysis.
Spectrum of Compound 1-1-2-1 ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.43 (q, J = 5.8 Hz, 1H), 4.58 (dt, J = 4.5, 10.9 Hz, 1H), 2.15-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.83 (d, J = 2.8 Hz, 3H), 1.72-1.66 (m, 2H), 1.52-1.41 (m, 2H), 1.12-1.02 (m, 2H), 0.94-0.86 (m, 7H ), 0.79 (d, J = 7.0 Hz, 3H).
Spectrum of Compound 1-1-2-2 ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.43 (q, J = 5.8 Hz, 1H), 4.60 (dt, J = 4.1, 10.9 Hz, 1H), 2.10-2.05 (m, 1H), 1.98-1.91 (m, 1H), 1.83 (d, J = 5.8 Hz, 3H), 1.72-1.67 (m, 2H), 1.53-1.40 (m, 2H), 1.11-1.03 (m, 2H), 0.94-0.86 (m, 7H ), 0.81 (d, J = 7.0 Hz, 3H).

(3) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R, 2S, 5R) -2 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium- 8-Wide (Compound 1-1-3)

(1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] obtained in Reference Example 1- (1) ] Hexane-2,4′-oxazaborolidine] -3′-ium-8-weide (Compound 1-1-1, 25.0 g) in dimethyl sulfoxide (475 mL) and potassium carbonate (13.38 g) And stirred at room temperature for 30 minutes. To this reaction liquid, (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate obtained in (2) (compound 1-1-2-1, 29. 08 g) and 18-crown-6 (25.60 g) were added while washing with dimethyl sulfoxide (25 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate (750 mL) under ice-cooling, and the ice-cooled reaction mixture was added to a solution of saturated aqueous ammonium chloride (250 mL) and water (250 mL) over 20 minutes. The reaction vessel was washed with ethyl acetate (250 mL) and was also combined. After separating the combined reaction liquid, heptane (500 mL) was added to the obtained organic layer. The obtained organic layer was washed once with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtering off insoluble matter, the filtrate was concentrated and purified without purification (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2, A solution containing 4′-oxazaborolidine] -3′-ium-8-weide (Compound 1-1-3) was used for the next reaction.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.94-6.85 (m, 1H), 6.64-6.54 (m, 1H), 6.19-6.09 (m, 1H) , 4.99-4.84 (m, 1H), 4.51-4.43 (m, 1H), 2.49-1.39 (m, 1H), 2.24-2.15 (m, 1H), 2.14-2.09 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.92 (m, 1H), 1.83-1.72 ( m, 2H), 1.67-1.58 (m, 2H), 1.50-1.42 (m, 4H), 1.39-1.30 (m, 1H), 1.08-0. 98 (m, 2H), 0.91-0.84 (m, 7H), 0.78-0.67 (m, 9H), 0.37-0.21 (m, 4H).
MS m / z; 520 ([M + Na] ⁺ )

Example 1-1-1a: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Synthesis of Form A crystals of benzenesulfonate (compound 1-1)

(1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((( 1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaboro To a solution of lysine] -3′-ium-8-weid (1-1-3), benzenesulfonic acid monohydrate (19.50 g) was added and stirred for 18 hours at room temperature. Filtered, washed with a mixed solvent of ethyl acetate and heptane (50 mL, 25 mL), and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1- ( (((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy ) Carbonyl) was obtained) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (Compound 1-1,33.0G) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 7.62-7.56 (m, 2H), 7.34-7.27 (m, 3H), 6.61-6.57 (m, 1H) , 5.17-5.05 (m, 1H), 4.50-4.44 (m, 1H), 2.65-2.51 (m, 1H), 2.29-2.18 (m, 2H), 2.15-2.10 (m, 1H), 2.10-2.06 (m, 1H), 1.97-1.92 (m, 1H), 1.83-1.74 ( m, 1H), 1.67-1.59 (m, 2H), 1.50-1.43 (m, 4H), 1.38-1.31 (m, 1H), 1.09-0. 98 (m, 2H), 0.91-0.81 (m, 7H), 0.75 (d, J = 7.0 Hz, 3H).
MS m / z; 428 ([M−H] ⁻ )
[Α] _D ²⁴ -5.8 (c 1.02, EtOH)

Example 1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1) form A crystals

Example obtained in 1-1-1a (1S, 2S, 3S, 5R, 6S) -2- amino-3-fluoro -6 - (((S) -1 - (((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, 33.0 g) Water (25 mL) was added to an acetone (125 mL) suspension and dissolved. The resulting solution was added dropwise to water (1225 mL) over 30 minutes and stirred at room temperature for 2 hours. The obtained solid was collected by filtration and washed with water (50 ml) to give the title compound (Compounds 1, 24.08 g) as a colorless solid, Form A crystals.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.61-6.55 (m, 1H), 4.90-4.77 (m, 1H), 4.50-4.43 (m, 1H) , 2.67-2.54 (m, 1H), 2.11-2.00 (m, 2H), 1.97-1.89 (m, 3H), 1.83-1.75 (m, 1H), 1.66-1.59 (m, 2H), 1.51-1.41 (m, 4H), 1.38-1.31 (m, 1H), 1.09-0.97 ( m, 2H), 0.91-0.80 (m, 7H), 0.75 (d, J = 7.0 Hz, 3H).
MS m / z; 428 ([M−H] ⁻ )

  Example 1-1-1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Synthesis of Form A crystals of benzenesulfonate (compound 1-1)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 obtained in Example 1 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1, 300 mg) in ethyl acetate (30 mL) suspension in benzene Sulfonic acid monohydrate (133 mg) was added, and the mixture was stirred at room temperature for 4 hours. The obtained solid was collected by filtration, washed with ethyl acetate, and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R , 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, 368 mg ) Was obtained as a colorless solid, Form A crystals.

Example 1-1-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Synthesis of Form B crystals of benzenesulfonate (1-1)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, Form A crystals, A suspension of 30 mg) in ethanol (0.4 ml) was dissolved by heating to 80 ° C., and then allowed to stand at room temperature for 1 day. The precipitated solid was collected by filtration, and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1) as a white solid, Form B crystals As a seed crystal. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, Form A crystals, To a suspension of 300 mg) in ethanol (1 ml), (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S , 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form B of benzenesulfonate (compound 1-1) After adding crystal seeds, Stir at 25 ° C. for 3 days. The obtained solid was collected by filtration and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1) as colorless solid, Form B Obtained as crystals.

Example 1-1-3: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid 2-propanol benzenesulfonate (compound 1-1) Composition

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, Form A crystals, 30 mg) of 2-propanol (0.6 ml) suspension was dissolved by heating to 80 ° C., and then allowed to stand at room temperature for 1 day. The precipitated solid was collected by filtration, and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid White solid of benzenesulfonate (compound 1-1), Form A crystals And seed crystals of a mixture of 2-propanol solvate. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, Form A crystals, 16 mg), and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((( 1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, B-form crystals, 3 mg) 2-propa A (1 ml, 0.5 ml) suspension was added to (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1, 7 mg, Form A) After adding seed crystals of crystals and 2-propanol hydrate, the mixture was stirred at 25 ° C. for 1 week. The obtained solid was collected by filtration and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) 2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (compound 1-1) Obtained as a propanol solvate.

Example 1-2-1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (compound 1-2) form A crystals

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 obtained in Example 1 To a suspension of isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1, 30 mg) in ethyl acetate (3 ml) was added ethane. Sulfonic acid (18.5 mg) was added and stirred at room temperature for 4 hours. The obtained solid was collected by filtration and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) 2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (compound 1-2, 385 mg), colorless solid, Obtained as Form A crystals.

Example 1-2-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R)- Synthesis of Form B Crystals of 2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (compound 1-2)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 obtained in Example 1 To a suspension of isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (Compound 1, 340 mg) in ethyl acetate (34 ml) was added ethane. Sulfonic acid (105 mg) was added and stirred at room temperature for 4 hours. The obtained solid was collected by filtration and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) 2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (compound 1-2, 385 mg), colorless solid, Obtained as Form B crystals.

Example 1-3: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2- Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonate (compound 1-3)

In the same manner as in Example 1-1-1, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1- ( (((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (1, 400 mg) and , P-toluenesulfonic acid monohydrate (213 mg), (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((( (1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonate (1- 3,470 mg) as a colorless solid It is obtained.

Example 1-4: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2- Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-10-camphorsulfonate (1-4)

In the same manner as in Example 1-1-1, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1- ( (((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1); From (−)-10-camphorsulfonic acid, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-10-camphorsulfonate (Compound 1- 4) was obtained as a colorless solid.

  Example 1-5: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2- Synthesis of Form B Crystals of Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (Compound 1)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid Form A of benzenesulfonate (1-1, 30 mg) A suspension of crystals in water (1 ml) was stirred at 25 ° C. for 1 week. The obtained solid was collected by filtration and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (Compound 1) was obtained as a colorless solid, Form B crystals.

Reference Example 2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- Synthesis of 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1)

(1) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-(((1-(((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium-8-weid ( Compound 2-1)

(1) (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3 obtained in Reference Example 1- (1) in the same manner as Reference Example 1- (3) -Fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium-8-weide (Compound 1-1-1, 3.00 g) To a dimethyl sulfoxide (60 mL) solution was added potassium carbonate (1.61 g), and the mixture was stirred at room temperature for 30 minutes. To this reaction solution, 1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (3.49 g) and 18-crown-6 (3.07 g) were added to dimethyl sulfoxide (3 mL). The mixture was added while washing and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (90 mL) under ice-cooling, and the ice-cooled reaction mixture was added to a solution of saturated aqueous ammonium chloride (30 mL) and water (30 mL) over 30 minutes. The reaction vessel was washed with ethyl acetate (30 mL), which was also combined. After separating the combined reaction liquid, heptane (90 mL) was added to the obtained organic layer. The obtained organic layer was washed once with a saturated saline solution, then insoluble matters were filtered off, and (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl was obtained without concentrating and purifying the filtrate. -3-Fluoro-6-(((1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] A solution containing hexane-2,4′-oxazaborolidine] -3′-ium-8-ide (Compound 2-1) was used for the next reaction.

(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1)

(1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-(((1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) Oxy) carbonyl) oxy) ethoxy) carbonyl) -5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazaborolidine] -3′-ium-8-ido (compound 2- Methanesulfonic acid (1.28 g) was added to the solution containing 1), and the mixture was stirred at room temperature for 20 hours, and the resulting solid was collected by filtration and washed with a mixed solvent of ethyl acetate / heptane = 2/1 (1S , 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy ) Carbonyl) oxy) ethoxy) carbonyl) bicycle [3.1.0] Hexane-2-carboxylic acid Methanesulfonate (1.45 g) was obtained as a colorless solid, resulting in (1S, 2S, 3S, 5R, 6S) -2-amino-3- Fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0 Water (145 mL) was added to a suspension of hexane-2-carboxylic acid methanesulfonate (1.45 g) in acetone (14.5 mL) and the mixture was stirred at room temperature for 4 hours. Washing with water gave the title compound (Compound 1, 1.25 g) as a colorless solid.

Example 2-1-1-1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1) obtained in Example 1-1-1 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate The powder X-ray diffraction pattern of the A-form crystal of (Compound 1-1) was measured using a Rigaku powder X-ray diffractometer (Ultima III) and Cu—Kα ray as an X-ray source. Peaks were observed in the vicinity of 2θ = 4.4 degrees, 17.1 degrees, 22.7 degrees, and 25.7 degrees.
The melting point was measured using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent apparatus at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere. As a result, an endothermic peak derived from melting was observed at 173 to 178 ° C.
The infrared spectrum was measured using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the conditions of total number of times of 20 times and total resolution of 4 cm ^{−1 by} the total reflection method (ATR method). Peaks were observed in the vicinity of 1762 cm-1, 1446 cm-1, 1257 cm-1, 1157 cm-1, 1072 cm-1, 1040 cm-1, 961 cm-1 and 733 cm-1.

Example 2-1-1-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1) obtained in Example 1-1-2 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate The B-form crystal of (Compound 1-1) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 4.6 degrees, 9. It has peaks at 2 degrees, 10.9 degrees and 17.8 degrees, (b) the melting point is 177 to 182 ° C., and (c) in the infrared absorption spectrum, the characteristic absorption bands are 1763 cm ⁻¹ , 1445 cm ^{−. 1} , 1261 cm ⁻¹ , 1071 cm ⁻¹ , 961 cm ⁻¹ and It was found to be at 730 cm ⁻¹ .

Example 2-1-1-3: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1) obtained in Example 1-1-3 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate The 2-propanol solvate of (Compound 1-1) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 9.9 degrees, It has peaks at 16.0 degrees, 17.8 degrees and 20.2 degrees, (b) there is a 9-10% weight loss near 127 ° C. in thermal mass measurement, (c) in suggested thermal analysis The endothermic peaks are 120-130 ° C and 173-178 ° C. It was.

Example 2-2-1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1 obtained in Example 1-2-1 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate The A-form crystal of (Compound 1-2) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 9.0 degrees, 12. It was recognized that it had peaks at 0 degrees, 17.8 degrees and 21.2 degrees, and (b) the melting point was 193 to 198 ° C.

Example 2-1-2-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1) obtained in Example 1-2-2 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate The B type crystal of (Compound 1-2) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 11.9 degrees, 14. It was recognized that it had peaks at 6 degrees, 16.8 degrees and 23.4 degrees, and (b) the melting point was 160 to 165 ° C.

Example 2-1-3: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((( ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonate (compound 1-3) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 8.2 degrees, 13.1 degrees, 21.3 And a peak at 24.6 degrees, and (b) a melting point of 172 to 177 ° C. was observed.

Example 2-1-4: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((( ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-camphorsulfonate (Compound 1-4) was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 9.0 degrees, 17.6 degrees, 20 It was confirmed that the film had peaks at 2 ° and 29.1 °, and (b) the melting point was 171 to 176 ° C.

Example 2-1-5-1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1) obtained in Example 1- (4) -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1) The A-type crystal was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 10.0 degrees, 13.7 degrees, 16.6. And 19.9 degrees, and (b) a melting point of 173 to 178 ° C. was observed.

Example 2-1-5-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1- () obtained in Example 1-5 ((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (compound 1) B The shape crystal was measured in the same manner as in Example 2-1-1-1, and (a) in powder X-ray diffraction (Cu-Kα), 2θ = 4.2 degrees, 11.3 degrees, 17.9 degrees and It has a peak at 20.4 degrees, (b) the melting point is 186 to 191 ° C., and (c) in the infrared absorption spectrum, the characteristic absorption bands are 1751 cm −1, 1452 cm −1, 1262 cm −1, 1081 cm −. Found to be at 1, 960 cm @ -1 and 602 cm @ -1. It was.

Reference Example 3: (1S, 2S, 3S, 5R, 6S) -2-amino-6- (ethoxycarbonyl) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (Reference Example 3) Composition

(1) (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (Reference Example 3) -1)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (compound 2, 4.00 g) in dioxane (24 mL), saturated To a sodium hydrogen carbonate aqueous solution (48 mL) suspension, allyl chloroformate (0.42 mL) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 20 hours. 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1, followed by extraction with ethyl acetate three times. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino. ) -3-Fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (Reference Example 3-1, 6.23 g) was obtained as colorless amorphous.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.27 (s, 1H), 5.98-5.81 (m, 1H), 5.43-5.03 (m, 3H), 4.59 -4.36 (m, 2H), 2.48-1.36 (m, 1H), 2.22-1.93 (m, 3H), 1.79 (brs, 1H), 1.71 ( t, J = 3.1 Hz, 1H).
MS m / z; 310 ([M + Na] ⁺ )

(2) (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′- Oxazolidine] -6-carboxylic acid (Reference Example 3-2)

The obtained (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (Reference Example 3) -1,6.23 g), paraformaldehyde (3.00 g), p-toluenesulfonic acid monohydrate (45 mg) in toluene (150 mL) was heated with a Dean-Stark water separator for 34 hours. Refluxed. The mixture was allowed to cool, diluted with ethyl acetate, and the organic layer was washed twice with saturated brine. After drying over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5 ′. -Oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -6-carboxylic acid (Reference Example 3-2, 5.65 g) was obtained as a colorless solid.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 5.89-5.78 (m, 1H), 5.49 (d, J = 4.5 Hz, 1H), 5.25-5.10 (m 3H), 4.65-4.48 (m, 3H), 2.54-2.35 (m, 2H), 2.27-2.11 (m, 2H), 1.96 (dd, J = 3.3, 6.6 Hz, 1H).
MS m / z; 300 ([M + H] ⁺ )

(3) (1S, 2S, 3S, 5R, 6S) -3′-allyl 6-ethyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ', 6-dicarboxylate (Reference Example 3-3)

The resulting (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′- Cesium carbonate (261 mg) was added to a suspension of oxazolidine] -6-carboxylic acid (Reference Example 3-2, 200 mg) in N, N-dimethylformamide (6 mL), and the mixture was stirred for 30 minutes at room temperature. 201 mg) was added, and the mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-5). 0:50) and (1S, 2S, 3S, 5R, 6S) -3′-allyl 6-ethyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4 '-Oxazolidine] -3', 6-dicarboxylate (Reference Example 3-3, 68 mg) was obtained as a colorless amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.01-5.92 (m, 1H), 5.60 (d, J = 4.5 Hz, 1H), 5.37-5.30 (m 1H), 5.29-5.21 (m, 2H), 4.77-4.62 (m, 3H), 4.20-4.12 (m, 2H), 2.62-2.46. (M, 2H), 2.37-2.25 (m, 1H), 2.22-2.17 (m, 1H), 1.27 (t, J = 1.0 Hz, 3H).
MS m / z; 350 ([M + Na] ⁺ )

(4) (1S, 2S, 3S, 5R, 6S) -2-amino-6- (ethoxycarbonyl) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (Reference Example 3)

The resulting (1S, 2S, 3S, 5R, 6S) -3′-allyl 6-ethyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 '1,6-Dimethylbarbituric acid (97 mg) and tetrakistriphenylphosphine palladium (12 mg) were added to a chloroform (mL) solution of 1,6-dicarboxylate (Reference Example 3-3, 68 mg) under a nitrogen atmosphere. And stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, acetonitrile was added to the residue, and the mixture was stirred at room temperature for 20 min. The obtained solid was collected by filtration and washed with water to give the title compound (3, 28 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 4.90-4.72 (m, 1H), 4.12-3.95 (m, 2H), 2.65-2.51 (m, 1H) , 2.15-1.82 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H).
MS m / z; 232 ([M + H] ⁺ )

Test Example 1: Solution stability test Compound 1-1 was tested for stability in solutions assuming the following digestive juices of the stomach and small intestine.
The residual ratio in each of the hydrochloric acid solution (pH 1.2) of Compound 1-1 and 20 mM phosphate buffer (pH 6.8) was measured according to the following test method.
The test compound is dissolved in a hydrochloric acid solution (pH 1.2) containing hydrochloric acid and sodium chloride or a 20 mM phosphate buffer (pH 6.8) containing disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride, and about 50 μg / A solution having a concentration of mL (around solubility when not dissolved) was prepared. This solution was incubated at 37 ° C. for 3 hours, the compound concentration before and after the incubation was quantified by high performance liquid chromatography, and the residual ratio was calculated.
The residual ratios of Compound 1-1 in hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.8) were 99.6% and 97.8%, respectively.
From the above, it was assumed that compound 1-1 had good stability in a solution that assumed gastric and small intestinal digestive juices, and existed stably in a prodrug form in the digestive tract.

Test Example 2: Compound 2 Production Test in Liver Microsomes Compound 1 and Compound 1-1 The production rate test of compound 2 in human and monkey liver microsomes was performed according to the following method. As a comparative control, ethyl ester of Compound 2 (Reference Example 3) was used.
The test compound was prepared in the presence of NADPH production system (0.16 mM NADP ⁺ , 2.4 mM MgCl ₂ , 1.5 mM glucose-6-phosphate), human liver microsome (Ms) fraction (Xenotech / H630B / lot.0810472), Or it incubated in the 0.250M phosphate buffer (pH7.4) containing 69 mM KCl with the monkey liver Ms fraction (BD Biosciences / 452413 / lot.94518) (37 degreeC, 15 minutes). The final concentrations of the test compound and liver Ms protein were 3 μM and 1 mg protein / mL, respectively. The reaction mixture after the incubation was added with 2 volumes of DMSO, stirred, and then centrifuged at 3000 rpm (4 ° C., 10 minutes). The obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system. The lower limit of quantification was 0.3 μM for all of Compound 1, Compound 1-1, and Compound 2.
Table 1 below shows the results of the production rate of Compound 2 in human and monkey liver microsomes for representative compounds.

ＮＴ：試験せず
ヒト肝ミクロソームによる参考例３から化合物２への変換率は低く、ほぼ100％未変化体（参考例３）のままであった。一方、化合物１、及び化合物１−１は、親化合物２への変換率が高く、ヒト肝ミクロソーム及びサル肝ミクロソームで変換が進行し、プロドラッグから親化合物への変換が想定できた。

NT: Not tested, conversion rate from Reference Example 3 to Compound 2 by human liver microsome was low, and remained almost 100% unchanged (Reference Example 3). On the other hand, Compound 1 and Compound 1-1 had a high conversion rate to parent compound 2, and conversion progressed in human liver microsomes and monkey liver microsomes, and conversion from a prodrug to the parent compound could be assumed.

Test Example 3: Measurement of Compound 2 Plasma Concentration in Monkeys A compound 2 and compound 2 plasma concentration measurement test in the oral administration of Compound 1-1 was conducted according to the following method.
Compound 2 and compound 1-1 were orally administered to male cynomolgus monkeys (satiated) at a dose of 4.92 μmol / kg (base: 0.5% methylcellulose (MC) solution, dose volume 5 mL / kg).
About 0.7 mL of blood was collected from the cephalic vein 2 hours and 4 hours after oral administration (anticoagulant: EDTA-2K). Plasma obtained by centrifugation (3000 rpm, 4 ° C., 10 minutes) was stored frozen at −80 ° C. until analysis. At the time of analysis, 200 μL of an acetonitrile / methanol mixture containing an internal standard substance was added to 50 μL of a plasma sample thawed under ice-cooling, stirred and then centrifuged (4 ° C., 10 minutes), and the resulting supernatant Was subjected to LC-MS / MS analysis. The lower limit of quantification of Compound 1 and Compound 2 was 1 ng / mL and 3 ng / mL, respectively.
The results of plasma concentrations of Compound 2 after oral administration of representative compounds are shown in Table 2 below.

以上より、化合物１−１は、化合物２の経口投与時に比べ、化合物２の血漿中濃度が飛躍的に向上した。

From the above, Compound 1-1 showed a dramatic improvement in the plasma concentration of Compound 2 compared to the oral administration of Compound 2.

Test Example 4: About 200 mg of Form A crystal of Compound 1-1 was weighed into a glass bottle and stored in an open state at a relative humidity of 75% (25 ° C.). As a result of confirming the crystal form after storage 7 days by powder X-ray diffraction, there was no change in the crystal form.

Test Example 5: About 30 mg of Compound 1-1, Form A crystals, was weighed into a glass bottle, sealed and stored at 65 ° C. One month after storage, the crystal form was confirmed by powder X-ray diffraction. As a result, there was no change in crystal form.

Test Example 6: Form 1-1 crystals of compound 1-1 were pulverized using a hammer mill (SP-2 (Sakai), rotation speed: 9500 rpm). As a result of confirming the crystal form after pulverization by powder X-ray diffraction, there was no change in the crystal form.

Test Example 7: An excess amount of Form A crystals of Compound 1-1 was added to 10 mL of pH 6.8 phosphate buffer and shaken quickly. The amount of dissolution after shaking was measured by HPLC, and the solubility was measured. This test was conducted at 25 ° C. As a result, the solubility of Form A crystals was 34.6 μg / mL.
The Form A crystal of Compound 1-1 is a more stable crystal form near room temperature, and is superior to other crystal forms in terms of stability during production and long-term storage.

  According to the invention, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- Stable salt form, crystalline form of 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid or a pharmaceutically acceptable salt thereof, and a process for producing the same Psychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, and drug addiction, cognitive disorders, Alzheimer's disease, It is expected to develop new types of drugs for neurological diseases such as Huntington's disease, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, and head disorders.

Claims (17)

(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(() having at least two or more of the following physical properties (a) to (c) (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid crystals of benzenesulfonate.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.4 degrees, 17.1 degrees, 22.7 degrees and 25.7 degrees;
(B) the melting point is 173-178 ° C.; and in (c) an infrared absorption spectrum, characteristic absorption band ^{1763cm -1, 1446 cm -1, 1257cm} -1, 1157cm -1, 1072cm -1, 1040cm -1, At 961 cm ⁻¹ and 733 cm ⁻¹ .   In a mixed solvent of ethyl acetate and heptane, (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3 After dissolving '-ium-8-weed or in ethyl acetate, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((( ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid was suspended and then benzene was added. Add sulfonic acid, Method for producing a crystal according to claim 1, characterized in that drying the resulting crystals. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(() having at least two or more of the following physical properties (a) to (c) (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid crystals of benzenesulfonate.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 4.6 degrees, 9.2 degrees, 10.9 degrees and 17.8 degrees;
(B) the melting point is 177-182 ° C.; and in (c) an infrared absorption spectrum, characteristic absorption band ^{1763cm -1, 1445 cm -1, 1261cm} -1, 1071cm -1, to 961cm ^-1 and 730 cm ^-1 is there.   (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5- Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid The crystals of claim 1 of benzenesulfonate are dissolved and the crystals obtained are dried. Or (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl The crystals according to claim 1 of -5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate are suspended to form claim 3. Described 4. The method for producing a crystal according to claim 3, wherein the crystal is added as a seed crystal, and the obtained crystal is dried. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(() having at least two or more of the following physical properties (a) to (c) (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate 2-propanol Japanese crystals.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.9 degrees, 16.0 degrees, 17.8 degrees, and 20.2 degrees; and (b) 127 by thermal mass measurement. There is a 9-10% weight loss around 0 ° C; and (c) in the suggested thermal analysis, the endothermic peaks are 120-130 ° C and 173-178 ° C.   To 2-propanol, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid The crystals of claim 1 of benzene sulfonate are dissolved and the crystals obtained are dissolved. Drying, or 2-propanol with (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid , Contract 6. The method for producing a crystal according to claim 5, wherein the crystal according to claim 5 is added as a seed crystal, and the obtained crystal is dried. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid crystals of ethanesulfonate.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 11.9 °, 14.6 °, 16.8 ° and 23.4 °; and (b) a melting point of 160 to 165 ° C. It is. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5 -After suspending -methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid, ethanesulfonic acid is added and the resulting crystals are dried. The method for producing a crystal according to claim 7, wherein: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid crystals of p-toluenesulfonate.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 8.2 degrees, 13.1 degrees, 21.3 degrees and 24.6 degrees; and (b) melting point is 172 to 177 ° C. It is.   (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid is suspended, p-toluenesulfonic acid is added, and the resulting crystals are dried. The method for producing a crystal according to claim 9. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-camphorsulfonate crystals.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 9.0 degrees, 17.6 degrees, 20.2 degrees, and 29.1 degrees; and (b) melting point of 171 to 176 ° C. It is.   (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid was suspended, (-)-camphorsulfonic acid was added, and the resulting crystals were The method for producing a crystal according to claim 11, wherein the crystal is dried. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid crystals.
(A) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 10.0 degrees, 13.7 degrees, 16.6 degrees and 19.9 degrees; and (b) melting point of 173 to 178 ° C. It is.   In a mixed solvent of acetone and water, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid obtained by dissolving the crystals of claim 1 of benzenesulfonate 14. The method for producing a crystal according to claim 13, wherein the crystal is dried. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(() having at least two or more of the following physical properties (a) to (c) Crystals of (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid.
(A) In powder X-ray diffraction (Cu-Kα), peaks at 2θ = 4.2 degrees, 11.3 degrees, 17.9 degrees and 20.4 degrees (b) Melting point is 186 to 191 ° C. And (c) In the infrared absorption spectrum, the characteristic absorption bands are at 1751 cm ⁻¹ , 1452 cm ⁻¹ , 1262 cm ⁻¹ , 1081 cm ⁻¹ , 960 cm ⁻¹ , and 602 cm ⁻¹ .   (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5- Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid The crystals of claim 1 of benzenesulfonate are suspended and the crystals obtained are dried. The method for producing a crystal according to claim 15, wherein:   Oral or parenteral use comprising the crystal of claim 1, 3, 5, 7, 9, 11, 13, or 15 and one or more pharmaceutically acceptable carriers, excipients or diluents Formulation.

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